%0 Journal Article %J Gastroenterology %D 2021 %T Association of Genetic Variation With Cirrhosis: A Multi-Trait Genome-Wide Association and Gene-Environment Interaction Study. %A Emdin, Connor A %A Haas, Mary %A Ajmera, Veeral %A Simon, Tracey G %A Homburger, Julian %A Neben, Cynthia %A Jiang, Lan %A Wei, Wei-Qi %A Feng, Qiping %A Zhou, Alicia %A Denny, Joshua %A Corey, Kathleen %A Loomba, Rohit %A Kathiresan, Sekar %A Khera, Amit V %X

BACKGROUND & AIMS: In contrast to most other common diseases, few genetic variants have been identified that impact risk of cirrhosis. We aimed to identify new genetic variants that predispose to cirrhosis, to test whether such variants, aggregated into a polygenic score, enable genomic risk stratification, and to test whether alcohol intake or body mass index interacts with polygenic predisposition.

METHODS: We conducted a multi-trait genome-wide association study combining cirrhosis and alanine aminotransferase levels performed in 5 discovery studies (UK Biobank, Vanderbilt BioVU, Atherosclerosis Risk in Communities study, and 2 case-control studies including 4829 individuals with cirrhosis and 72,705 controls and 362,539 individuals with alanine aminotransferase levels). Identified variants were replicated in 3 studies (Partners HealthCare Biobank, FinnGen, and Biobank Japan including 3554 individuals with cirrhosis and 343,826 controls). A polygenic score was tested in Partners HealthCare Biobank.

RESULTS: Five previously reported and 7 newly identified genetic variants were associated with cirrhosis in both the discovery studies multi-trait genome-wide association study (P < 5 × 10) and the replication studies (P < .05), including a missense variant in the APOE gene and a noncoding variant near EFN1A. These 12 variants were used to generate a polygenic score. Among Partners HealthCare Biobank individuals, high polygenic score-defined as the top quintile of the distribution-was associated with significantly increased risk of cirrhosis (odds ratio, 2.26; P < .001) and related comorbidities compared with the lowest quintile. Risk was even more pronounced among those with extreme polygenic risk (top 1% of the distribution, odds ratio, 3.16; P < .001). The impact of extreme polygenic risk was substantially more pronounced in those with elevated alcohol consumption or body mass index. Modeled as risk by age 75 years, probability of cirrhosis with extreme polygenic risk was 13.7%, 20.1%, and 48.2% among individuals with no or modest, moderate, and increased alcohol consumption, respectively (P < .001). Similarly, probability among those with extreme polygenic risk was 6.5%, 10.3%, and 19.5% among individuals with normal weight, overweight, and obesity, respectively (P < .001).

CONCLUSIONS: Twelve independent genetic variants, 7 of which are newly identified in this study, conferred risk for cirrhosis. Aggregated into a polygenic score, these variants identified a subset of the population at substantially increased risk who are most susceptible to the hepatotoxic effects of excess alcohol consumption or obesity.

%B Gastroenterology %V 160 %P 1620-1633.e13 %8 2021 Apr %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/33310085?dopt=Abstract %R 10.1053/j.gastro.2020.12.011 %0 Journal Article %J Genome Med %D 2021 %T Genetic and non-genetic factors affecting the expression of COVID-19-relevant genes in the large airway epithelium. %A Kasela, Silva %A Ortega, Victor E %A Martorella, Molly %A Garudadri, Suresh %A Nguyen, Jenna %A Ampleford, Elizabeth %A Pasanen, Anu %A Nerella, Srilaxmi %A Buschur, Kristina L %A Barjaktarevic, Igor Z %A Barr, R Graham %A Bleecker, Eugene R %A Bowler, Russell P %A Comellas, Alejandro P %A Cooper, Christopher B %A Couper, David J %A Criner, Gerard J %A Curtis, Jeffrey L %A Han, MeiLan K %A Hansel, Nadia N %A Hoffman, Eric A %A Kaner, Robert J %A Krishnan, Jerry A %A Martinez, Fernando J %A McDonald, Merry-Lynn N %A Meyers, Deborah A %A Paine, Robert %A Peters, Stephen P %A Castro, Mario %A Denlinger, Loren C %A Erzurum, Serpil C %A Fahy, John V %A Israel, Elliot %A Jarjour, Nizar N %A Levy, Bruce D %A Li, Xingnan %A Moore, Wendy C %A Wenzel, Sally E %A Zein, Joe %A Langelier, Charles %A Woodruff, Prescott G %A Lappalainen, Tuuli %A Christenson, Stephanie A %K Adult %K Aged %K Aged, 80 and over %K Angiotensin-Converting Enzyme 2 %K Asthma %K Bronchi %K Cardiovascular Diseases %K COVID-19 %K Gene Expression %K Genetic Variation %K Humans %K Middle Aged %K Obesity %K Pulmonary Disease, Chronic Obstructive %K Quantitative Trait Loci %K Respiratory Mucosa %K Risk Factors %K SARS-CoV-2 %K Smoking %X

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression.

METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants.

RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections.

CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.

%B Genome Med %V 13 %P 66 %8 2021 04 21 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33883027?dopt=Abstract %R 10.1186/s13073-021-00866-2 %0 Journal Article %J Science %D 2021 %T Haplotype-resolved diverse human genomes and integrated analysis of structural variation. %A Ebert, Peter %A Audano, Peter A %A Zhu, Qihui %A Rodriguez-Martin, Bernardo %A Porubsky, David %A Bonder, Marc Jan %A Sulovari, Arvis %A Ebler, Jana %A Zhou, Weichen %A Serra Mari, Rebecca %A Yilmaz, Feyza %A Zhao, Xuefang %A Hsieh, PingHsun %A Lee, Joyce %A Kumar, Sushant %A Lin, Jiadong %A Rausch, Tobias %A Chen, Yu %A Ren, Jingwen %A Santamarina, Martin %A Höps, Wolfram %A Ashraf, Hufsah %A Chuang, Nelson T %A Yang, Xiaofei %A Munson, Katherine M %A Lewis, Alexandra P %A Fairley, Susan %A Tallon, Luke J %A Clarke, Wayne E %A Basile, Anna O %A Byrska-Bishop, Marta %A Corvelo, André %A Evani, Uday S %A Lu, Tsung-Yu %A Chaisson, Mark J P %A Chen, Junjie %A Li, Chong %A Brand, Harrison %A Wenger, Aaron M %A Ghareghani, Maryam %A Harvey, William T %A Raeder, Benjamin %A Hasenfeld, Patrick %A Regier, Allison A %A Abel, Haley J %A Hall, Ira M %A Flicek, Paul %A Stegle, Oliver %A Gerstein, Mark B %A Tubio, Jose M C %A Mu, Zepeng %A Li, Yang I %A Shi, Xinghua %A Hastie, Alex R %A Ye, Kai %A Chong, Zechen %A Sanders, Ashley D %A Zody, Michael C %A Talkowski, Michael E %A Mills, Ryan E %A Devine, Scott E %A Lee, Charles %A Korbel, Jan O %A Marschall, Tobias %A Eichler, Evan E %K Female %K Genetic Variation %K Genome, Human %K Genotype %K Haplotypes %K High-Throughput Nucleotide Sequencing %K Humans %K INDEL Mutation %K Interspersed Repetitive Sequences %K Male %K Population Groups %K Quantitative Trait Loci %K Retroelements %K Sequence Analysis, DNA %K Sequence Inversion %K Whole Genome Sequencing %X

Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average minimum contig length needed to cover 50% of the genome: 26 million base pairs) integrate all forms of genetic variation, even across complex loci. We identified 107,590 structural variants (SVs), of which 68% were not discovered with short-read sequencing, and 278 SV hotspots (spanning megabases of gene-rich sequence). We characterized 130 of the most active mobile element source elements and found that 63% of all SVs arise through homology-mediated mechanisms. This resource enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1526 expression quantitative trait loci as well as SV candidates for adaptive selection within the human population.

%B Science %V 372 %8 2021 04 02 %G eng %N 6537 %1 https://www.ncbi.nlm.nih.gov/pubmed/33632895?dopt=Abstract %R 10.1126/science.abf7117 %0 Journal Article %J Sci Transl Med %D 2021 %T SVEP1 is a human coronary artery disease locus that promotes atherosclerosis. %A Jung, In-Hyuk %A Elenbaas, Jared S %A Alisio, Arturo %A Santana, Katherine %A Young, Erica P %A Kang, Chul Joo %A Kachroo, Puja %A Lavine, Kory J %A Razani, Babak %A Mecham, Robert P %A Stitziel, Nathan O %X

A low-frequency variant of sushi, von Willebrand factor type A, EGF, and pentraxin domain-containing protein 1 (SVEP1), an extracellular matrix protein, is associated with risk of coronary disease in humans independent of plasma lipids. Despite a robust statistical association, if and how SVEP1 might contribute to atherosclerosis remained unclear. Here, using Mendelian randomization and complementary mouse models, we provide evidence that SVEP1 promotes atherosclerosis in humans and mice and is expressed by vascular smooth muscle cells (VSMCs) within the atherosclerotic plaque. VSMCs also interact with SVEP1, causing proliferation and dysregulation of key differentiation pathways, including integrin and Notch signaling. Fibroblast growth factor receptor transcription increases in VSMCs interacting with SVEP1 and is further increased by the coronary disease-associated variant p.D2702G. These effects ultimately drive inflammation and promote atherosclerosis. Together, our results suggest that VSMC-derived SVEP1 is a proatherogenic factor and support the concept that pharmacological inhibition of SVEP1 should protect against atherosclerosis in humans.

%B Sci Transl Med %V 13 %8 2021 Mar 24 %G eng %N 586 %1 https://www.ncbi.nlm.nih.gov/pubmed/33762433?dopt=Abstract %R 10.1126/scitranslmed.abe0357 %0 Journal Article %J Circ Genom Precis Med %D 2021 %T Transethnic Transferability of a Genome-Wide Polygenic Score for Coronary Artery Disease. %A Fahed, Akl C %A Aragam, Krishna G %A Hindy, George %A Chen, Yii-Der Ida %A Chaudhary, Kumardeep %A Dobbyn, Amanda %A Krumholz, Harlan M %A Sheu, Wayne H H %A Rich, Stephen S %A Rotter, Jerome I %A Chowdhury, Rajiv %A Cho, Judy %A Do, Ron %A Ellinor, Patrick T %A Kathiresan, Sekar %A Khera, Amit V %B Circ Genom Precis Med %V 14 %P e003092 %8 2021 Feb %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33284643?dopt=Abstract %R 10.1161/CIRCGEN.120.003092 %0 Journal Article %J Nat Commun %D 2020 %T Analysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy. %A Pirruccello, James P %A Bick, Alexander %A Wang, Minxian %A Chaffin, Mark %A Friedman, Samuel %A Yao, Jie %A Guo, Xiuqing %A Venkatesh, Bharath Ambale %A Taylor, Kent D %A Post, Wendy S %A Rich, Stephen %A Lima, Joao A C %A Rotter, Jerome I %A Philippakis, Anthony %A Lubitz, Steven A %A Ellinor, Patrick T %A Khera, Amit V %A Kathiresan, Sekar %A Aragam, Krishna G %K Cardiomyopathy, Dilated %K Genome-Wide Association Study %K Heart %K Humans %K Magnetic Resonance Imaging %K Myocardium %K Polymorphism, Single Nucleotide %X

Dilated cardiomyopathy (DCM) is an important cause of heart failure and the leading indication for heart transplantation. Many rare genetic variants have been associated with DCM, but common variant studies of the disease have yielded few associated loci. As structural changes in the heart are a defining feature of DCM, we report a genome-wide association study of cardiac magnetic resonance imaging (MRI)-derived left ventricular measurements in 36,041 UK Biobank participants, with replication in 2184 participants from the Multi-Ethnic Study of Atherosclerosis. We identify 45 previously unreported loci associated with cardiac structure and function, many near well-established genes for Mendelian cardiomyopathies. A polygenic score of MRI-derived left ventricular end systolic volume strongly associates with incident DCM in the general population. Even among carriers of TTN truncating mutations, this polygenic score influences the size and function of the human heart. These results further implicate common genetic polymorphisms in the pathogenesis of DCM.

