@article {148, title = {Accurate, scalable cohort variant calls using DeepVariant and GLnexus.}, journal = {Bioinformatics}, year = {2021}, month = {2021 Jan 05}, abstract = {

MOTIVATION: Population-scale sequenced cohorts are foundational resources for genetic analyses, but processing raw reads into analysis-ready cohort-level variants remains challenging.

RESULTS: We introduce an open-source cohort-calling method that uses the highly-accurate caller DeepVariant and scalable merging tool GLnexus. Using callset quality metrics based on variant recall and precision in benchmark samples and Mendelian consistency in father-mother-child trios, we optimized the method across a range of cohort sizes, sequencing methods, and sequencing depths. The resulting callsets show consistent quality improvements over those generated using existing best practices with reduced cost. We further evaluate our pipeline in the deeply sequenced 1000 Genomes Project (1KGP) samples and show superior callset quality metrics and imputation reference panel performance compared to an independently-generated GATK Best Practices pipeline.

AVAILABILITY AND IMPLEMENTATION: We publicly release the 1KGP individual-level variant calls and cohort callset (https://console.cloud.google.com/storage/browser/brain-genomics-public/research/cohort/1KGP) to foster additional development and evaluation of cohort merging methods as well as broad studies of genetic variation. Both DeepVariant (https://github.com/google/deepvariant) and GLnexus (https://github.com/dnanexus-rnd/GLnexus) are open-sourced, and the optimized GLnexus setup discovered in this study is also integrated into GLnexus public releases v1.2.2 and later.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

}, issn = {1367-4811}, doi = {10.1093/bioinformatics/btaa1081}, author = {Yun, Taedong and Li, Helen and Chang, Pi-Chuan and Lin, Michael F and Carroll, Andrew and McLean, Cory Y} } @article {133, title = {Association of Genetic Variation With Cirrhosis: A Multi-Trait Genome-Wide Association and Gene-Environment Interaction Study.}, journal = {Gastroenterology}, volume = {160}, year = {2021}, month = {2021 Apr}, pages = {1620-1633.e13}, abstract = {

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~{\texttimes} 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.

}, issn = {1528-0012}, doi = {10.1053/j.gastro.2020.12.011}, author = {Emdin, Connor A and Haas, Mary and Ajmera, Veeral and Simon, Tracey G and Homburger, Julian and Neben, Cynthia and Jiang, Lan and Wei, Wei-Qi and Feng, Qiping and Zhou, Alicia and Denny, Joshua and Corey, Kathleen and Loomba, Rohit and Kathiresan, Sekar and Khera, Amit V} } @article {151, title = {Association of structural variation with cardiometabolic traits in Finns.}, journal = {Am J Hum Genet}, volume = {108}, year = {2021}, month = {2021 04 01}, pages = {583-596}, abstract = {

The contribution of genome structural variation (SV) to quantitative traits associated with cardiometabolic diseases remains largely unknown. Here, we present the results of a study examining genetic association between SVs and cardiometabolic traits in the Finnish population. We used sensitive methods to identify and genotype 129,166 high-confidence SVs from deep whole-genome sequencing (WGS) data of 4,848 individuals. We tested the 64,572 common and low-frequency SVs for association with 116 quantitative traits and tested candidate associations using exome sequencing and array genotype data from an additional 15,205 individuals. We discovered 31 genome-wide significant associations at 15 loci, including 2 loci at which SVs have strong phenotypic effects: (1) a deletion of the ALB promoter that is greatly enriched in the Finnish population and causes decreased serum albumin level in carriers (p = 1.47~{\texttimes} 10) and is also associated with increased levels of total cholesterol (p = 1.22~{\texttimes} 10) and 14 additional cholesterol-related traits, and (2) a multi-allelic copy number variant (CNV) at PDPR that is strongly associated with pyruvate (p = 4.81~{\texttimes} 10) and alanine (p = 6.14~{\texttimes} 10) levels and resides within a structurally complex genomic region that has accumulated many rearrangements over evolutionary time. We also confirmed six previously reported associations, including five led by stronger signals in single nucleotide variants (SNVs) and one linking recurrent HP gene deletion and cholesterol levels (p = 6.24~{\texttimes} 10), which was also found to be strongly associated with increased glycoprotein level (p = 3.53~{\texttimes} 10). Our study confirms that integrating SVs in trait-mapping studies will expand our knowledge of genetic factors underlying disease risk.

