A unified framework for joint-tissue transcriptome-wide association and Mendelian randomization analysis.

TitleA unified framework for joint-tissue transcriptome-wide association and Mendelian randomization analysis.
Publication TypeJournal Article
Year of Publication2020
AuthorsZhou, D, Jiang, Y, Zhong, X, Cox, NJ, Liu, C, Gamazon, ER
JournalNat Genet
Volume52
Issue11
Pagination1239-1246
Date Published2020 11
ISSN1546-1718
KeywordsAnimals, Gene Expression Profiling, Genetic Association Studies, Humans, Lipoproteins, LDL, Mendelian Randomization Analysis, Mice, Models, Genetic, Multifactorial Inheritance, Predictive Value of Tests
Abstract

Here, we present a joint-tissue imputation (JTI) approach and a Mendelian randomization framework for causal inference, MR-JTI. JTI borrows information across transcriptomes of different tissues, leveraging shared genetic regulation, to improve prediction performance in a tissue-dependent manner. Notably, JTI includes the single-tissue imputation method PrediXcan as a special case and outperforms other single-tissue approaches (the Bayesian sparse linear mixed model and Dirichlet process regression). MR-JTI models variant-level heterogeneity (primarily due to horizontal pleiotropy, addressing a major challenge of transcriptome-wide association study interpretation) and performs causal inference with type I error control. We make explicit the connection between the genetic architecture of gene expression and of complex traits and the suitability of Mendelian randomization as a causal inference strategy for transcriptome-wide association studies. We provide a resource of imputation models generated from GTEx and PsychENCODE panels. Analysis of biobanks and meta-analysis data, and extensive simulations show substantially improved statistical power, replication and causal mapping rate for JTI relative to existing approaches.

DOI10.1038/s41588-020-0706-2
Alternate JournalNat Genet
PubMed ID33020666
PubMed Central IDPMC7606598
Grant ListUL1 TR000445 / TR / NCATS NIH HHS / United States
R01 HG011138 / HG / NHGRI NIH HHS / United States
S10 RR025141 / RR / NCRR NIH HHS / United States
U01 MH103340 / MH / NIMH NIH HHS / United States
R01 HD074711 / HD / NICHD NIH HHS / United States
RC2 GM092618 / GM / NIGMS NIH HHS / United States
U01 HG006378 / HG / NHGRI NIH HHS / United States
U01 HG009086 / HG / NHGRI NIH HHS / United States
R01 MH113362 / MH / NIMH NIH HHS / United States
R35 HG010718 / HG / NHGRI NIH HHS / United States
U01 MH116489 / MH / NIMH NIH HHS / United States
U19 HL065962 / HL / NHLBI NIH HHS / United States
R01 MH110920 / MH / NIMH NIH HHS / United States
P50 GM115305 / GM / NIGMS NIH HHS / United States
UL1 RR024975 / RR / NCRR NIH HHS / United States
R01 NS032830 / NS / NINDS NIH HHS / United States
U01 HG004798 / HG / NHGRI NIH HHS / United States
UL1 TR002243 / TR / NCATS NIH HHS / United States