%B Nat Commun %V 11 %P 2254 %8 2020 05 07 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32382064?dopt=Abstract %R 10.1038/s41467-020-15823-7 %0 Journal Article %J JAMA Netw Open %D 2020 %T Association of Rare Pathogenic DNA Variants for Familial Hypercholesterolemia, Hereditary Breast and Ovarian Cancer Syndrome, and Lynch Syndrome With Disease Risk in Adults According to Family History. %A Patel, Aniruddh P %A Wang, Minxian %A Fahed, Akl C %A Mason-Suares, Heather %A Brockman, Deanna %A Pelletier, Renee %A Amr, Sami %A Machini, Kalotina %A Hawley, Megan %A Witkowski, Leora %A Koch, Christopher %A Philippakis, Anthony %A Cassa, Christopher A %A Ellinor, Patrick T %A Kathiresan, Sekar %A Ng, Kenney %A Lebo, Matthew %A Khera, Amit V %K Aged %K Cohort Studies %K Colorectal Neoplasms, Hereditary Nonpolyposis %K Female %K Genetic Predisposition to Disease %K Hereditary Breast and Ovarian Cancer Syndrome %K Heterozygote %K Humans %K Hyperlipoproteinemia Type II %K Male %K Middle Aged %K Pedigree %K Proportional Hazards Models %K United Kingdom %K Whole Exome Sequencing %X

Importance: Pathogenic DNA variants associated with familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome are widely recognized as clinically important and actionable when identified, leading some clinicians to recommend population-wide genomic screening.

Objectives: To assess the prevalence and clinical importance of pathogenic or likely pathogenic variants associated with each of 3 genomic conditions (familial hypercholesterolemia, hereditary breast and ovarian cancer syndrome, and Lynch syndrome) within the context of contemporary clinical care.

Design, Setting, and Participants: This cohort study used gene-sequencing data from 49 738 participants in the UK Biobank who were recruited from 22 sites across the UK between March 21, 2006, and October 1, 2010. Inpatient hospital data date back to 1977; cancer registry data, to 1957; and death registry data, to 2006. Statistical analysis was performed from July 22, 2019, to November 15, 2019.

Exposures: Pathogenic or likely pathogenic DNA variants classified by a clinical laboratory geneticist.

Main Outcomes and Measures: Composite end point specific to each genomic condition based on atherosclerotic cardiovascular disease events for familial hypercholesterolemia, breast or ovarian cancer for hereditary breast and ovarian cancer syndrome, and colorectal or uterine cancer for Lynch syndrome.

Results: Among 49 738 participants (mean [SD] age, 57 [8] years; 27 144 female [55%]), 441 (0.9%) harbored a pathogenic or likely pathogenic variant associated with any of 3 genomic conditions, including 131 (0.3%) for familial hypercholesterolemia, 235 (0.5%) for hereditary breast and ovarian cancer syndrome, and 76 (0.2%) for Lynch syndrome. Presence of these variants was associated with increased risk of disease: for familial hypercholesterolemia, 28 of 131 carriers (21.4%) vs 4663 of 49 607 noncarriers (9.4%) developed atherosclerotic cardiovascular disease; for hereditary breast and ovarian cancer syndrome, 32 of 116 female carriers (27.6%) vs 2080 of 27 028 female noncarriers (7.7%) developed associated cancers; and for Lynch syndrome, 17 of 76 carriers (22.4%) vs 929 of 49 662 noncarriers (1.9%) developed colorectal or uterine cancer. The predicted probability of disease at age 75 years despite contemporary clinical care was 45.3% for carriers of familial hypercholesterolemia, 41.1% for hereditary breast and ovarian cancer syndrome, and 38.3% for Lynch syndrome. Across the 3 conditions, 39.7% (175 of 441) of the carriers reported a family history of disease vs 23.2% (34 517 of 148 772) of noncarriers.

Conclusions and Relevance: The findings suggest that approximately 1% of the middle-aged adult population in the UK Biobank harbored a pathogenic variant associated with any of 3 genomic conditions. These variants were associated with an increased risk of disease despite contemporary clinical care and were not reliably detected by family history.

%B JAMA Netw Open %V 3 %P e203959 %8 2020 04 01 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/32347951?dopt=Abstract %R 10.1001/jamanetworkopen.2020.3959 %0 Journal Article %J Brain %D 2020 %T Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17 458 subjects. %A Niestroj, Lisa-Marie %A Perez-Palma, Eduardo %A Howrigan, Daniel P %A Zhou, Yadi %A Cheng, Feixiong %A Saarentaus, Elmo %A Nürnberg, Peter %A Stevelink, Remi %A Daly, Mark J %A Palotie, Aarno %A Lal, Dennis %K DNA Copy Number Variations %K Epilepsy %K Female %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Male %X

Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5-3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.

%B Brain %V 143 %P 2106-2118 %8 2020 07 01 %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/32568404?dopt=Abstract %R 10.1093/brain/awaa171 %0 Journal Article %J Forensic Sci Int Genet %D 2020 %T Forensic evaluation of the Asia Pacific ancestry-informative MAPlex assay. %A Xavier, C %A de la Puente, M %A Phillips, C %A Eduardoff, M %A Heidegger, A %A Mosquera-Miguel, A %A Freire-Aradas, A %A Lagace, R %A Wootton, S %A Power, D %A Parson, W %A Lareu, M V %A Daniel, R %X

DNA intelligence, and particularly the inference of biogeographical ancestry (BGA) is increasing in interest, and relevance within the forensic genetics community. The majority of current MPS-based forensic ancestry-informative assays focus on the differentiation of major global populations. The recently published MAPlex (Multiplex for the Asia Pacific) panel contains 144 SNPs and 20 microhaplotypes and aims to improve the differentiation of populations in the Asia Pacific region. This study reports the first forensic evaluation of the MAPlex panel using AmpliSeq technology and Ion S5 sequencing. This study reports on the overall performance of MAPlex including the assay's sequence coverage distribution and stability, baseline noise and description of problematic SNPs. Dilution series, artificially degraded and mixed DNA samples were also analysed to evaluate the sensitivity of the panel with challenging or compromised forensic samples. As the first panel to combine biallelic SNPs, multiple-allele SNPs and microhaplotypes, the MAPlex assay demonstrated an enhanced capacity for mixture detection, not easily performed with common binary SNPs. This performance evaluation indicates that MAPlex is a robust, stable and highly sensitive assay that is applicable to forensic casework for the prediction of BGA.

%B Forensic Sci Int Genet %V 48 %P 102344 %8 2020 09 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/32615397?dopt=Abstract %R 10.1016/j.fsigen.2020.102344 %0 Journal Article %J BMC Med Genomics %D 2020 %T Genome-wide association meta-analysis for early age-related macular degeneration highlights novel loci and insights for advanced disease. %A Winkler, Thomas W %A Grassmann, Felix %A Brandl, Caroline %A Kiel, Christina %A Günther, Felix %A Strunz, Tobias %A Weidner, Lorraine %A Zimmermann, Martina E %A Korb, Christina A %A Poplawski, Alicia %A Schuster, Alexander K %A Müller-Nurasyid, Martina %A Peters, Annette %A Rauscher, Franziska G %A Elze, Tobias %A Horn, Katrin %A Scholz, Markus %A Cañadas-Garre, Marisa %A McKnight, Amy Jayne %A Quinn, Nicola %A Hogg, Ruth E %A Küchenhoff, Helmut %A Heid, Iris M %A Stark, Klaus J %A Weber, Bernhard H F %K Case-Control Studies %K Genetic Loci %K Genetic Markers %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Humans %K Macular Degeneration %K Polymorphism, Single Nucleotide %X

BACKGROUND: Advanced age-related macular degeneration (AMD) is a leading cause of blindness. While around half of the genetic contribution to advanced AMD has been uncovered, little is known about the genetic architecture of early AMD.

METHODS: To identify genetic factors for early AMD, we conducted a genome-wide association study (GWAS) meta-analysis (14,034 cases, 91,214 controls, 11 sources of data including the International AMD Genomics Consortium, IAMDGC, and UK Biobank, UKBB). We ascertained early AMD via color fundus photographs by manual grading for 10 sources and via an automated machine learning approach for > 170,000 photographs from UKBB. We searched for early AMD loci via GWAS and via a candidate approach based on 14 previously suggested early AMD variants.

RESULTS: Altogether, we identified 10 independent loci with statistical significance for early AMD: (i) 8 from our GWAS with genome-wide significance (P < 5 × 10), (ii) one previously suggested locus with experiment-wise significance (P < 0.05/14) in our non-overlapping data and with genome-wide significance when combining the reported and our non-overlapping data (together 17,539 cases, 105,395 controls), and (iii) one further previously suggested locus with experiment-wise significance in our non-overlapping data. Of these 10 identified loci, 8 were novel and 2 known for early AMD. Most of the 10 loci overlapped with known advanced AMD loci (near ARMS2/HTRA1, CFH, C2, C3, CETP, TNFRSF10A, VEGFA, APOE), except two that have not yet been identified with statistical significance for any AMD. Among the 17 genes within these two loci, in-silico functional annotation suggested CD46 and TYR as the most likely responsible genes. Presence or absence of an early AMD effect distinguished the known pathways of advanced AMD genetics (complement/lipid pathways versus extracellular matrix metabolism).

CONCLUSIONS: Our GWAS on early AMD identified novel loci, highlighted shared and distinct genetics between early and advanced AMD and provides insights into AMD etiology. Our data provide a resource comparable in size to the existing IAMDGC data on advanced AMD genetics enabling a joint view. The biological relevance of this joint view is underscored by the ability of early AMD effects to differentiate the major pathways for advanced AMD.

%B BMC Med Genomics %V 13 %P 120 %8 2020 08 26 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32843070?dopt=Abstract %R 10.1186/s12920-020-00760-7 %0 Journal Article %J Circ Genom Precis Med %D 2020 %T Heterozygous Gene Deficiency and Risk of Coronary Artery Disease. %A Nomura, Akihiro %A Emdin, Connor A %A Won, Hong Hee %A Peloso, Gina M %A Natarajan, Pradeep %A Ardissino, Diego %A Danesh, John %A Schunkert, Heribert %A Correa, Adolfo %A Bown, Matthew J %A Samani, Nilesh J %A Erdmann, Jeanette %A McPherson, Ruth %A Watkins, Hugh %A Saleheen, Danish %A Elosua, Roberto %A Kawashiri, Masa-Aki %A Tada, Hayato %A Gupta, Namrata %A Shah, Svati H %A Rader, Daniel J %A Gabriel, Stacey %A Khera, Amit V %A Kathiresan, Sekar %X

BACKGROUND: Familial sitosterolemia is a rare Mendelian disorder characterized by hyperabsorption and decreased biliary excretion of dietary sterols. Affected individuals typically have complete genetic deficiency-homozygous loss-of-function (LoF) variants-in the or genes and have substantially elevated plasma sitosterol and LDL (low-density lipoprotein) cholesterol (LDL-C) levels. The impact of partial genetic deficiency of or -as occurs in heterozygous carriers of LoF variants-on LDL-C and risk of coronary artery disease (CAD) has remained uncertain.