}, keywords = {Alleles, Cardiovascular Diseases, Cholesterol, DNA Copy Number Variations, Female, Finland, Genome, Human, Genomic Structural Variation, Genotype, High-Throughput Nucleotide Sequencing, Humans, Male, Mitochondrial Proteins, Promoter Regions, Genetic, Pyruvate Dehydrogenase (Lipoamide)-Phosphatase, Pyruvic Acid, Serum Albumin, Human}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2021.03.008}, author = {Chen, Lei and Abel, Haley J and Das, Indraniel and Larson, David E and Ganel, Liron and Kanchi, Krishna L and Regier, Allison A and Young, Erica P and Kang, Chul Joo and Scott, Alexandra J and Chiang, Colby and Wang, Xinxin and Lu, Shuangjia and Christ, Ryan and Service, Susan K and Chiang, Charleston W K and Havulinna, Aki S and Kuusisto, Johanna and Boehnke, Michael and Laakso, Markku and Palotie, Aarno and Ripatti, Samuli and Freimer, Nelson B and Locke, Adam E and Stitziel, Nathan O and Hall, Ira M} } @article {117, title = {Analysis of cardiac magnetic resonance imaging in 36,000 individuals yields genetic insights into dilated cardiomyopathy.}, journal = {Nat Commun}, volume = {11}, year = {2020}, month = {2020 05 07}, pages = {2254}, abstract = {

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.

}, keywords = {Cardiomyopathy, Dilated, Genome-Wide Association Study, Heart, Humans, Magnetic Resonance Imaging, Myocardium, Polymorphism, Single Nucleotide}, issn = {2041-1723}, doi = {10.1038/s41467-020-15823-7}, author = {Pirruccello, James P and Bick, Alexander and Wang, Minxian and Chaffin, Mark and Friedman, Samuel and Yao, Jie and Guo, Xiuqing and Venkatesh, Bharath Ambale and Taylor, Kent D and Post, Wendy S and Rich, Stephen and Lima, Joao A C and Rotter, Jerome I and Philippakis, Anthony and Lubitz, Steven A and Ellinor, Patrick T and Khera, Amit V and Kathiresan, Sekar and Aragam, Krishna G} } @article {144, title = {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.}, journal = {JAMA Netw Open}, volume = {3}, year = {2020}, month = {2020 04 01}, pages = {e203959}, abstract = {

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.

}, keywords = {Aged, Cohort Studies, Colorectal Neoplasms, Hereditary Nonpolyposis, Female, Genetic Predisposition to Disease, Hereditary Breast and Ovarian Cancer Syndrome, Heterozygote, Humans, Hyperlipoproteinemia Type II, Male, Middle Aged, Pedigree, Proportional Hazards Models, United Kingdom, Whole Exome Sequencing}, issn = {2574-3805}, doi = {10.1001/jamanetworkopen.2020.3959}, author = {Patel, Aniruddh P and Wang, Minxian and Fahed, Akl C and Mason-Suares, Heather and Brockman, Deanna and Pelletier, Renee and Amr, Sami and Machini, Kalotina and Hawley, Megan and Witkowski, Leora and Koch, Christopher and Philippakis, Anthony and Cassa, Christopher A and Ellinor, Patrick T and Kathiresan, Sekar and Ng, Kenney and Lebo, Matthew and Khera, Amit V} } @article {72, title = {Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging.}, journal = {Am J Hum Genet}, volume = {105}, year = {2019}, month = {2019 Sep 05}, pages = {493-508}, abstract = {

Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.07.007}, author = {Flex, Elisabetta and Martinelli, Simone and Van Dijck, Anke and Ciolfi, Andrea and Cecchetti, Serena and Coluzzi, Elisa and Pannone, Luca and Andreoli, Cristina and Radio, Francesca Clementina and Pizzi, Simone and Carpentieri, Giovanna and Bruselles, Alessandro and Catanzaro, Giuseppina and Pedace, Lucia and Miele, Evelina and Carcarino, Elena and Ge, Xiaoyan and Chijiwa, Chieko and Lewis, M E Suzanne and Meuwissen, Marije and Kenis, Sandra and Van der Aa, Nathalie and Larson, Austin and Brown, Kathleen and Wasserstein, Melissa P and Skotko, Brian G and Begtrup, Amber and Person, Richard and Karayiorgou, Maria and Roos, J Louw and Van Gassen, Koen L and Koopmans, Marije and Bijlsma, Emilia K and Santen, Gijs W E and Barge-Schaapveld, Daniela Q C M and Ruivenkamp, Claudia A L and Hoffer, Mariette J V and Lalani, Seema R and Streff, Haley and Craigen, William J and Graham, Brett H and van den Elzen, Annette P M and Kamphuis, Daan J and {\~O}unap, Katrin and Reinson, Karit and Pajusalu, Sander and Wojcik, Monica H and Viberti, Clara and Di Gaetano, Cornelia and Bertini, Enrico and Petrucci, Simona and De Luca, Alessandro and Rota, Rossella and Ferretti, Elisabetta and Matullo, Giuseppe and Dallapiccola, Bruno and Sgura, Antonella and Walkiewicz, Magdalena and Kooy, R Frank and Tartaglia, Marco} } @article {55, title = {ACAT: A Fast and Powerful p Value Combination Method for Rare-Variant Analysis in Sequencing Studies.}, journal = {Am J Hum Genet}, volume = {104}, year = {2019}, month = {2019 Mar 07}, pages = {410-421}, abstract = {

Set-based analysis that jointly tests the association of variants in a group has emerged as a popular tool for analyzing rare and low-frequency variants in sequencing studies. The existing set-based tests can suffer significant power loss when only a small proportion of variants are causal, and their powers can be sensitive to the number, effect sizes, and effect directions of the causal variants and the choices of weights. Here we propose an aggregated Cauchy association test (ACAT), a general, powerful, and computationally efficient p value combination method for boosting power in sequencing studies. First, by combining variant-level p values, we use ACAT to construct a set-based test (ACAT-V) that is particularly powerful in the presence of only a small number of causal variants in a variant set. Second, by combining different variant-set-level p values, we use ACAT to construct an omnibus test (ACAT-O) that combines the strength of multiple complimentary set-based tests, including the burden test, sequence kernel association test (SKAT), and ACAT-V. Through analysis of extensively simulated data and the whole-genome sequencing data from the Atherosclerosis Risk in Communities (ARIC) study, we demonstrate that ACAT-V complements the SKAT and the burden test, and that ACAT-O has a substantially more robust and higher power than those of the alternative tests.

}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2019.01.002}, author = {Liu, Yaowu and Chen, Sixing and Li, Zilin and Morrison, Alanna C and Boerwinkle, Eric and Lin, Xihong} } @article {78, title = {Accurate circular consensus long-read sequencing improves variant detection and assembly of a human genome.}, journal = {Nat Biotechnol}, volume = {37}, year = {2019}, month = {2019 Oct}, pages = {1155-1162}, abstract = {

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 {\textquoteright}genome in a bottle{\textquoteright} (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.

