Exploiting the GTEx resources to decipher the mechanisms at GWAS loci

被引：167

作者：

Barbeira, Alvaro N. ^{[1
]}

Bonazzola, Rodrigo ^{[1
]}

Gamazon, Eric R. ^{[2
,3
,4
,5
]}

Liang, Yanyu ^{[1
]}

Park, YoSon ^{[6
,7
]}

Kim-Hellmuth, Sarah ^{[8
,9
,10
]}

Wang, Gao ^{[11
]}

Jiang, Zhuoxun ^{[1
]}

Zhou, Dan ^{[2
]}

Hormozdiari, Farhad ^{[12
,13
]}

Liu, Boxiang ^{[14
]}

Rao, Abhiram ^{[14
]}

Hamel, Andrew R. ^{[12
,15
]}

Pividori, Milton D. ^{[1
]}

Aguet, Francois ^{[12
]}

Bastarache, Lisa ^{[16
,17
]}

Jordan, Daniel M. ^{[18
,19
,20
]}

Verbanck, Marie ^{[18
,19
,20
,21
]}

Do, Ron ^{[18
,19
,20
]}

Stephens, Matthew ^{[11
]}

Ardlie, Kristin ^{[12
]}

McCarthy, Mark ^{[22
]}

Montgomery, Stephen B. ^{[23
,24
]}

Segre, Ayellet V. ^{[12
,15
]}

Brown, Christopher D. ^{[6
]}

Lappalainen, Tuuli ^{[9
,10
]}

Wen, Xiaoquan ^{[25
]}

Im, Hae Kyung ^{[1
]}

机构：

[1] Univ Chicago, Dept Med, Med Genet Sect, 5841 S Maryland Ave, Chicago, IL 60637 USA

[2] Vanderbilt Univ, Med Ctr, Dept Med, Div Med Genet, Nashville, TN USA

[3] Vanderbilt Univ, Data Sci Inst, 221 Kirkland Hall, Nashville, TN 37235 USA

[4] Univ Cambridge, Clare Hall, Cambridge, England

[5] Univ Cambridge, MRC Epidemiol Unit, Cambridge, England

[6] Univ Penn, Dept Genet, Perelman Sch Med, Philadelphia, PA 19104 USA

[7] Univ Penn, Dept Syst Pharmacol & Translat Therapeut, Perelman Sch Med, Philadelphia, PA 19104 USA

[8] Max Planck Inst Psychiat, Stat Genet, Munich, Germany

[9] New York Genome Ctr, New York, NY USA

[10] Columbia Univ, Dept Syst Biol, New York, NY USA

[11] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA

[12] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[13] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[14] Stanford Univ, Dept Biol, Stanford, CA 94305 USA

[15] Harvard Med Sch, Massachusetts Eye & Ear, Ocular Genom Inst, Boston, MA 02115 USA

[16] Vanderbilt Univ, Dept Med, Dept Biomed Informat, Nashville, TN USA

[17] Vanderbilt Univ, Dept Mol Physiol & Biophys, Sch Med, Ctr Human Genet Res, Nashville, TN 37232 USA

[18] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA

[19] Icahn Sch Med Mt Sinai, Inst Genom & Multiscale Biol, New York, NY 10029 USA

[20] Icahn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY 10029 USA

[21] Univ Paris EA 7537 BIOSTM, Paris, France

[22] Univ Oxford, Oxford, England

[23] Stanford Univ, Dept Genet, Stanford, CA 94305 USA

[24] Stanford Univ, Dept Pathol, Stanford, CA 94305 USA

[25] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA

来源：

GENOME BIOLOGY | 2021年 / 22卷 / 01期

基金：

欧盟地平线“2020”;

关键词：

GENETIC-VARIATION; WIDE ASSOCIATION; APOLIPOPROTEIN-B; DISEASE; CHOLESTEROL; ABCG8; EQTL; COLOCALIZATION; ARCHITECTURE; INTEGRATION;

D O I：

10.1186/s13059-020-02252-4

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 [微生物学]; 090105 [作物生产系统与生态工程];

摘要：

The resources generated by the GTEx consortium offer unprecedented opportunities to advance our understanding of the biology of human diseases. Here, we present an in-depth examination of the phenotypic consequences of transcriptome regulation and a blueprint for the functional interpretation of genome-wide association study-discovered loci. Across a broad set of complex traits and diseases, we demonstrate widespread dose-dependent effects of RNA expression and splicing. We develop a data-driven framework to benchmark methods that prioritize causal genes and find no single approach outperforms the combination of multiple approaches. Using colocalization and association approaches that take into account the observed allelic heterogeneity of gene expression, we propose potential target genes for 47% (2519 out of 5385) of the GWAS loci examined.

引用

页数：24

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