METHODS: We first recruited 9 sitosterolemia families, identified causative LoF variants in or , and evaluated the associations of these or LoF variants with plasma phytosterols and lipid levels. We next assessed for LoF variants in or in CAD cases (n=29 321) versus controls (n=357 326). We tested the association of rare LoF variants in or with blood lipids and risk for CAD. Rare LoF variants were defined as protein-truncating variants with minor allele frequency <0.1% in or .

RESULTS: In sitosterolemia families, 7 pedigrees harbored causative LoF variants in and 2 pedigrees in . Homozygous LoF variants in either or led to marked elevations in sitosterol and LDL-C. Of those sitosterolemia families, heterozygous carriers of LoF variants exhibited increased sitosterol and LDL-C levels compared with noncarriers. Within large-scale CAD case-control cohorts, prevalence of rare LoF variants in and in was ≈0.1% each. heterozygous LoF variant carriers had significantly elevated LDL-C levels (25 mg/dL [95% CI, 14-35]; =1.1×10) and were at 2-fold increased risk of CAD (odds ratio, 2.06 [95% CI, 1.27-3.35]; =0.004). By contrast, heterozygous LoF carrier status was not associated with increased LDL-C or risk of CAD.

CONCLUSIONS: Although familial sitosterolemia is traditionally considered as a recessive disorder, we observed that heterozygous carriers of an LoF variant in had significantly increased sitosterol and LDL-C levels and a 2-fold increase in risk of CAD.

%B Circ Genom Precis Med %V 13 %P 417-423 %8 2020 10 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/32862661?dopt=Abstract %R 10.1161/CIRCGEN.119.002871 %0 Journal Article %J Science %D 2020 %T The impact of sex on gene expression across human tissues. %A Oliva, Meritxell %A Muñoz-Aguirre, Manuel %A Kim-Hellmuth, Sarah %A Wucher, Valentin %A Gewirtz, Ariel D H %A Cotter, Daniel J %A Parsana, Princy %A Kasela, Silva %A Balliu, Brunilda %A Viñuela, Ana %A Castel, Stephane E %A Mohammadi, Pejman %A Aguet, François %A Zou, Yuxin %A Khramtsova, Ekaterina A %A Skol, Andrew D %A Garrido-Martín, Diego %A Reverter, Ferran %A Brown, Andrew %A Evans, Patrick %A Gamazon, Eric R %A Payne, Anthony %A Bonazzola, Rodrigo %A Barbeira, Alvaro N %A Hamel, Andrew R %A Martinez-Perez, Angel %A Soria, José Manuel %A Pierce, Brandon L %A Stephens, Matthew %A Eskin, Eleazar %A Dermitzakis, Emmanouil T %A Segrè, Ayellet V %A Im, Hae Kyung %A Engelhardt, Barbara E %A Ardlie, Kristin G %A Montgomery, Stephen B %A Battle, Alexis J %A Lappalainen, Tuuli %A Guigo, Roderic %A Stranger, Barbara E %K Chromosomes, Human, X %K Disease %K Epigenesis, Genetic %K Female %K Gene Expression %K Gene Expression Regulation %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K Organ Specificity %K Promoter Regions, Genetic %K Quantitative Trait Loci %K Sex Characteristics %K Sex Factors %X

Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation.

%B Science %V 369 %8 2020 09 11 %G eng %N 6509 %1 https://www.ncbi.nlm.nih.gov/pubmed/32913072?dopt=Abstract %R 10.1126/science.aba3066 %0 Journal Article %J Nature %D 2020 %T Inherited causes of clonal haematopoiesis in 97,691 whole genomes. %A Bick, Alexander G %A Weinstock, Joshua S %A Nandakumar, Satish K %A Fulco, Charles P %A Bao, Erik L %A Zekavat, Seyedeh M %A Szeto, Mindy D %A Liao, Xiaotian %A Leventhal, Matthew J %A Nasser, Joseph %A Chang, Kyle %A Laurie, Cecelia %A Burugula, Bala Bharathi %A Gibson, Christopher J %A Lin, Amy E %A Taub, Margaret A %A Aguet, François %A Ardlie, Kristin %A Mitchell, Braxton D %A Barnes, Kathleen C %A Moscati, Arden %A Fornage, Myriam %A Redline, Susan %A Psaty, Bruce M %A Silverman, Edwin K %A Weiss, Scott T %A Palmer, Nicholette D %A Vasan, Ramachandran S %A Burchard, Esteban G %A Kardia, Sharon L R %A He, Jiang %A Kaplan, Robert C %A Smith, Nicholas L %A Arnett, Donna K %A Schwartz, David A %A Correa, Adolfo %A de Andrade, Mariza %A Guo, Xiuqing %A Konkle, Barbara A %A Custer, Brian %A Peralta, Juan M %A Gui, Hongsheng %A Meyers, Deborah A %A McGarvey, Stephen T %A Chen, Ida Yii-Der %A Shoemaker, M Benjamin %A Peyser, Patricia A %A Broome, Jai G %A Gogarten, Stephanie M %A Wang, Fei Fei %A Wong, Quenna %A Montasser, May E %A Daya, Michelle %A Kenny, Eimear E %A North, Kari E %A Launer, Lenore J %A Cade, Brian E %A Bis, Joshua C %A Cho, Michael H %A Lasky-Su, Jessica %A Bowden, Donald W %A Cupples, L Adrienne %A Mak, Angel C Y %A Becker, Lewis C %A Smith, Jennifer A %A Kelly, Tanika N %A Aslibekyan, Stella %A Heckbert, Susan R %A Tiwari, Hemant K %A Yang, Ivana V %A Heit, John A %A Lubitz, Steven A %A Johnsen, Jill M %A Curran, Joanne E %A Wenzel, Sally E %A Weeks, Daniel E %A Rao, Dabeeru C %A Darbar, Dawood %A Moon, Jee-Young %A Tracy, Russell P %A Buth, Erin J %A Rafaels, Nicholas %A Loos, Ruth J F %A Durda, Peter %A Liu, Yongmei %A Hou, Lifang %A Lee, Jiwon %A Kachroo, Priyadarshini %A Freedman, Barry I %A Levy, Daniel %A Bielak, Lawrence F %A Hixson, James E %A Floyd, James S %A Whitsel, Eric A %A Ellinor, Patrick T %A Irvin, Marguerite R %A Fingerlin, Tasha E %A Raffield, Laura M %A Armasu, Sebastian M %A Wheeler, Marsha M %A Sabino, Ester C %A Blangero, John %A Williams, L Keoki %A Levy, Bruce D %A Sheu, Wayne Huey-Herng %A Roden, Dan M %A Boerwinkle, Eric %A Manson, JoAnn E %A Mathias, Rasika A %A Desai, Pinkal %A Taylor, Kent D %A Johnson, Andrew D %A Auer, Paul L %A Kooperberg, Charles %A Laurie, Cathy C %A Blackwell, Thomas W %A Smith, Albert V %A Zhao, Hongyu %A Lange, Ethan %A Lange, Leslie %A Rich, Stephen S %A Rotter, Jerome I %A Wilson, James G %A Scheet, Paul %A Kitzman, Jacob O %A Lander, Eric S %A Engreitz, Jesse M %A Ebert, Benjamin L %A Reiner, Alexander P %A Jaiswal, Siddhartha %A Abecasis, Gonçalo %A Sankaran, Vijay G %A Kathiresan, Sekar %A Natarajan, Pradeep %K Adult %K Africa %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K alpha Karyopherins %K Cell Self Renewal %K Clonal Hematopoiesis %K DNA-Binding Proteins %K Female %K Genetic Predisposition to Disease %K Genome, Human %K Germ-Line Mutation %K Hematopoietic Stem Cells %K Humans %K Intracellular Signaling Peptides and Proteins %K Male %K Middle Aged %K National Heart, Lung, and Blood Institute (U.S.) %K Phenotype %K Precision Medicine %K Proto-Oncogene Proteins %K Tripartite Motif Proteins %K United States %K Whole Genome Sequencing %X

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.

%B Nature %V 586 %P 763-768 %8 2020 10 %G eng %N 7831 %1 https://www.ncbi.nlm.nih.gov/pubmed/33057201?dopt=Abstract %R 10.1038/s41586-020-2819-2 %0 Journal Article %J Genetics %D 2020 %T Lung Function in African American Children with Asthma Is Associated with Novel Regulatory Variants of the KIT Ligand and Gene-By-Air-Pollution Interaction. %A Mak, Angel C Y %A Sajuthi, Satria %A Joo, Jaehyun %A Xiao, Shujie %A Sleiman, Patrick M %A White, Marquitta J %A Lee, Eunice Y %A Saef, Benjamin %A Hu, Donglei %A Gui, Hongsheng %A Keys, Kevin L %A Lurmann, Fred %A Jain, Deepti %A Abecasis, Gonçalo %A Kang, Hyun Min %A Nickerson, Deborah A %A Germer, Soren %A Zody, Michael C %A Winterkorn, Lara %A Reeves, Catherine %A Huntsman, Scott %A Eng, Celeste %A Salazar, Sandra %A Oh, Sam S %A Gilliland, Frank D %A Chen, Zhanghua %A Kumar, Rajesh %A Martínez, Fernando D %A Wu, Ann Chen %A Ziv, Elad %A Hakonarson, Hakon %A Himes, Blanca E %A Williams, L Keoki %A Seibold, Max A %A Burchard, Esteban G %X

Baseline lung function, quantified as forced expiratory volume in the first second of exhalation (FEV), is a standard diagnostic criterion used by clinicians to identify and classify lung diseases. Using whole-genome sequencing data from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine project, we identified a novel genetic association with FEV on chromosome 12 in 867 African American children with asthma ( = 1.26 × 10, β = 0.302). Conditional analysis within 1 Mb of the tag signal (rs73429450) yielded one major and two other weaker independent signals within this peak. We explored statistical and functional evidence for all variants in linkage disequilibrium with the three independent signals and yielded nine variants as the most likely candidates responsible for the association with FEV Hi-C data and expression QTL analysis demonstrated that these variants physically interacted with (KIT ligand, also known as ), and their minor alleles were associated with increased expression of the gene in nasal epithelial cells. Gene-by-air-pollution interaction analysis found that the candidate variant rs58475486 interacted with past-year ambient sulfur dioxide exposure ( = 0.003, β = 0.32). This study identified a novel protective genetic association with FEV, possibly mediated through , in African American children with asthma. This is the first study that has identified a genetic association between lung function and , which has established a role in orchestrating allergic inflammation in asthma.