}, issn = {1546-1696}, doi = {10.1038/s41587-019-0217-9}, author = {Wenger, Aaron M and Peluso, Paul and Rowell, William J and Chang, Pi-Chuan and Hall, Richard J and Concepcion, Gregory T and Ebler, Jana and Fungtammasan, Arkarachai and Kolesnikov, Alexey and Olson, Nathan D and T{\"o}pfer, Armin and Alonge, Michael and Mahmoud, Medhat and Qian, Yufeng and Chin, Chen-Shan and Phillippy, Adam M and Schatz, Michael C and Myers, Gene and DePristo, Mark A and Ruan, Jue and Marschall, Tobias and Sedlazeck, Fritz J and Zook, Justin M and Li, Heng and Koren, Sergey and Carroll, Andrew and Rank, David R and Hunkapiller, Michael W} } @article {80, title = {Ancestral Admixture Is the Main Determinant of Global Biodiversity in Fission Yeast.}, journal = {Mol Biol Evol}, volume = {36}, year = {2019}, month = {2019 09 01}, pages = {1975-1989}, abstract = {

Mutation and recombination are key evolutionary processes governing phenotypic variation and reproductive isolation. We here demonstrate that biodiversity within all globally known strains of Schizosaccharomyces pombe arose through admixture between two divergent ancestral lineages. Initial hybridization was inferred to have occurred \~{}20-60 sexual outcrossing generations ago consistent with recent, human-induced migration at the onset of intensified transcontinental trade. Species-wide heritable phenotypic variation was explained near-exclusively by strain-specific arrangements of alternating ancestry components with evidence for transgressive segregation. Reproductive compatibility between strains was likewise predicted by the degree of shared ancestry. To assess the genetic determinants of ancestry block distribution across the genome, we characterized the type, frequency, and position of structural genomic variation using nanopore and single-molecule real-time sequencing. Despite being associated with double-strand break initiation points, over 800 segregating structural variants exerted overall little influence on the introgression landscape or on reproductive compatibility between strains. In contrast, we found strong ancestry disequilibrium consistent with negative epistatic selection shaping genomic ancestry combinations during the course of hybridization. This study provides a detailed, experimentally tractable example that genomes of natural populations are mosaics reflecting different evolutionary histories. Exploiting genome-wide heterogeneity in the history of ancestral recombination and lineage-specific mutations sheds new light on the population history of S. pombe and highlights the importance of hybridization as a creative force in generating biodiversity.

}, issn = {1537-1719}, doi = {10.1093/molbev/msz126}, author = {Tusso, Sergio and Nieuwenhuis, Bart P S and Sedlazeck, Fritz J and Davey, John W and Jeffares, Daniel C and Wolf, Jochen B W} } @article {54, title = {Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 Sep}, pages = {2135-2144}, abstract = {

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.

}, issn = {1530-0366}, doi = {10.1038/s41436-019-0475-4}, author = {Chiang, Theodore and Liu, Xiuping and Wu, Tsung-Jung and Hu, Jianhong and Sedlazeck, Fritz J and White, Simon and Schaid, Daniel and Andrade, Mariza de and Jarvik, Gail P and Crosslin, David and Stanaway, Ian and Carrell, David S and Connolly, John J and Hakonarson, Hakon and Groopman, Emily E and Gharavi, Ali G and Fedotov, Alexander and Bi, Weimin and Leduc, Magalie S and Murdock, David R and Jiang, Yunyun and Meng, Linyan and Eng, Christine M and Wen, Shu and Yang, Yaping and Muzny, Donna M and Boerwinkle, Eric and Salerno, William and Venner, Eric and Gibbs, Richard A} } @article {37, title = {Accurate detection of complex structural variations using single-molecule sequencing.}, journal = {Nat Methods}, volume = {15}, year = {2018}, month = {2018 06}, pages = {461-468}, abstract = {

Structural variations are the greatest source of genetic variation, but they remain poorly understood because of technological limitations. Single-molecule long-read sequencing has the potential to dramatically advance the field, although high error rates are a challenge with existing methods. Addressing this need, we introduce open-source methods for long-read alignment (NGMLR; https://github.com/philres/ngmlr ) and structural variant identification (Sniffles; https://github.com/fritzsedlazeck/Sniffles ) that provide unprecedented sensitivity and precision for variant detection, even in repeat-rich regions and for complex nested events that can have substantial effects on human health. In several long-read datasets, including healthy and cancerous human genomes, we discovered thousands of novel variants and categorized systematic errors in short-read approaches. NGMLR and Sniffles can automatically filter false events and operate on low-coverage data, thereby reducing the high costs that have hindered the application of long reads in clinical and research settings.

