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Journal ArticleDOI

Synthesis of 53 tissue and cell line expression QTL datasets reveals master eQTLs

TL;DR: Analysis of 45 full human GWAS scans indicates eQTLs are enriched overall, and above nSNPs, among positive statistical signals in genetic mapping studies, and account for a significant fraction of the strongest human trait effects.
Abstract: Gene expression genetic studies in human tissues and cells identify cis- and trans-acting expression quantitative trait loci (eQTLs). These eQTLs provide insights into regulatory mechanisms underlying disease risk. However, few studies systematically characterized eQTL results across cell and tissues types. We synthesized eQTL results from >50 datasets, including new primary data from human brain, peripheral plaque and kidney samples, in order to discover features of human eQTLs. We find a substantial number of robust cis-eQTLs and far fewer trans-eQTLs consistent across tissues. Analysis of 45 full human GWAS scans indicates eQTLs are enriched overall, and above nSNPs, among positive statistical signals in genetic mapping studies, and account for a significant fraction of the strongest human trait effects. Expression QTLs are enriched for gene centricity, higher population allele frequencies, in housekeeping genes, and for coincidence with regulatory features, though there is little evidence of 5′ or 3′ positional bias. Several regulatory categories are not enriched including microRNAs and their predicted binding sites and long, intergenic non-coding RNAs. Among the most tissue-ubiquitous cis-eQTLs, there is enrichment for genes involved in xenobiotic metabolism and mitochondrial function, suggesting these eQTLs may have adaptive origins. Several strong eQTLs (CDK5RAP2, NBPFs) coincide with regions of reported human lineage selection. The intersection of new kidney and plaque eQTLs with related GWAS suggest possible gene prioritization. For example, butyrophilins are now linked to arterial pathogenesis via multiple genetic and expression studies. Expression QTL and GWAS results are made available as a community resource through the NHLBI GRASP database [ http://apps.nhlbi.nih.gov/grasp/ ]. Expression QTLs inform the interpretation of human trait variability, and may account for a greater fraction of phenotypic variability than protein-coding variants. The synthesis of available tissue eQTL data highlights many strong cis-eQTLs that may have important biologic roles and could serve as positive controls in future studies. Our results indicate some strong tissue-ubiquitous eQTLs may have adaptive origins in humans. Efforts to expand the genetic, splicing and tissue coverage of known eQTLs will provide further insights into human gene regulation.

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Citations
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Journal ArticleDOI
TL;DR: Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer’s disease but also with LOAD.
Abstract: Risk for late-onset Alzheimer’s disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer’s or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and Aβ processing are associated not only with early-onset autosomal dominant Alzheimer’s disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.

1,641 citations

Journal ArticleDOI
TL;DR: The findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.
Abstract: Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.

421 citations

Journal ArticleDOI
TL;DR: A dual strategy to identify common and low-frequency protein-coding variation associated with age at natural menopause and enrichment of signals in or near genes involved in delayed puberty are reported, highlighting the first molecular links between the onset and end of reproductive lifespan.
Abstract: Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

316 citations

Journal ArticleDOI
Mariaelisa Graff1, Robert A. Scott2, Anne E. Justice1, Kristin L. Young1  +346 moreInstitutions (101)
TL;DR: In additional genome-wide meta-analyses adjusting for PA and interaction with PA, 11 novel adiposity loci are identified, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
Abstract: Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.

275 citations


Cites methods from "Synthesis of 53 tissue and cell lin..."

  • ...We examined the cis-associations of the novel BMI, WCadjBMI or WHRadjBMI loci with the expression of nearby genes from various tissues by performing a look-up in a library of>100 published expression datasets, as described previously by Zhang et al [48]....

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  • ...We examined the cis-associations of the novel BMI, WCadjBMI or WHRadjBMI loci with the expression of nearby genes from various tissues by performing a look-up in a library of>100 published expression datasets, as described previously by Zhang et al [48]....

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Journal ArticleDOI
TL;DR: Using multiple blood pressure measurements in GERA doubled the variance explained, and expression quantitative trait locus analysis of blood pressure loci showed enrichment in aorta and tibial artery.
Abstract: Longitudinal electronic health records on 99,785 Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort individuals provided 1,342,814 systolic and diastolic blood pressure measurements for a genome-wide association study on long-term average systolic, diastolic, and pulse pressure. We identified 39 new loci among 75 genome-wide significant loci (P ≤ 5 × 10-8), with most replicating in the combined International Consortium for Blood Pressure (ICBP; n = 69,396) and UK Biobank (UKB; n = 152,081) studies. Combining GERA with ICBP yielded 36 additional new loci, with most replicating in UKB. Combining all three studies (n = 321,262) yielded 241 additional genome-wide significant loci, although no replication sample was available for these. All associated loci explained 2.9%, 2.5%, and 3.1% of variation in systolic, diastolic, and pulse pressure, respectively, in GERA non-Hispanic whites. Using multiple blood pressure measurements in GERA doubled the variance explained. A normalized risk score was associated with time to onset of hypertension (hazards ratio = 1.18, P = 8.2 × 10-45). Expression quantitative trait locus analysis of blood pressure loci showed enrichment in aorta and tibial artery.

