%0 Journal Article %J Science %D 2020 %T Cell type-specific genetic regulation of gene expression across human tissues. %A Kim-Hellmuth, Sarah %A Aguet, François %A Oliva, Meritxell %A Muñoz-Aguirre, Manuel %A Kasela, Silva %A Wucher, Valentin %A Castel, Stephane E %A Hamel, Andrew R %A Viñuela, Ana %A Roberts, Amy L %A Mangul, Serghei %A Wen, Xiaoquan %A Wang, Gao %A Barbeira, Alvaro N %A Garrido-Martín, Diego %A Nadel, Brian B %A Zou, Yuxin %A Bonazzola, Rodrigo %A Quan, Jie %A Brown, Andrew %A Martinez-Perez, Angel %A Soria, José Manuel %A Getz, Gad %A Dermitzakis, Emmanouil T %A Small, Kerrin S %A Stephens, Matthew %A Xi, Hualin S %A Im, Hae Kyung %A Guigo, Roderic %A Segrè, Ayellet V %A Stranger, Barbara E %A Ardlie, Kristin G %A Lappalainen, Tuuli %K Cells %K Gene Expression Regulation %K Humans %K Organ Specificity %K Quantitative Trait Loci %K RNA, Long Noncoding %K Transcriptome %X

The Genotype-Tissue Expression (GTEx) project has identified expression and splicing quantitative trait loci in cis (QTLs) for the majority of genes across a wide range of human tissues. However, the functional characterization of these QTLs has been limited by the heterogeneous cellular composition of GTEx tissue samples. We mapped interactions between computational estimates of cell type abundance and genotype to identify cell type-interaction QTLs for seven cell types and show that cell type-interaction expression QTLs (eQTLs) provide finer resolution to tissue specificity than bulk tissue cis-eQTLs. Analyses of genetic associations with 87 complex traits show a contribution from cell type-interaction QTLs and enables the discovery of hundreds of previously unidentified colocalized loci that are masked in bulk tissue.

%B Science %V 369 %8 2020 09 11 %G eng %N 6509 %1 https://www.ncbi.nlm.nih.gov/pubmed/32913075?dopt=Abstract %R 10.1126/science.aaz8528 %0 Journal Article %J Science %D 2020 %T Determinants of telomere length across human tissues. %A Demanelis, Kathryn %A Jasmine, Farzana %A Chen, Lin S %A Chernoff, Meytal %A Tong, Lin %A Delgado, Dayana %A Zhang, Chenan %A Shinkle, Justin %A Sabarinathan, Mekala %A Lin, Hannah %A Ramirez, Eduardo %A Oliva, Meritxell %A Kim-Hellmuth, Sarah %A Stranger, Barbara E %A Lai, Tsung-Po %A Aviv, Abraham %A Ardlie, Kristin G %A Aguet, François %A Ahsan, Habibul %A Doherty, Jennifer A %A Kibriya, Muhammad G %A Pierce, Brandon L %K Aging %K Genetic Markers %K Genetic Variation %K Humans %K Organ Specificity %K Telomere %K Telomere Homeostasis %K Telomere Shortening %X

Telomere shortening is a hallmark of aging. Telomere length (TL) in blood cells has been studied extensively as a biomarker of human aging and disease; however, little is known regarding variability in TL in nonblood, disease-relevant tissue types. Here, we characterize variability in TLs from 6391 tissue samples, representing >20 tissue types and 952 individuals from the Genotype-Tissue Expression (GTEx) project. We describe differences across tissue types, positive correlation among tissue types, and associations with age and ancestry. We show that genetic variation affects TL in multiple tissue types and that TL may mediate the effect of age on gene expression. Our results provide the foundational knowledge regarding TL in healthy tissues that is needed to interpret epidemiological studies of TL and human health.

%B Science %V 369 %8 2020 09 11 %G eng %N 6509 %1 https://www.ncbi.nlm.nih.gov/pubmed/32913074?dopt=Abstract %R 10.1126/science.aaz6876 %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 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 Genome Biol %D 2020 %T A vast resource of allelic expression data spanning human tissues. %A Castel, Stephane E %A Aguet, François %A Mohammadi, Pejman %A Ardlie, Kristin G %A Lappalainen, Tuuli %X

Allele expression (AE) analysis robustly measures cis-regulatory effects. Here, we present and demonstrate the utility of a vast AE resource generated from the GTEx v8 release, containing 15,253 samples spanning 54 human tissues for a total of 431 million measurements of AE at the SNP level and 153 million measurements at the haplotype level. In addition, we develop an extension of our tool phASER that allows effect sizes of cis-regulatory variants to be estimated using haplotype-level AE data. This AE resource is the largest to date, and we are able to make haplotype-level data publicly available. We anticipate that the availability of this resource will enable future studies of regulatory variation across human tissues.

%B Genome Biol %V 21 %P 234 %8 2020 09 11 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/32912332?dopt=Abstract %R 10.1186/s13059-020-02122-z %0 Journal Article %J Nat Genet %D 2018 %T Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk. %A Castel, Stephane E %A Cervera, Alejandra %A Mohammadi, Pejman %A Aguet, François %A Reverter, Ferran %A Wolman, Aaron %A Guigo, Roderic %A Iossifov, Ivan %A Vasileva, Ana %A Lappalainen, Tuuli %X

Coding variants represent many of the strongest associations between genotype and phenotype; however, they exhibit inter-individual differences in effect, termed 'variable penetrance'. Here, we study how cis-regulatory variation modifies the penetrance of coding variants. Using functional genomic and genetic data from the Genotype-Tissue Expression Project (GTEx), we observed that in the general population, purifying selection has depleted haplotype combinations predicted to increase pathogenic coding variant penetrance. Conversely, in cancer and autism patients, we observed an enrichment of penetrance increasing haplotype configurations for pathogenic variants in disease-implicated genes, providing evidence that regulatory haplotype configuration of coding variants affects disease risk. Finally, we experimentally validated this model by editing a Mendelian single-nucleotide polymorphism (SNP) using CRISPR/Cas9 on distinct expression haplotypes with the transcriptome as a phenotypic readout. Our results demonstrate that joint regulatory and coding variant effects are an important part of the genetic architecture of human traits and contribute to modified penetrance of disease-causing variants.

%B Nat Genet %V 50 %P 1327-1334 %8 2018 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/30127527?dopt=Abstract %R 10.1038/s41588-018-0192-y