%B Genetics %V 215 %P 869-886 %8 2020 07 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/32327564?dopt=Abstract %R 10.1534/genetics.120.303231 %0 Journal Article %J Cell %D 2020 %T Major Impacts of Widespread Structural Variation on Gene Expression and Crop Improvement in Tomato. %A Alonge, Michael %A Wang, Xingang %A Benoit, Matthias %A Soyk, Sebastian %A Pereira, Lara %A Zhang, Lei %A Suresh, Hamsini %A Ramakrishnan, Srividya %A Maumus, Florian %A Ciren, Danielle %A Levy, Yuval %A Harel, Tom Hai %A Shalev-Schlosser, Gili %A Amsellem, Ziva %A Razifard, Hamid %A Caicedo, Ana L %A Tieman, Denise M %A Klee, Harry %A Kirsche, Melanie %A Aganezov, Sergey %A Ranallo-Benavidez, T Rhyker %A Lemmon, Zachary H %A Kim, Jennifer %A Robitaille, Gina %A Kramer, Melissa %A Goodwin, Sara %A McCombie, W Richard %A Hutton, Samuel %A Van Eck, Joyce %A Gillis, Jesse %A Eshed, Yuval %A Sedlazeck, Fritz J %A van der Knaap, Esther %A Schatz, Michael C %A Lippman, Zachary B %K Alleles %K Crops, Agricultural %K Cytochrome P-450 Enzyme System %K Ecotype %K Epistasis, Genetic %K Fruit %K Gene Duplication %K Gene Expression Regulation, Plant %K Genome, Plant %K Genomic Structural Variation %K Genotype %K Inbreeding %K Lycopersicon esculentum %K Molecular Sequence Annotation %K Phenotype %K Plant Breeding %K Quantitative Trait Loci %X

Structural variants (SVs) underlie important crop improvement and domestication traits. However, resolving the extent, diversity, and quantitative impact of SVs has been challenging. We used long-read nanopore sequencing to capture 238,490 SVs in 100 diverse tomato lines. This panSV genome, along with 14 new reference assemblies, revealed large-scale intermixing of diverse genotypes, as well as thousands of SVs intersecting genes and cis-regulatory regions. Hundreds of SV-gene pairs exhibit subtle and significant expression changes, which could broadly influence quantitative trait variation. By combining quantitative genetics with genome editing, we show how multiple SVs that changed gene dosage and expression levels modified fruit flavor, size, and production. In the last example, higher order epistasis among four SVs affecting three related transcription factors allowed introduction of an important harvesting trait in modern tomato. Our findings highlight the underexplored role of SVs in genotype-to-phenotype relationships and their widespread importance and utility in crop improvement.

%B Cell %V 182 %P 145-161.e23 %8 2020 07 09 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32553272?dopt=Abstract %R 10.1016/j.cell.2020.05.021 %0 Journal Article %J PLoS Genet %D 2020 %T A missense variant in Mitochondrial Amidoxime Reducing Component 1 gene and protection against liver disease. %A Emdin, Connor A %A Haas, Mary E %A Khera, Amit V %A Aragam, Krishna %A Chaffin, Mark %A Klarin, Derek %A Hindy, George %A Jiang, Lan %A Wei, Wei-Qi %A Feng, Qiping %A Karjalainen, Juha %A Havulinna, Aki %A Kiiskinen, Tuomo %A Bick, Alexander %A Ardissino, Diego %A Wilson, James G %A Schunkert, Heribert %A McPherson, Ruth %A Watkins, Hugh %A Elosua, Roberto %A Bown, Matthew J %A Samani, Nilesh J %A Baber, Usman %A Erdmann, Jeanette %A Gupta, Namrata %A Danesh, John %A Saleheen, Danish %A Chang, Kyong-Mi %A Vujkovic, Marijana %A Voight, Ben %A Damrauer, Scott %A Lynch, Julie %A Kaplan, David %A Serper, Marina %A Tsao, Philip %A Mercader, Josep %A Hanis, Craig %A Daly, Mark %A Denny, Joshua %A Gabriel, Stacey %A Kathiresan, Sekar %K Alleles %K Cholesterol, LDL %K Coronary Artery Disease %K Datasets as Topic %K Fatty Liver %K Female %K Genetic Predisposition to Disease %K Homozygote %K Humans %K Liver %K Liver Cirrhosis %K Liver Cirrhosis, Alcoholic %K Loss of Function Mutation %K Male %K Middle Aged %K Mitochondrial Proteins %K Mutation, Missense %K Oxidoreductases %X

Analyzing 12,361 all-cause cirrhosis cases and 790,095 controls from eight cohorts, we identify a common missense variant in the Mitochondrial Amidoxime Reducing Component 1 gene (MARC1 p.A165T) that associates with protection from all-cause cirrhosis (OR 0.91, p = 2.3*10-11). This same variant also associates with lower levels of hepatic fat on computed tomographic imaging and lower odds of physician-diagnosed fatty liver as well as lower blood levels of alanine transaminase (-0.025 SD, 3.7*10-43), alkaline phosphatase (-0.025 SD, 1.2*10-37), total cholesterol (-0.030 SD, p = 1.9*10-36) and LDL cholesterol (-0.027 SD, p = 5.1*10-30) levels. We identified a series of additional MARC1 alleles (low-frequency missense p.M187K and rare protein-truncating p.R200Ter) that also associated with lower cholesterol levels, liver enzyme levels and reduced risk of cirrhosis (0 cirrhosis cases for 238 R200Ter carriers versus 17,046 cases of cirrhosis among 759,027 non-carriers, p = 0.04) suggesting that deficiency of the MARC1 enzyme may lower blood cholesterol levels and protect against cirrhosis.

%B PLoS Genet %V 16 %P e1008629 %8 2020 04 %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/32282858?dopt=Abstract %R 10.1371/journal.pgen.1008629 %0 Journal Article %J Nat Commun %D 2020 %T Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions. %A Fahed, Akl C %A Wang, Minxian %A Homburger, Julian R %A Patel, Aniruddh P %A Bick, Alexander G %A Neben, Cynthia L %A Lai, Carmen %A Brockman, Deanna %A Philippakis, Anthony %A Ellinor, Patrick T %A Cassa, Christopher A %A Lebo, Matthew %A Ng, Kenney %A Lander, Eric S %A Zhou, Alicia Y %A Kathiresan, Sekar %A Khera, Amit V %K Aged %K Breast Neoplasms %K Case-Control Studies %K Colorectal Neoplasms %K Coronary Artery Disease %K Female %K Genetic Predisposition to Disease %K Genome, Human %K Humans %K Male %K Middle Aged %K Multifactorial Inheritance %K Odds Ratio %K Penetrance %K Risk Factors %X

Genetic variation can predispose to disease both through (i) monogenic risk variants that disrupt a physiologic pathway with large effect on disease and (ii) polygenic risk that involves many variants of small effect in different pathways. Few studies have explored the interplay between monogenic and polygenic risk. Here, we study 80,928 individuals to examine whether polygenic background can modify penetrance of disease in tier 1 genomic conditions - familial hypercholesterolemia, hereditary breast and ovarian cancer, and Lynch syndrome. Among carriers of a monogenic risk variant, we estimate substantial gradients in disease risk based on polygenic background - the probability of disease by age 75 years ranged from 17% to 78% for coronary artery disease, 13% to 76% for breast cancer, and 11% to 80% for colon cancer. We propose that accounting for polygenic background is likely to increase accuracy of risk estimation for individuals who inherit a monogenic risk variant.

%B Nat Commun %V 11 %P 3635 %8 2020 08 20 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32820175?dopt=Abstract %R 10.1038/s41467-020-17374-3 %0 Journal Article %J Genet Med %D 2020 %T Spinal muscular atrophy diagnosis and carrier screening from genome sequencing data. %A Chen, Xiao %A Sanchis-Juan, Alba %A French, Courtney E %A Connell, Andrew J %A Delon, Isabelle %A Kingsbury, Zoya %A Chawla, Aditi %A Halpern, Aaron L %A Taft, Ryan J %A Bentley, David R %A Butchbach, Matthew E R %A Raymond, F Lucy %A Eberle, Michael A %K Base Sequence %K Child %K Child, Preschool %K Humans %K Muscular Atrophy, Spinal %K Survival of Motor Neuron 1 Protein %X

PURPOSE: Spinal muscular atrophy (SMA), caused by loss of the SMN1 gene, is a leading cause of early childhood death. Due to the near identical sequences of SMN1 and SMN2, analysis of this region is challenging. Population-wide SMA screening to quantify the SMN1 copy number (CN) is recommended by the American College of Medical Genetics and Genomics.

METHODS: We developed a method that accurately identifies the CN of SMN1 and SMN2 using genome sequencing (GS) data by analyzing read depth and eight informative reference genome differences between SMN1/2.

RESULTS: We characterized SMN1/2 in 12,747 genomes, identified 1568 samples with SMN1 gains or losses and 6615 samples with SMN2 gains or losses, and calculated a pan-ethnic carrier frequency of 2%, consistent with previous studies. Additionally, 99.8% of our SMN1 and 99.7% of SMN2 CN calls agreed with orthogonal methods, with a recall of 100% for SMA and 97.8% for carriers, and a precision of 100% for both SMA and carriers.

CONCLUSION: This SMN copy-number caller can be used to identify both carrier and affected status of SMA, enabling SMA testing to be offered as a comprehensive test in neonatal care and an accurate carrier screening tool in GS sequencing projects.

%B Genet Med %V 22 %P 945-953 %8 2020 05 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/32066871?dopt=Abstract %R 10.1038/s41436-020-0754-0 %0 Journal Article %J J Am Coll Cardiol %D 2020 %T Titin Truncating Variants in Adults Without Known Congestive Heart Failure. %A Pirruccello, James P %A Bick, Alexander %A Chaffin, Mark %A Aragam, Krishna G %A Choi, Seung Hoan %A Lubitz, Steven A %A Ho, Carolyn Y %A Ng, Kenney %A Philippakis, Anthony %A Ellinor, Patrick T %A Kathiresan, Sekar %A Khera, Amit V %K Adult %K Aged %K Asymptomatic Diseases %K Connectin %K Female %K Genetic Variation %K Heart Failure %K Humans %K Male %K Middle Aged %B J Am Coll Cardiol %V 75 %P 1239-1241 %8 2020 03 17 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/32164899?dopt=Abstract %R 10.1016/j.jacc.2020.01.013 %0 Journal Article %J Science %D 2020 %T Transcriptomic signatures across human tissues identify functional rare genetic variation. %A Ferraro, Nicole M %A Strober, Benjamin J %A Einson, Jonah %A Abell, Nathan S %A Aguet, François %A Barbeira, Alvaro N %A Brandt, Margot %A Bucan, Maja %A Castel, Stephane E %A Davis, Joe R %A Greenwald, Emily %A Hess, Gaelen T %A Hilliard, Austin T %A Kember, Rachel L %A Kotis, Bence %A Park, YoSon %A Peloso, Gina %A Ramdas, Shweta %A Scott, Alexandra J %A Smail, Craig %A Tsang, Emily K %A Zekavat, Seyedeh M %A Ziosi, Marcello %A Ardlie, Kristin G %A Assimes, Themistocles L %A Bassik, Michael C %A Brown, Christopher D %A Correa, Adolfo %A Hall, Ira %A Im, Hae Kyung %A Li, Xin %A Natarajan, Pradeep %A Lappalainen, Tuuli %A Mohammadi, Pejman %A Montgomery, Stephen B %A Battle, Alexis %K Genetic Variation %K Genome, Human %K Humans %K Multifactorial Inheritance %K Organ Specificity %K Transcriptome %X

Rare genetic variants are abundant across the human genome, and identifying their function and phenotypic impact is a major challenge. Measuring aberrant gene expression has aided in identifying functional, large-effect rare variants (RVs). Here, we expanded detection of genetically driven transcriptome abnormalities by analyzing gene expression, allele-specific expression, and alternative splicing from multitissue RNA-sequencing data, and demonstrate that each signal informs unique classes of RVs. We developed Watershed, a probabilistic model that integrates multiple genomic and transcriptomic signals to predict variant function, validated these predictions in additional cohorts and through experimental assays, and used them to assess RVs in the UK Biobank, the Million Veterans Program, and the Jackson Heart Study. Our results link thousands of RVs to diverse molecular effects and provide evidence to associate RVs affecting the transcriptome with human traits.