265 citations

References
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Journal ArticleDOI
TL;DR: Details of the aims and methods of Bioconductor, the collaborative creation of extensible software for computational biology and bioinformatics, and current challenges are described.
Abstract: The Bioconductor project is an initiative for the collaborative creation of extensible software for computational biology and bioinformatics. The goals of the project include: fostering collaborative development and widespread use of innovative software, reducing barriers to entry into interdisciplinary scientific research, and promoting the achievement of remote reproducibility of research results. We describe details of our aims and methods, identify current challenges, compare Bioconductor to other open bioinformatics projects, and provide working examples.

12,142 citations


"Synthesis of 53 tissue and cell lin..." refers methods in this paper

  • ...Data were retrieved using the biomaRt package [87], available through the Bioconductor repository [88]....

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Journal ArticleDOI
Paul Burton1, David Clayton2, Lon R. Cardon, Nicholas John Craddock3  +192 moreInstitutions (4)
07 Jun 2007-Nature
TL;DR: This study has demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in theBritish population is generally modest.
Abstract: There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

9,244 citations

Journal ArticleDOI
TL;DR: How BLAT was optimized is described, which is more accurate and 500 times faster than popular existing tools for mRNA/DNA alignments and 50 times faster for protein alignments at sensitivity settings typically used when comparing vertebrate sequences.
Abstract: Analyzing vertebrate genomes requires rapid mRNA/DNA and cross-species protein alignments A new tool, BLAT, is more accurate and 500 times faster than popular existing tools for mRNA/DNA alignments and 50 times faster for protein alignments at sensitivity settings typically used when comparing vertebrate sequences BLAT's speed stems from an index of all nonoverlapping K-mers in the genome This index fits inside the RAM of inexpensive computers, and need only be computed once for each genome assembly BLAT has several major stages It uses the index to find regions in the genome likely to be homologous to the query sequence It performs an alignment between homologous regions It stitches together these aligned regions (often exons) into larger alignments (typically genes) Finally, BLAT revisits small internal exons possibly missed at the first stage and adjusts large gap boundaries that have canonical splice sites where feasible This paper describes how BLAT was optimized Effects on speed and sensitivity are explored for various K-mer sizes, mismatch schemes, and number of required index matches BLAT is compared with other alignment programs on various test sets and then used in several genome-wide applications http://genomeucscedu hosts a web-based BLAT server for the human genome

8,326 citations


"Synthesis of 53 tissue and cell lin..." refers methods in this paper

  • ...However, BLAT analysis [49] revealed that the chr4 and chr7 transcripts map with 83....

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Journal ArticleDOI
John T. Lonsdale, Jeffrey Thomas, Mike Salvatore, Rebecca Phillips, Edmund Lo, Saboor Shad, Richard Hasz, Gary Walters, Fernando U. Garcia1, Nancy Young2, Barbara A. Foster3, Mike Moser3, Ellen Karasik3, Bryan Gillard3, Kimberley Ramsey3, Susan L. Sullivan, Jason Bridge, Harold Magazine, John Syron, Johnelle Fleming, Laura A. Siminoff4, Heather M. Traino4, Maghboeba Mosavel4, Laura Barker4, Scott D. Jewell5, Daniel C. Rohrer5, Dan Maxim5, Dana Filkins5, Philip Harbach5, Eddie Cortadillo5, Bree Berghuis5, Lisa Turner5, Eric Hudson5, Kristin Feenstra5, Leslie H. Sobin6, James A. Robb6, Phillip Branton, Greg E. Korzeniewski6, Charles Shive6, David Tabor6, Liqun Qi6, Kevin Groch6, Sreenath Nampally6, Steve Buia6, Angela Zimmerman6, Anna M. Smith6, Robin Burges6, Karna Robinson6, Kim Valentino6, Deborah Bradbury6, Mark Cosentino6, Norma Diaz-Mayoral6, Mary Kennedy6, Theresa Engel6, Penelope Williams6, Kenyon Erickson, Kristin G. Ardlie7, Wendy Winckler7, Gad Getz7, Gad Getz8, David S. DeLuca7, MacArthur Daniel MacArthur7, MacArthur Daniel MacArthur8, Manolis Kellis7, Alexander Thomson7, Taylor Young7, Ellen Gelfand7, Molly Donovan7, Yan Meng7, George B. Grant7, Deborah C. Mash9, Yvonne Marcus9, Margaret J. Basile9, Jun Liu8, Jun Zhu10, Zhidong Tu10, Nancy J. Cox11, Dan L. Nicolae11, Eric R. Gamazon11, Hae Kyung Im11, Anuar Konkashbaev11, Jonathan K. Pritchard12, Jonathan K. Pritchard11, Matthew Stevens11, Timothée Flutre11, Xiaoquan Wen11, Emmanouil T. Dermitzakis13, Tuuli Lappalainen13, Roderic Guigó, Jean Monlong, Michael Sammeth, Daphne Koller14, Alexis Battle14, Sara Mostafavi14, Mark I. McCarthy15, Manual Rivas15, Julian Maller15, Ivan Rusyn16, Andrew B. Nobel16, Fred A. Wright16, Andrey A. Shabalin16, Mike Feolo17, Nataliya Sharopova17, Anne Sturcke17, Justin Paschal17, James M. Anderson17, Elizabeth L. Wilder17, Leslie Derr17, Eric D. Green17, Jeffery P. Struewing17, Gary F. Temple17, Simona Volpi17, Joy T. Boyer17, Elizabeth J. Thomson17, Mark S. Guyer17, Cathy Ng17, Assya Abdallah17, Deborah Colantuoni17, Thomas R. Insel17, Susan E. Koester17, Roger Little17, Patrick Bender17, Thomas Lehner17, Yin Yao17, Carolyn C. Compton17, Jimmie B. Vaught17, Sherilyn Sawyer17, Nicole C. Lockhart17, Joanne P. Demchok17, Helen F. Moore17 
TL;DR: The Genotype-Tissue Expression (GTEx) project is described, which will establish a resource database and associated tissue bank for the scientific community to study the relationship between genetic variation and gene expression in human tissues.
Abstract: Genome-wide association studies have identified thousands of loci for common diseases, but, for the majority of these, the mechanisms underlying disease susceptibility remain unknown. Most associated variants are not correlated with protein-coding changes, suggesting that polymorphisms in regulatory regions probably contribute to many disease phenotypes. Here we describe the Genotype-Tissue Expression (GTEx) project, which will establish a resource database and associated tissue bank for the scientific community to study the relationship between genetic variation and gene expression in human tissues.