}, keywords = {DNA Mutational Analysis, Genome, Human, Genomics, High-Throughput Nucleotide Sequencing, Humans, Sequence Analysis, DNA}, issn = {1548-7105}, doi = {10.1038/s41592-018-0001-7}, author = {Sedlazeck, Fritz J and Rescheneder, Philipp and Smolka, Moritz and Fang, Han and Nattestad, Maria and von Haeseler, Arndt and Schatz, Michael C} } @article {38, title = {Analysis of predicted loss-of-function variants in UK Biobank identifies variants protective for disease.}, journal = {Nat Commun}, volume = {9}, year = {2018}, month = {2018 04 24}, pages = {1613}, abstract = {

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.

}, keywords = {Databases, Genetic, Diabetes Mellitus, Type 2, Disease, Gene Frequency, Genetic Testing, Genetic Variation, Humans, Obesity, Phenotype, Proteins, Respiratory Hypersensitivity, United Kingdom}, issn = {2041-1723}, doi = {10.1038/s41467-018-03911-8}, author = {Emdin, Connor A and Khera, Amit V and Chaffin, Mark and Klarin, Derek and Natarajan, Pradeep and Aragam, Krishna and Haas, Mary and Bick, Alexander and Zekavat, Seyedeh M and Nomura, Akihiro and Ardissino, Diego and Wilson, James G and Schunkert, Heribert and McPherson, Ruth and Watkins, Hugh and Elosua, Roberto and Bown, Matthew J and Samani, Nilesh J and Baber, Usman and Erdmann, Jeanette and Gupta, Namrata and Danesh, John and Chasman, Daniel and Ridker, Paul and Denny, Joshua and Bastarache, Lisa and Lichtman, Judith H and D{\textquoteright}Onofrio, Gail and Mattera, Jennifer and Spertus, John A and Sheu, Wayne H-H and Taylor, Kent D and Psaty, Bruce M and Rich, Stephen S and Post, Wendy and Rotter, Jerome I and Chen, Yii-Der Ida and Krumholz, Harlan and Saleheen, Danish and Gabriel, Stacey and Kathiresan, Sekar} } @article {12, title = {ANGPTL3 Deficiency and Protection Against Coronary Artery Disease.}, journal = {J Am Coll Cardiol}, volume = {69}, year = {2017}, month = {2017 Apr 25}, pages = {2054-2063}, abstract = {

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.

}, keywords = {Adult, Angiopoietin-Like Protein 3, Angiopoietin-like Proteins, Angiopoietins, Animals, Atherosclerosis, Case-Control Studies, Coronary Artery Disease, Female, Humans, Lipids, Male, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Mutation, Missense, Myocardial Infarction, Risk Factors}, issn = {1558-3597}, doi = {10.1016/j.jacc.2017.02.030}, author = {Stitziel, Nathan O and Khera, Amit V and Wang, Xiao and Bierhals, Andrew J and Vourakis, A Christina and Sperry, Alexandra E and Natarajan, Pradeep and Klarin, Derek and Emdin, Connor A and Zekavat, Seyedeh M and Nomura, Akihiro and Erdmann, Jeanette and Schunkert, Heribert and Samani, Nilesh J and Kraus, William E and Shah, Svati H and Yu, Bing and Boerwinkle, Eric and Rader, Daniel J and Gupta, Namrata and Frossard, Philippe M and Rasheed, Asif and Danesh, John and Lander, Eric S and Gabriel, Stacey and Saleheen, Danish and Musunuru, Kiran and Kathiresan, Sekar} }