• Exploring the phenotypic consequences of tissue specific gene expression variation inferred from GWAS summary statistics

      Barbeira, AN; Dickinson, SP; Bonazzola, R; Zheng, J; Wheeler, HE; Torres, JM; Torstenson, ES; Shah, KP; Garcia, T; Edwards, TL; Stahl, EA; Huckins, LM; Aguet, F; Ardlie, KG; Cummings, BB; Gelfand, ET; Getz, G; Hadley, K; Handsaker, RE; Huang, KH; Kashin, S; Karczewski, KJ; Lek, M; Li, X; MacArthur, DG; Nedzel, JL; Nguyen, DT; Noble, MS; Segrè, AV; Trowbridge, CA; Tukiainen, T; Abell, NS; Balliu, B; Barshir, R; Basha, O; Battle, A; Bogu, GK; Brown, A; Brown, CD; Castel, SE; Chen, LS; Chiang, C; Conrad, DF; Damani, FN; Davis, JR; Delaneau, O; Dermitzakis, ET; Engelhardt, BE; Eskin, E; Ferreira, PG; Frésard, L; Gamazon, ER; Garrido-Martín, D; Gewirtz, ADH; Gliner, G; Gloudemans, MJ; Guigo, R; Hall, IM; Han, B; He, Y; Hormozdiari, F; Howald, C; Jo, B; Kang, EY; Kim, Y; Kim-Hellmuth, S; Lappalainen, T; Li, G; Li, X; Liu, B; Mangul, S; McCarthy, MI; McDowell, IC; Mohammadi, P; Monlong, J; Montgomery, SB; Muñoz-Aguirre, M; Ndungu, AW; Nobel, AB; Oliva, M; Ongen, H; Palowitch, JJ; Panousis, N; Papasaikas, P; Park, YS; Parsana, P; Payne, AJ; Peterson, CB; Quan, J; Reverter, F; Sabatti, C; Saha, A; Sammeth, M; Scott, AJ; Shabalin, AA; Sodaei, R; Stephens, M; Stranger, BE; Strober, BJ; Sul, JH; Gardiner, Heather Marie|0000-0003-2017-991X; Siminoff, Laura|0000-0002-6775-665X (2018-12-01)
      © 2018 The Author(s). Scalable, integrative methods to understand mechanisms that link genetic variants with phenotypes are needed. Here we derive a mathematical expression to compute PrediXcan (a gene mapping approach) results using summary data (S-PrediXcan) and show its accuracy and general robustness to misspecified reference sets. We apply this framework to 44 GTEx tissues and 100+ phenotypes from GWAS and meta-analysis studies, creating a growing public catalog of associations that seeks to capture the effects of gene expression variation on human phenotypes. Replication in an independent cohort is shown. Most of the associations are tissue specific, suggesting context specificity of the trait etiology. Colocalized significant associations in unexpected tissues underscore the need for an agnostic scanning of multiple contexts to improve our ability to detect causal regulatory mechanisms. Monogenic disease genes are enriched among significant associations for related traits, suggesting that smaller alterations of these genes may cause a spectrum of milder phenotypes.
    • Genetic effects on gene expression across human tissues

      Aguet, F; Brown, AA; Castel, SE; Davis, JR; He, Y; Jo, B; Mohammadi, P; Park, YS; Parsana, P; Segrè, AV; Strober, BJ; Zappala, Z; Cummings, BB; Gelfand, ET; Hadley, K; Huang, KH; Lek, M; Li, X; Nedzel, JL; Nguyen, DY; Noble, MS; Sullivan, TJ; Tukiainen, T; MacArthur, DG; Getz, G; Addington, A; Guan, P; Koester, S; Little, AR; Lockhart, NC; Moore, HM; Rao, A; Struewing, JP; Volpi, S; Brigham, LE; Hasz, R; Hunter, M; Johns, C; Johnson, M; Kopen, G; Leinweber, WF; Lonsdale, JT; McDonald, A; Mestichelli, B; Myer, K; Roe, B; Salvatore, M; Shad, S; Thomas, JA; Walters, G; Washington, M; Wheeler, J; Bridge, J; Foster, BA; Gillard, BM; Karasik, E; Kumar, R; Miklos, M; Moser, MT; Jewell, SD; Montroy, RG; Rohrer, DC; Valley, D; Mash, DC; Davis, DA; Sobin, L; Barcus, ME; Branton, PA; Abell, NS; Balliu, B; Delaneau, O; Frésard, L; Gamazon, ER; Garrido-Martín, D; Gewirtz, ADH; Gliner, G; Gloudemans, MJ; Han, B; He, AZ; Hormozdiari, F; Li, X; Liu, B; Kang, EY; McDowell, IC; Ongen, H; Palowitch, JJ; Peterson, CB; Quon, G; Ripke, S; Saha, A; Shabalin, AA; Shimko, TC; Sul, JH; Teran, NA; Tsang, EK; Zhang, H; Zhou, YH; Bustamante, CD; Cox, NJ; Guigó, R; Siminoff, Laura|0000-0002-6775-665X; Gardiner, Heather Marie|0000-0003-2017-991X (2017-10-11)
      © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. 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.