%B Science %V 369 %8 2020 09 11 %G eng %N 6509 %1 https://www.ncbi.nlm.nih.gov/pubmed/32913073?dopt=Abstract %R 10.1126/science.aaz5900 %0 Journal Article %J Nat Commun %D 2020 %T Type 2 and interferon inflammation regulate SARS-CoV-2 entry factor expression in the airway epithelium. %A Sajuthi, Satria P %A DeFord, Peter %A Li, Yingchun %A Jackson, Nathan D %A Montgomery, Michael T %A Everman, Jamie L %A Rios, Cydney L %A Pruesse, Elmar %A Nolin, James D %A Plender, Elizabeth G %A Wechsler, Michael E %A Mak, Angel C Y %A Eng, Celeste %A Salazar, Sandra %A Medina, Vivian %A Wohlford, Eric M %A Huntsman, Scott %A Nickerson, Deborah A %A Germer, Soren %A Zody, Michael C %A Abecasis, Gonçalo %A Kang, Hyun Min %A Rice, Kenneth M %A Kumar, Rajesh %A Oh, Sam %A Rodriguez-Santana, Jose %A Burchard, Esteban G %A Seibold, Max A %K Angiotensin-Converting Enzyme 2 %K Betacoronavirus %K Child %K Coronavirus Infections %K COVID-19 %K Epithelial Cells %K Gene Expression Profiling %K Gene Expression Regulation %K Genetic Variation %K Host-Pathogen Interactions %K Humans %K Inflammation %K Interferons %K Interleukin-13 %K Middle Aged %K Nasal Mucosa %K Pandemics %K Peptidyl-Dipeptidase A %K Pneumonia, Viral %K SARS-CoV-2 %K Serine Endopeptidases %K Virus Internalization %X

Coronavirus disease 2019 (COVID-19) is caused by SARS-CoV-2, an emerging virus that utilizes host proteins ACE2 and TMPRSS2 as entry factors. Understanding the factors affecting the pattern and levels of expression of these genes is important for deeper understanding of SARS-CoV-2 tropism and pathogenesis. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci for both ACE2 and TMPRSS2, that vary in frequency across world populations. We find TMPRSS2 is part of a mucus secretory network, highly upregulated by type 2 (T2) inflammation through the action of interleukin-13, and that the interferon response to respiratory viruses highly upregulates ACE2 expression. IL-13 and virus infection mediated effects on ACE2 expression were also observed at the protein level in the airway epithelium. Finally, we define airway responses to common coronavirus infections in children, finding that these infections generate host responses similar to other viral species, including upregulation of IL6 and ACE2. Our results reveal possible mechanisms influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.

%B Nat Commun %V 11 %P 5139 %8 2020 10 12 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/33046696?dopt=Abstract %R 10.1038/s41467-020-18781-2 %0 Journal Article %J bioRxiv %D 2020 %T Type 2 and interferon inflammation strongly regulate SARS-CoV-2 related gene expression in the airway epithelium. %A Sajuthi, Satria P %A DeFord, Peter %A Jackson, Nathan D %A Montgomery, Michael T %A Everman, Jamie L %A Rios, Cydney L %A Pruesse, Elmar %A Nolin, James D %A Plender, Elizabeth G %A Wechsler, Michael E %A Mak, Angel Cy %A Eng, Celeste %A Salazar, Sandra %A Medina, Vivian %A Wohlford, Eric M %A Huntsman, Scott %A Nickerson, Deborah A %A Germer, Soren %A Zody, Michael C %A Abecasis, Gonçalo %A Kang, Hyun Min %A Rice, Kenneth M %A Kumar, Rajesh %A Oh, Sam %A Rodriguez-Santana, Jose %A Burchard, Esteban G %A Seibold, Max A %X

Coronavirus disease 2019 (COVID-19) outcomes vary from asymptomatic infection to death. This disparity may reflect different airway levels of the SARS-CoV-2 receptor, ACE2, and the spike protein activator, TMPRSS2. Here we explore the role of genetics and co-expression networks in regulating these genes in the airway, through the analysis of nasal airway transcriptome data from 695 children. We identify expression quantitative trait loci (eQTL) for both and , that vary in frequency across world populations. Importantly, we find is part of a mucus secretory network, highly upregulated by T2 inflammation through the action of interleukin-13, and that interferon response to respiratory viruses highly upregulates expression. Finally, we define airway responses to coronavirus infections in children, finding that these infections upregulate while also stimulating a more pronounced cytotoxic immune response relative to other respiratory viruses. Our results reveal mechanisms likely influencing SARS-CoV-2 infectivity and COVID-19 clinical outcomes.

%B bioRxiv %8 2020 Apr 10 %G eng %1 https://www.ncbi.nlm.nih.gov/pubmed/32511326?dopt=Abstract %R 10.1101/2020.04.09.034454 %0 Journal Article %J Nat Biotechnol %D 2019 %T Accurate circular consensus long-read sequencing improves variant detection and assembly of a human genome. %A Wenger, Aaron M %A Peluso, Paul %A Rowell, William J %A Chang, Pi-Chuan %A Hall, Richard J %A Concepcion, Gregory T %A Ebler, Jana %A Fungtammasan, Arkarachai %A Kolesnikov, Alexey %A Olson, Nathan D %A Töpfer, Armin %A Alonge, Michael %A Mahmoud, Medhat %A Qian, Yufeng %A Chin, Chen-Shan %A Phillippy, Adam M %A Schatz, Michael C %A Myers, Gene %A DePristo, Mark A %A Ruan, Jue %A Marschall, Tobias %A Sedlazeck, Fritz J %A Zook, Justin M %A Li, Heng %A Koren, Sergey %A Carroll, Andrew %A Rank, David R %A Hunkapiller, Michael W %X

The DNA sequencing technologies in use today produce either highly accurate short reads or less-accurate long reads. We report the optimization of circular consensus sequencing (CCS) to improve the accuracy of single-molecule real-time (SMRT) sequencing (PacBio) and generate highly accurate (99.8%) long high-fidelity (HiFi) reads with an average length of 13.5 kilobases (kb). We applied our approach to sequence the well-characterized human HG002/NA24385 genome and obtained precision and recall rates of at least 99.91% for single-nucleotide variants (SNVs), 95.98% for insertions and deletions <50 bp (indels) and 95.99% for structural variants. Our CCS method matches or exceeds the ability of short-read sequencing to detect small variants and structural variants. We estimate that 2,434 discordances are correctable mistakes in the 'genome in a bottle' (GIAB) benchmark set. Nearly all (99.64%) variants can be phased into haplotypes, further improving variant detection. De novo genome assembly using CCS reads alone produced a contiguous and accurate genome with a contig N50 of >15 megabases (Mb) and concordance of 99.997%, substantially outperforming assembly with less-accurate long reads.

%B Nat Biotechnol %V 37 %P 1155-1162 %8 2019 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/31406327?dopt=Abstract %R 10.1038/s41587-019-0217-9 %0 Journal Article %J Genet Med %D 2019 %T Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel. %A Chiang, Theodore %A Liu, Xiuping %A Wu, Tsung-Jung %A Hu, Jianhong %A Sedlazeck, Fritz J %A White, Simon %A Schaid, Daniel %A Andrade, Mariza de %A Jarvik, Gail P %A Crosslin, David %A Stanaway, Ian %A Carrell, David S %A Connolly, John J %A Hakonarson, Hakon %A Groopman, Emily E %A Gharavi, Ali G %A Fedotov, Alexander %A Bi, Weimin %A Leduc, Magalie S %A Murdock, David R %A Jiang, Yunyun %A Meng, Linyan %A Eng, Christine M %A Wen, Shu %A Yang, Yaping %A Muzny, Donna M %A Boerwinkle, Eric %A Salerno, William %A Venner, Eric %A Gibbs, Richard A %X

PURPOSE: To provide a validated method to confidently identify exon-containing copy-number variants (CNVs), with a low false discovery rate (FDR), in targeted sequencing data from a clinical laboratory with particular focus on single-exon CNVs.

METHODS: DNA sequence coverage data are normalized within each sample and subsequently exonic CNVs are identified in a batch of samples, when the target log ratio of the sample to the batch median exceeds defined thresholds. The quality of exonic CNV calls is assessed by C-scores (Z-like scores) using thresholds derived from gold standard samples and simulation studies. We integrate an ExonQC threshold to lower FDR and compare performance with alternate software (VisCap).

RESULTS: Thirteen CNVs were used as a truth set to validate Atlas-CNV and compared with VisCap. We demonstrated FDR reduction in validation, simulation, and 10,926 eMERGESeq samples without sensitivity loss. Sixty-four multiexon and 29 single-exon CNVs with high C-scores were assessed by Multiplex Ligation-dependent Probe Amplification (MLPA).

CONCLUSION: Atlas-CNV is validated as a method to identify exonic CNVs in targeted sequencing data generated in the clinical laboratory. The ExonQC and C-score assignment can reduce FDR (identification of targets with high variance) and improve calling accuracy of single-exon CNVs respectively. We propose guidelines and criteria to identify high confidence single-exon CNVs.

%B Genet Med %V 21 %P 2135-2144 %8 2019 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/30890783?dopt=Abstract %R 10.1038/s41436-019-0475-4 %0 Journal Article %J Science %D 2019 %T Genetic regulatory variation in populations informs transcriptome analysis in rare disease. %A Mohammadi, Pejman %A Castel, Stephane E %A Cummings, Beryl B %A Einson, Jonah %A Sousa, Christina %A Hoffman, Paul %A Donkervoort, Sandra %A Jiang, Zhuoxun %A Mohassel, Payam %A Foley, A Reghan %A Wheeler, Heather E %A Im, Hae Kyung %A Bonnemann, Carsten G %A MacArthur, Daniel G %A Lappalainen, Tuuli %X

Transcriptome data can facilitate the interpretation of the effects of rare genetic variants. Here, we introduce ANEVA (analysis of expression variation) to quantify genetic variation in gene dosage from allelic expression (AE) data in a population. Application of ANEVA to the Genotype-Tissues Expression (GTEx) data showed that this variance estimate is robust and correlated with selective constraint in a gene. Using these variance estimates in a dosage outlier test (ANEVA-DOT) applied to AE data from 70 Mendelian muscular disease patients showed accuracy in detecting genes with pathogenic variants in previously resolved cases and led to one confirmed and several potential new diagnoses. Using our reference estimates from GTEx data, ANEVA-DOT can be incorporated in rare disease diagnostic pipelines to use RNA-sequencing data more effectively.

%B Science %V 366 %P 351-356 %8 2019 10 18 %G eng %N 6463 %1 https://www.ncbi.nlm.nih.gov/pubmed/31601707?dopt=Abstract %R 10.1126/science.aay0256 %0 Journal Article %J Genet Med %D 2019 %T Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes. %A Guo, Hui %A Duyzend, Michael H %A Coe, Bradley P %A Baker, Carl %A Hoekzema, Kendra %A Gerdts, Jennifer %A Turner, Tychele N %A Zody, Michael C %A Beighley, Jennifer S %A Murali, Shwetha C %A Nelson, Bradley J %A Bamshad, Michael J %A Nickerson, Deborah A %A Bernier, Raphael A %A Eichler, Evan E %X

PURPOSE: To maximize the discovery of potentially pathogenic variants to better understand the diagnostic utility of genome sequencing (GS) and to assess how the presence of multiple risk events might affect the phenotypic severity in autism spectrum disorders (ASD).