6,545 citations

Journal ArticleDOI
05 Aug 2010-Nature
TL;DR: The results identify several novel loci associated with plasma lipids that are also associated with CAD and provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
Abstract: Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.

3,469 citations


"Synthesis of 53 tissue and cell lin..." refers background in this paper

  • ...Strong eQTLs are often highly correlated with markers of disease and quantitative traits at loci identified in GWAS [8-13], suggesting that these eQTLs account for a significant fraction of human phenotypic variability....

    [...]

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John T. Lonsdale, Jeffrey Thomas, Mike Salvatore, Rebecca Phillips, Edmund Lo, Saboor Shad, Richard Hasz, Gary Walters, Fernando U. Garcia, Nancy Young, Barbara A. Foster, Mike Moser, Ellen Karasik, Bryan Gillard, Kimberley Ramsey, Susan L. Sullivan, Jason Bridge, Harold Magazine, John Syron, Johnelle Fleming, Laura A. Siminoff, Heather M. Traino, Maghboeba Mosavel, Laura Barker, Scott D. Jewell, Daniel C. Rohrer, Dan Maxim, Dana Filkins, Philip Harbach, Eddie Cortadillo, Bree Berghuis, Lisa Turner, Eric Hudson, Kristin Feenstra, Leslie H. Sobin, James A. Robb, Phillip Branton, Greg E. Korzeniewski, Charles Shive, David Tabor, Liqun Qi, Kevin Groch, Sreenath Nampally, Steve Buia, Angela Zimmerman, Anna M. Smith, Robin Burges, Karna Robinson, Kim Valentino, Deborah Bradbury, Mark Cosentino, Norma Diaz-Mayoral, Mary Kennedy, Theresa Engel, Penelope Williams, Kenyon Erickson, Kristin G. Ardlie, Wendy Winckler, Gad Getz, Gad Getz, David S. DeLuca, MacArthur Daniel MacArthur, MacArthur Daniel MacArthur, Manolis Kellis, Alexander Thomson, Taylor Young, Ellen Gelfand, Molly Donovan, Yan Meng, George B. Grant, Deborah C. Mash, Yvonne Marcus, Margaret J. Basile, Jun Liu, Jun Zhu, Zhidong Tu, Nancy J. Cox, Dan L. Nicolae, Eric R. Gamazon, Hae Kyung Im, Anuar Konkashbaev, Jonathan K. Pritchard, Jonathan K. Pritchard, Matthew Stevens, Timothée Flutre, Xiaoquan Wen, Emmanouil T. Dermitzakis, Tuuli Lappalainen, Roderic Guigó, Jean Monlong, Michael Sammeth, Daphne Koller, Alexis Battle, Sara Mostafavi, Mark I. McCarthy, Manual Rivas, Julian Maller, Ivan Rusyn, Andrew B. Nobel, Fred A. Wright, Andrey A. Shabalin, Mike Feolo, Nataliya Sharopova, Anne Sturcke, Justin Paschal, James M. Anderson, Elizabeth L. Wilder, Leslie Derr, Eric D. Green, Jeffery P. Struewing, Gary F. Temple, Simona Volpi, Joy T. Boyer, Elizabeth J. Thomson, Mark S. Guyer, Cathy Ng, Assya Abdallah, Deborah Colantuoni, Thomas R. Insel, Susan E. Koester, Roger Little, Patrick Bender, Thomas Lehner, Yin Yao, Carolyn C. Compton, Jimmie B. Vaught, Sherilyn Sawyer, Nicole C. Lockhart, Joanne P. Demchok, Helen F. Moore