METHODS: GS was applied to 180 simplex and multiplex ASD families (578 individuals, 213 patients) with exome sequencing and array comparative genomic hybridization further applied to a subset for validation and cross-platform comparisons.

RESULTS: We found that 40.8% of patients carried variants with evidence of disease risk, including a de novo frameshift variant in NR4A2 and two de novo missense variants in SYNCRIP, while 21.1% carried clinically relevant pathogenic or likely pathogenic variants. Patients with more than one risk variant (9.9%) were more severely affected with respect to cognitive ability compared with patients with a single or no-risk variant. We observed no instance among the 27 multiplex families where a pathogenic or likely pathogenic variant was transmitted to all affected members in the family.

CONCLUSION: The study demonstrates the diagnostic utility of GS, especially for multiple risk variants that contribute to the phenotypic severity, shows the genetic heterogeneity in multiplex families, and provides evidence for new genes for follow up.

%B Genet Med %V 21 %P 1611-1620 %8 2019 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/30504930?dopt=Abstract %R 10.1038/s41436-018-0380-2 %0 Journal Article %J Am J Hum Genet %D 2019 %T Pathogenic Abnormal Splicing Due to Intronic Deletions that Induce Biophysical Space Constraint for Spliceosome Assembly. %A Bryen, Samantha J %A Joshi, Himanshu %A Evesson, Frances J %A Girard, Cyrille %A Ghaoui, Roula %A Waddell, Leigh B %A Testa, Alison C %A Cummings, Beryl %A Arbuckle, Susan %A Graf, Nicole %A Webster, Richard %A MacArthur, Daniel G %A Laing, Nigel G %A Davis, Mark R %A Lührmann, Reinhard %A Cooper, Sandra T %X

A precise genetic diagnosis is the single most important step for families with genetic disorders to enable personalized and preventative medicine. In addition to genetic variants in coding regions (exons) that can change a protein sequence, abnormal pre-mRNA splicing can be devastating for the encoded protein, inducing a frameshift or in-frame deletion/insertion of multiple residues. Non-coding variants that disrupt splicing are extremely challenging to identify. Stemming from an initial clinical discovery in two index Australian families, we define 25 families with genetic disorders caused by a class of pathogenic non-coding splice variant due to intronic deletions. These pathogenic intronic deletions spare all consensus splice motifs, though they critically shorten the minimal distance between the 5' splice-site (5'SS) and branchpoint. The mechanistic basis for abnormal splicing is due to biophysical constraint precluding U1/U2 spliceosome assembly, which stalls in A-complexes (that bridge the 5'SS and branchpoint). Substitution of deleted nucleotides with non-specific sequences restores spliceosome assembly and normal splicing, arguing against loss of an intronic element as the primary causal basis. Incremental lengthening of 5'SS-branchpoint length in our index EMD case subject defines 45-47 nt as the critical elongation enabling (inefficient) spliceosome assembly for EMD intron 5. The 5'SS-branchpoint space constraint mechanism, not currently factored by genomic informatics pipelines, is relevant to diagnosis and precision medicine across the breadth of Mendelian disorders and cancer genomics.

%B Am J Hum Genet %V 105 %P 573-587 %8 2019 Sep 05 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/31447096?dopt=Abstract %R 10.1016/j.ajhg.2019.07.013 %0 Journal Article %J Am J Hum Genet %D 2019 %T Redefining the Etiologic Landscape of Cerebellar Malformations. %A Aldinger, Kimberly A %A Timms, Andrew E %A Thomson, Zachary %A Mirzaa, Ghayda M %A Bennett, James T %A Rosenberg, Alexander B %A Roco, Charles M %A Hirano, Matthew %A Abidi, Fatima %A Haldipur, Parthiv %A Cheng, Chi V %A Collins, Sarah %A Park, Kaylee %A Zeiger, Jordan %A Overmann, Lynne M %A Alkuraya, Fowzan S %A Biesecker, Leslie G %A Braddock, Stephen R %A Cathey, Sara %A Cho, Megan T %A Chung, Brian H Y %A Everman, David B %A Zarate, Yuri A %A Jones, Julie R %A Schwartz, Charles E %A Goldstein, Amy %A Hopkin, Robert J %A Krantz, Ian D %A Ladda, Roger L %A Leppig, Kathleen A %A McGillivray, Barbara C %A Sell, Susan %A Wusik, Katherine %A Gleeson, Joseph G %A Nickerson, Deborah A %A Bamshad, Michael J %A Gerrelli, Dianne %A Lisgo, Steven N %A Seelig, Georg %A Ishak, Gisele E %A Barkovich, A James %A Curry, Cynthia J %A Glass, Ian A %A Millen, Kathleen J %A Doherty, Dan %A Dobyns, William B %X

Cerebellar malformations are diverse congenital anomalies frequently associated with developmental disability. Although genetic and prenatal non-genetic causes have been described, no systematic analysis has been performed. Here, we present a large-exome sequencing study of Dandy-Walker malformation (DWM) and cerebellar hypoplasia (CBLH). We performed exome sequencing in 282 individuals from 100 families with DWM or CBLH, and we established a molecular diagnosis in 36 of 100 families, with a significantly higher yield for CBLH (51%) than for DWM (16%). The 41 variants impact 27 neurodevelopmental-disorder-associated genes, thus demonstrating that CBLH and DWM are often features of monogenic neurodevelopmental disorders. Though only seven monogenic causes (19%) were identified in more than one individual, neuroimaging review of 131 additional individuals confirmed cerebellar abnormalities in 23 of 27 genetic disorders (85%). Prenatal risk factors were frequently found among individuals without a genetic diagnosis (30 of 64 individuals [47%]). Single-cell RNA sequencing of prenatal human cerebellar tissue revealed gene enrichment in neuronal and vascular cell types; this suggests that defective vasculogenesis may disrupt cerebellar development. Further, de novo gain-of-function variants in PDGFRB, a tyrosine kinase receptor essential for vascular progenitor signaling, were associated with CBLH, and this discovery links genetic and non-genetic etiologies. Our results suggest that genetic defects impact specific cerebellar cell types and implicate abnormal vascular development as a mechanism for cerebellar malformations. We also confirmed a major contribution for non-genetic prenatal factors in individuals with cerebellar abnormalities, substantially influencing diagnostic evaluation and counseling regarding recurrence risk and prognosis.

%B Am J Hum Genet %V 105 %P 606-615 %8 2019 Sep 05 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/31474318?dopt=Abstract %R 10.1016/j.ajhg.2019.07.019 %0 Journal Article %J Bioinformatics %D 2019 %T svtools: population-scale analysis of structural variation. %A Larson, David E %A Abel, Haley J %A Chiang, Colby %A Badve, Abhijit %A Das, Indraniel %A Eldred, James M %A Layer, Ryan M %A Hall, Ira M %X

SUMMARY: Large-scale human genetics studies are now employing whole genome sequencing with the goal of conducting comprehensive trait mapping analyses of all forms of genome variation. However, methods for structural variation (SV) analysis have lagged far behind those for smaller scale variants, and there is an urgent need to develop more efficient tools that scale to the size of human populations. Here, we present a fast and highly scalable software toolkit (svtools) and cloud-based pipeline for assembling high quality SV maps-including deletions, duplications, mobile element insertions, inversions and other rearrangements-in many thousands of human genomes. We show that this pipeline achieves similar variant detection performance to established per-sample methods (e.g. LUMPY), while providing fast and affordable joint analysis at the scale of ≥100 000 genomes. These tools will help enable the next generation of human genetics studies.

AVAILABILITY AND IMPLEMENTATION: svtools is implemented in Python and freely available (MIT) from https://github.com/hall-lab/svtools.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

%B Bioinformatics %V 35 %P 4782-4787 %8 2019 Nov 01 %G eng %N 22 %1 https://www.ncbi.nlm.nih.gov/pubmed/31218349?dopt=Abstract %R 10.1093/bioinformatics/btz492 %0 Journal Article %J Am J Hum Genet %D 2019 %T Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals. %X

Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABA receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.

%B Am J Hum Genet %V 105 %P 267-282 %8 2019 Aug 01 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/31327507?dopt=Abstract %R 10.1016/j.ajhg.2019.05.020 %0 Journal Article %J Nat Commun %D 2018 %T Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease. %A Emdin, Connor A %A Khera, Amit V %A Chaffin, Mark %A Klarin, Derek %A Natarajan, Pradeep %A Aragam, Krishna %A Haas, Mary %A Bick, Alexander %A Zekavat, Seyedeh M %A Nomura, Akihiro %A Ardissino, Diego %A Wilson, James G %A Schunkert, Heribert %A McPherson, Ruth %A Watkins, Hugh %A Elosua, Roberto %A Bown, Matthew J %A Samani, Nilesh J %A Baber, Usman %A Erdmann, Jeanette %A Gupta, Namrata %A Danesh, John %A Chasman, Daniel %A Ridker, Paul %A Denny, Joshua %A Bastarache, Lisa %A Lichtman, Judith H %A D'Onofrio, Gail %A Mattera, Jennifer %A Spertus, John A %A Sheu, Wayne H-H %A Taylor, Kent D %A Psaty, Bruce M %A Rich, Stephen S %A Post, Wendy %A Rotter, Jerome I %A Chen, Yii-Der Ida %A Krumholz, Harlan %A Saleheen, Danish %A Gabriel, Stacey %A Kathiresan, Sekar %K Databases, Genetic %K Diabetes Mellitus, Type 2 %K Disease %K Gene Frequency %K Genetic Testing %K Genetic Variation %K Humans %K Obesity %K Phenotype %K Proteins %K Respiratory Hypersensitivity %K United Kingdom %X

Less than 3% of protein-coding genetic variants are predicted to result in loss of protein function through the introduction of a stop codon, frameshift, or the disruption of an essential splice site; however, such predicted loss-of-function (pLOF) variants provide insight into effector transcript and direction of biological effect. In >400,000 UK Biobank participants, we conduct association analyses of 3759 pLOF variants with six metabolic traits, six cardiometabolic diseases, and twelve additional diseases. We identified 18 new low-frequency or rare (allele frequency < 5%) pLOF variant-phenotype associations. pLOF variants in the gene GPR151 protect against obesity and type 2 diabetes, in the gene IL33 against asthma and allergic disease, and in the gene IFIH1 against hypothyroidism. In the gene PDE3B, pLOF variants associate with elevated height, improved body fat distribution and protection from coronary artery disease. Our findings prioritize genes for which pharmacologic mimics of pLOF variants may lower risk for disease.

%B Nat Commun %V 9 %P 1613 %8 2018 04 24 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/29691411?dopt=Abstract %R 10.1038/s41467-018-03911-8 %0 Journal Article %J Stroke %D 2018 %T Cardioembolic Stroke Risk and Recovery After Anticoagulation-Related Intracerebral Hemorrhage. %A Murphy, Meredith P %A Kuramatsu, Joji B %A Leasure, Audrey %A Falcone, Guido J %A Kamel, Hooman %A Sansing, Lauren H %A Kourkoulis, Christina %A Schwab, Kristin %A Elm, Jordan J %A Gurol, M Edip %A Tran, Huy %A Greenberg, Steven M %A Viswanathan, Anand %A Anderson, Christopher D %A Schwab, Stefan %A Rosand, Jonathan %A Shi, Fu-Dong %A Kittner, Steven J %A Testai, Fernando D %A Woo, Daniel %A Langefeld, Carl D %A James, Michael L %A Koch, Sebastian %A Huttner, Hagen B %A Biffi, Alessandro %A Sheth, Kevin N %X

Background and Purpose- Whether to resume oral anticoagulation treatment after intracerebral hemorrhage (ICH) remains an unresolved question. Previous studies focused primarily on recurrent stroke after ICH. We sought to investigate the association between cardioembolic stroke risk, oral anticoagulation therapy resumption, and functional recovery among ICH survivors in the absence of recurrent stroke. Methods- We conducted a joint analysis of 3 observational studies: (1) the multicenter RETRACE study (German-Wide Multicenter Analysis of Oral Anticoagulation Associated Intracerebral Hemorrhage); (2) the Massachusetts General Hospital ICH study (n=166); and (3) the ERICH study (Ethnic/Racial Variations of Intracerebral Hemorrhage; n=131). We included 941 survivors of ICH in the setting of active oral anticoagulation therapy for prevention of cardioembolic stroke because of nonvalvular atrial fibrillation and without evidence of ischemic stroke and recurrent ICH at 1 year from the index event. We created univariable and multivariable models to explore associations between cardioembolic stroke risk (based on CHADS-VASc scores) and functional recovery after ICH, defined as achieving modified Rankin Scale score of ≤3 at 1 year for participants with modified Rankin Scale score of >3 at discharge. Results- In multivariable analyses, the CHADS-VASc score was associated with a decreased likelihood of functional recovery (odds ratio, 0.83 per 1 point increase; 95% CI, 0.79-0.86) at 1 year. Anticoagulation resumption was independently associated with a higher likelihood of recovery, regardless of CHADS-VASc score (odds ratio, 1.89; 95% CI, 1.32-2.70). We found an interaction between CHADS-VASc score and anticoagulation resumption in terms of association with increased likelihood of functional recovery (interaction P=0.011). Conclusions- Increasing cardioembolic stroke risk is associated with a decreased likelihood of functional recovery at 1 year after ICH, but this association was weaker among participants resuming oral anticoagulation therapy. These findings support, including recovery metrics, in future studies of anticoagulation resumption after ICH.

%B Stroke %V 49 %P 2652-2658 %8 2018 Nov %G eng %N 11 %1 https://www.ncbi.nlm.nih.gov/pubmed/30355194?dopt=Abstract %R 10.1161/STROKEAHA.118.021799 %0 Journal Article %J Nat Commun %D 2018 %T Functional equivalence of genome sequencing analysis pipelines enables harmonized variant calling across human genetics projects. %A Regier, Allison A %A Farjoun, Yossi %A Larson, David E %A Krasheninina, Olga %A Kang, Hyun Min %A Howrigan, Daniel P %A Chen, Bo-Juen %A Kher, Manisha %A Banks, Eric %A Ames, Darren C %A English, Adam C %A Li, Heng %A Xing, Jinchuan %A Zhang, Yeting %A Matise, Tara %A Abecasis, Goncalo R %A Salerno, Will %A Zody, Michael C %A Neale, Benjamin M %A Hall, Ira M %K Genome, Human %K Human Genetics %K Humans %K Whole Genome Sequencing %X

Hundreds of thousands of human whole genome sequencing (WGS) datasets will be generated over the next few years. These data are more valuable in aggregate: joint analysis of genomes from many sources increases sample size and statistical power. A central challenge for joint analysis is that different WGS data processing pipelines cause substantial differences in variant calling in combined datasets, necessitating computationally expensive reprocessing. This approach is no longer tenable given the scale of current studies and data volumes. Here, we define WGS data processing standards that allow different groups to produce functionally equivalent (FE) results, yet still innovate on data processing pipelines. We present initial FE pipelines developed at five genome centers and show that they yield similar variant calling results and produce significantly less variability than sequencing replicates. This work alleviates a key technical bottleneck for genome aggregation and helps lay the foundation for community-wide human genetics studies.

%B Nat Commun %V 9 %P 4038 %8 2018 10 02 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/30279509?dopt=Abstract %R 10.1038/s41467-018-06159-4 %0 Journal Article %J Nat Genet %D 2018 %T Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. %A Khera, Amit V %A Chaffin, Mark %A Aragam, Krishna G %A Haas, Mary E %A Roselli, Carolina %A Choi, Seung Hoan %A Natarajan, Pradeep %A Lander, Eric S %A Lubitz, Steven A %A Ellinor, Patrick T %A Kathiresan, Sekar %X

A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation. Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature, it has not yet been possible to use polygenic predictors to identify individuals at risk comparable to monogenic mutations. Here, we develop and validate genome-wide polygenic scores for five common diseases. The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively. For coronary artery disease, this prevalence is 20-fold higher than the carrier frequency of rare monogenic mutations conferring comparable risk. We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues.

%B Nat Genet %V 50 %P 1219-1224 %8 2018 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/30104762?dopt=Abstract %R 10.1038/s41588-018-0183-z %0 Journal Article %J Am J Respir Crit Care Med %D 2018 %T Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma. %A Mak, Angel C Y %A White, Marquitta J %A Eckalbar, Walter L %A Szpiech, Zachary A %A Oh, Sam S %A Pino-Yanes, Maria %A Hu, Donglei %A Goddard, Pagé %A Huntsman, Scott %A Galanter, Joshua %A Wu, Ann Chen %A Himes, Blanca E %A Germer, Soren %A Vogel, Julia M %A Bunting, Karen L %A Eng, Celeste %A Salazar, Sandra %A Keys, Kevin L %A Liberto, Jennifer %A Nuckton, Thomas J %A Nguyen, Thomas A %A Torgerson, Dara G %A Kwok, Pui-Yan %A Levin, Albert M %A Celedón, Juan C %A Forno, Erick %A Hakonarson, Hakon %A Sleiman, Patrick M %A Dahlin, Amber %A Tantisira, Kelan G %A Weiss, Scott T %A Serebrisky, Denise %A Brigino-Buenaventura, Emerita %A Farber, Harold J %A Meade, Kelley %A Lenoir, Michael A %A Avila, Pedro C %A Sen, Saunak %A Thyne, Shannon M %A Rodriguez-Cintron, William %A Winkler, Cheryl A %A Moreno-Estrada, Andrés %A Sandoval, Karla %A Rodriguez-Santana, Jose R %A Kumar, Rajesh %A Williams, L Keoki %A Ahituv, Nadav %A Ziv, Elad %A Seibold, Max A %A Darnell, Robert B %A Zaitlen, Noah %A Hernandez, Ryan D %A Burchard, Esteban G %X

RATIONALE: Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response.

OBJECTIVES: To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children.

METHODS: We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR.

MEASUREMENTS AND MAIN RESULTS: We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 × 10) and suggestive (P < 7.06 × 10) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings.

CONCLUSIONS: The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.

%B Am J Respir Crit Care Med %V 197 %P 1552-1564 %8 2018 Jun 15 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/29509491?dopt=Abstract %R 10.1164/rccm.201712-2529OC %0 Journal Article %J J Am Coll Cardiol %D 2017 %T ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. %A Stitziel, Nathan O %A Khera, Amit V %A Wang, Xiao %A Bierhals, Andrew J %A Vourakis, A Christina %A Sperry, Alexandra E %A Natarajan, Pradeep %A Klarin, Derek %A Emdin, Connor A %A Zekavat, Seyedeh M %A Nomura, Akihiro %A Erdmann, Jeanette %A Schunkert, Heribert %A Samani, Nilesh J %A Kraus, William E %A Shah, Svati H %A Yu, Bing %A Boerwinkle, Eric %A Rader, Daniel J %A Gupta, Namrata %A Frossard, Philippe M %A Rasheed, Asif %A Danesh, John %A Lander, Eric S %A Gabriel, Stacey %A Saleheen, Danish %A Musunuru, Kiran %A Kathiresan, Sekar %K Adult %K Angiopoietin-Like Protein 3 %K Angiopoietin-like Proteins %K Angiopoietins %K Animals %K Atherosclerosis %K Case-Control Studies %K Coronary Artery Disease %K Female %K Humans %K Lipids %K Male %K Mice, Inbred C57BL %K Mice, Knockout %K Middle Aged %K Mutation, Missense %K Myocardial Infarction %K Risk Factors %X

BACKGROUND: Familial combined hypolipidemia, a Mendelian condition characterized by substantial reductions in all 3 major lipid fractions, is caused by mutations that inactivate the gene angiopoietin-like 3 (ANGPTL3). Whether ANGPTL3 deficiency reduces risk of coronary artery disease (CAD) is unknown.

OBJECTIVES: The study goal was to leverage 3 distinct lines of evidence-a family that included individuals with complete (compound heterozygote) ANGPTL3 deficiency, a population based-study of humans with partial (heterozygote) ANGPTL3 deficiency, and biomarker levels in patients with myocardial infarction (MI)-to test whether ANGPTL3 deficiency is associated with lower risk for CAD.

METHODS: We assessed coronary atherosclerotic burden in 3 individuals with complete ANGPTL3 deficiency and 3 wild-type first-degree relatives using computed tomography angiography. In the population, ANGPTL3 loss-of-function (LOF) mutations were ascertained in up to 21,980 people with CAD and 158,200 control subjects. LOF mutations were defined as nonsense, frameshift, and splice-site variants, along with missense variants resulting in <25% of wild-type ANGPTL3 activity in a mouse model. In a biomarker study, circulating ANGPTL3 concentration was measured in 1,493 people who presented with MI and 3,232 control subjects.

RESULTS: The 3 individuals with complete ANGPTL3 deficiency showed no evidence of coronary atherosclerotic plaque. ANGPTL3 gene sequencing demonstrated that approximately 1 in 309 people was a heterozygous carrier for an LOF mutation. Compared with those without mutation, heterozygous carriers of ANGPTL3 LOF mutations demonstrated a 17% reduction in circulating triglycerides and a 12% reduction in low-density lipoprotein cholesterol. Carrier status was associated with a 34% reduction in odds of CAD (odds ratio: 0.66; 95% confidence interval: 0.44 to 0.98; p = 0.04). Individuals in the lowest tertile of circulating ANGPTL3 concentrations, compared with the highest, had reduced odds of MI (adjusted odds ratio: 0.65; 95% confidence interval: 0.55 to 0.77; p < 0.001).

CONCLUSIONS: ANGPTL3 deficiency is associated with protection from CAD.

%B J Am Coll Cardiol %V 69 %P 2054-2063 %8 2017 Apr 25 %G eng %N 16 %1 https://www.ncbi.nlm.nih.gov/pubmed/28385496?dopt=Abstract %R 10.1016/j.jacc.2017.02.030 %0 Journal Article %J Nature %D 2017 %T Genetic effects on gene expression across human tissues. %A Battle, Alexis %A Brown, Christopher D %A Engelhardt, Barbara E %A Montgomery, Stephen B %K Alleles %K Chromosomes, Human %K Disease %K Female %K Gene Expression Profiling %K Gene Expression Regulation %K Genetic Variation %K Genome, Human %K Genotype %K Humans %K Male %K Organ Specificity %K Quantitative Trait Loci %X

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease.

%B Nature %V 550 %P 204-213 %8 2017 10 11 %G eng %N 7675 %1 https://www.ncbi.nlm.nih.gov/pubmed/29022597?dopt=Abstract %R 10.1038/nature24277 %0 Journal Article %J Nat Methods %D 2017 %T Genome-wide profiling of heritable and de novo STR variations. %A Willems, Thomas %A Zielinski, Dina %A Yuan, Jie %A Gordon, Assaf %A Gymrek, Melissa %A Erlich, Yaniv %K Algorithms %K Chromosome Mapping %K DNA Fingerprinting %K Genetic Predisposition to Disease %K Genetic Variation %K Genome, Human %K High-Throughput Nucleotide Sequencing %K Humans %K Microsatellite Repeats %K Sequence Alignment %K Sequence Analysis, DNA %K Software %X

Short tandem repeats (STRs) are highly variable elements that play a pivotal role in multiple genetic diseases, population genetics applications, and forensic casework. However, it has proven problematic to genotype STRs from high-throughput sequencing data. Here, we describe HipSTR, a novel haplotype-based method for robustly genotyping and phasing STRs from Illumina sequencing data, and we report a genome-wide analysis and validation of de novo STR mutations. HipSTR is freely available at https://hipstr-tool.github.io/HipSTR.

%B Nat Methods %V 14 %P 590-592 %8 2017 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/28436466?dopt=Abstract %R 10.1038/nmeth.4267 %0 Journal Article %J Cell %D 2017 %T Genomic Patterns of De Novo Mutation in Simplex Autism. %A Turner, Tychele N %A Coe, Bradley P %A Dickel, Diane E %A Hoekzema, Kendra %A Nelson, Bradley J %A Zody, Michael C %A Kronenberg, Zev N %A Hormozdiari, Fereydoun %A Raja, Archana %A Pennacchio, Len A %A Darnell, Robert B %A Eichler, Evan E %K Animals %K Autistic Disorder %K DNA Copy Number Variations %K DNA Mutational Analysis %K Female %K Genome-Wide Association Study %K Humans %K INDEL Mutation %K Male %K Mice %K Polymorphism, Single Nucleotide %X

To further our understanding of the genetic etiology of autism, we generated and analyzed genome sequence data from 516 idiopathic autism families (2,064 individuals). This resource includes >59 million single-nucleotide variants (SNVs) and 9,212 private copy number variants (CNVs), of which 133,992 and 88 are de novo mutations (DNMs), respectively. We estimate a mutation rate of ∼1.5 × 10 SNVs per site per generation with a significantly higher mutation rate in repetitive DNA. Comparing probands and unaffected siblings, we observe several DNM trends. Probands carry more gene-disruptive CNVs and SNVs, resulting in severe missense mutations and mapping to predicted fetal brain promoters and embryonic stem cell enhancers. These differences become more pronounced for autism genes (p = 1.8 × 10, OR = 2.2). Patients are more likely to carry multiple coding and noncoding DNMs in different genes, which are enriched for expression in striatal neurons (p = 3 × 10), suggesting a path forward for genetically characterizing more complex cases of autism.

%B Cell %V 171 %P 710-722.e12 %8 2017 Oct 19 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/28965761?dopt=Abstract %R 10.1016/j.cell.2017.08.047 %0 Journal Article %J N Engl J Med %D 2017 %T Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. %A Posey, Jennifer E %A Harel, Tamar %A Liu, Pengfei %A Rosenfeld, Jill A %A James, Regis A %A Coban Akdemir, Zeynep H %A Walkiewicz, Magdalena %A Bi, Weimin %A Xiao, Rui %A Ding, Yan %A Xia, Fan %A Beaudet, Arthur L %A Muzny, Donna M %A Gibbs, Richard A %A Boerwinkle, Eric %A Eng, Christine M %A Sutton, V Reid %A Shaw, Chad A %A Plon, Sharon E %A Yang, Yaping %A Lupski, James R %K Exome %K Genetic Diseases, Inborn %K Genetic Variation %K Genotyping Techniques %K High-Throughput Nucleotide Sequencing %K Humans %K Phenotype %K Retrospective Studies %K Sequence Analysis, DNA %X

BACKGROUND: Whole-exome sequencing can provide insight into the relationship between observed clinical phenotypes and underlying genotypes.

METHODS: We conducted a retrospective analysis of data from a series of 7374 consecutive unrelated patients who had been referred to a clinical diagnostic laboratory for whole-exome sequencing; our goal was to determine the frequency and clinical characteristics of patients for whom more than one molecular diagnosis was reported. The phenotypic similarity between molecularly diagnosed pairs of diseases was calculated with the use of terms from the Human Phenotype Ontology.

RESULTS: A molecular diagnosis was rendered for 2076 of 7374 patients (28.2%); among these patients, 101 (4.9%) had diagnoses that involved two or more disease loci. We also analyzed parental samples, when available, and found that de novo variants accounted for 67.8% (61 of 90) of pathogenic variants in autosomal dominant disease genes and 51.7% (15 of 29) of pathogenic variants in X-linked disease genes; both variants were de novo in 44.7% (17 of 38) of patients with two monoallelic variants. Causal copy-number variants were found in 12 patients (11.9%) with multiple diagnoses. Phenotypic similarity scores were significantly lower among patients in whom the phenotype resulted from two distinct mendelian disorders that affected different organ systems (50 patients) than among patients with disorders that had overlapping phenotypic features (30 patients) (median score, 0.21 vs. 0.36; P=1.77×10).

CONCLUSIONS: In our study, we found multiple molecular diagnoses in 4.9% of cases in which whole-exome sequencing was informative. Our results show that structured clinical ontologies can be used to determine the degree of overlap between two mendelian diseases in the same patient; the diseases can be distinct or overlapping. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. (Funded by the National Institutes of Health and the Ting Tsung and Wei Fong Chao Foundation.).

%B N Engl J Med %V 376 %P 21-31 %8 2017 Jan 05 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/27959697?dopt=Abstract %R 10.1056/NEJMoa1516767 %0 Journal Article %J N Engl J Med %D 2016 %T Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease. %A Khera, Amit V %A Emdin, Connor A %A Drake, Isabel %A Natarajan, Pradeep %A Bick, Alexander G %A Cook, Nancy R %A Chasman, Daniel I %A Baber, Usman %A Mehran, Roxana %A Rader, Daniel J %A Fuster, Valentin %A Boerwinkle, Eric %A Melander, Olle %A Orho-Melander, Marju %A Ridker, Paul M %A Kathiresan, Sekar %K Aged %K Cohort Studies %K Coronary Disease %K Cross-Sectional Studies %K Female %K Genetic Predisposition to Disease %K Healthy Lifestyle %K Humans %K Incidence %K Male %K Middle Aged %K Multifactorial Inheritance %K Patient Compliance %K Polymorphism, Genetic %K Risk %X

BACKGROUND: Both genetic and lifestyle factors contribute to individual-level risk of coronary artery disease. The extent to which increased genetic risk can be offset by a healthy lifestyle is unknown.

METHODS: Using a polygenic score of DNA sequence polymorphisms, we quantified genetic risk for coronary artery disease in three prospective cohorts - 7814 participants in the Atherosclerosis Risk in Communities (ARIC) study, 21,222 in the Women's Genome Health Study (WGHS), and 22,389 in the Malmö Diet and Cancer Study (MDCS) - and in 4260 participants in the cross-sectional BioImage Study for whom genotype and covariate data were available. We also determined adherence to a healthy lifestyle among the participants using a scoring system consisting of four factors: no current smoking, no obesity, regular physical activity, and a healthy diet.

RESULTS: The relative risk of incident coronary events was 91% higher among participants at high genetic risk (top quintile of polygenic scores) than among those at low genetic risk (bottom quintile of polygenic scores) (hazard ratio, 1.91; 95% confidence interval [CI], 1.75 to 2.09). A favorable lifestyle (defined as at least three of the four healthy lifestyle factors) was associated with a substantially lower risk of coronary events than an unfavorable lifestyle (defined as no or only one healthy lifestyle factor), regardless of the genetic risk category. Among participants at high genetic risk, a favorable lifestyle was associated with a 46% lower relative risk of coronary events than an unfavorable lifestyle (hazard ratio, 0.54; 95% CI, 0.47 to 0.63). This finding corresponded to a reduction in the standardized 10-year incidence of coronary events from 10.7% for an unfavorable lifestyle to 5.1% for a favorable lifestyle in ARIC, from 4.6% to 2.0% in WGHS, and from 8.2% to 5.3% in MDCS. In the BioImage Study, a favorable lifestyle was associated with significantly less coronary-artery calcification within each genetic risk category.

CONCLUSIONS: Across four studies involving 55,685 participants, genetic and lifestyle factors were independently associated with susceptibility to coronary artery disease. Among participants at high genetic risk, a favorable lifestyle was associated with a nearly 50% lower relative risk of coronary artery disease than was an unfavorable lifestyle. (Funded by the National Institutes of Health and others.).

%B N Engl J Med %V 375 %P 2349-2358 %8 2016 Dec 15 %G eng %N 24 %1 https://www.ncbi.nlm.nih.gov/pubmed/27959714?dopt=Abstract %R 10.1056/NEJMoa1605086 %0 Journal Article %J Am J Hum Genet %D 2016 %T Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNA. %A Turner, Tychele N %A Hormozdiari, Fereydoun %A Duyzend, Michael H %A McClymont, Sarah A %A Hook, Paul W %A Iossifov, Ivan %A Raja, Archana %A Baker, Carl %A Hoekzema, Kendra %A Stessman, Holly A %A Zody, Michael C %A Nelson, Bradley J %A Huddleston, John %A Sandstrom, Richard %A Smith, Joshua D %A Hanna, David %A Swanson, James M %A Faustman, Elaine M %A Bamshad, Michael J %A Stamatoyannopoulos, John %A Nickerson, Deborah A %A McCallion, Andrew S %A Darnell, Robert %A Eichler, Evan E %K Autistic Disorder %K DNA %K Exome %K Female %K Genome, Human %K Humans %K Male %K Pedigree %K Polymorphism, Single Nucleotide %X

We performed whole-genome sequencing (WGS) of 208 genomes from 53 families affected by simplex autism. For the majority of these families, no copy-number variant (CNV) or candidate de novo gene-disruptive single-nucleotide variant (SNV) had been detected by microarray or whole-exome sequencing (WES). We integrated multiple CNV and SNV analyses and extensive experimental validation to identify additional candidate mutations in eight families. We report that compared to control individuals, probands showed a significant (p = 0.03) enrichment of de novo and private disruptive mutations within fetal CNS DNase I hypersensitive sites (i.e., putative regulatory regions). This effect was only observed within 50 kb of genes that have been previously associated with autism risk, including genes where dosage sensitivity has already been established by recurrent disruptive de novo protein-coding mutations (ARID1B, SCN2A, NR3C2, PRKCA, and DSCAM). In addition, we provide evidence of gene-disruptive CNVs (in DISC1, WNT7A, RBFOX1, and MBD5), as well as smaller de novo CNVs and exon-specific SNVs missed by exome sequencing in neurodevelopmental genes (e.g., CANX, SAE1, and PIK3CA). Our results suggest that the detection of smaller, often multiple CNVs affecting putative regulatory elements might help explain additional risk of simplex autism.

%B Am J Hum Genet %V 98 %P 58-74 %8 2016 Jan 07 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/26749308?dopt=Abstract %R 10.1016/j.ajhg.2015.11.023