A Multi-tissue Transcriptome Analysis of Human Metabolites Guides Interpretability of Associations Based on Multi-SNP Models for Gene Expression

Anne Ndungu; Anthony Payne; Jason M Torres; Martijn van de Bunt; Mark I McCarthy

doi:10.1016/j.ajhg.2020.01.003

A Multi-tissue Transcriptome Analysis of Human Metabolites Guides Interpretability of Associations Based on Multi-SNP Models for Gene Expression

Am J Hum Genet. 2020 Feb 6;106(2):188-201. doi: 10.1016/j.ajhg.2020.01.003. Epub 2020 Jan 23.

Authors

Anne Ndungu¹, Anthony Payne¹, Jason M Torres¹, Martijn van de Bunt², Mark I McCarthy³

Affiliations

¹ The Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK.
² The Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7LE, UK; Department of Bioinformatics and Data Mining, Novo Nordisk A/S, Måløv, 2760, DK.
³ The Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7BN, UK; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, OX3 7LE, UK. Electronic address: mccarthy.mark@gene.com.

Abstract

There is particular interest in transcriptome-wide association studies (TWAS) gene-level tests based on multi-SNP predictive models of gene expression-for identifying causal genes at loci associated with complex traits. However, interpretation of TWAS associations may be complicated by divergent effects of model SNPs on phenotype and gene expression. We developed an iterative modeling scheme for obtaining multi-SNP models of gene expression and applied this framework to generate expression models for 43 human tissues from the Genotype-Tissue Expression (GTEx) Project. We characterized the performance of single- and multi-SNP models for identifying causal genes in GWAS data for 46 circulating metabolites. We show that: (A) multi-SNP models captured more variation in expression than did the top cis-eQTL (median 2-fold improvement); (B) predicted expression based on multi-SNP models was associated (false discovery rate < 0.01) with metabolite levels for 826 unique gene-metabolite pairs, but, after stepwise conditional analyses, 90% were dominated by a single eQTL SNP; (C) among the 35% of associations where a SNP in the expression model was a significant cis-eQTL and metabolomic-QTL (met-QTL), 92% demonstrated colocalization between these signals, but interpretation was often complicated by incomplete overlap of QTLs in multi-SNP models; and (D) using a "truth" set of causal genes at 61 met-QTLs, the sensitivity was high (67%), but the positive predictive value was low, as only 8% of TWAS associations (19% when restricted to colocalized associations at met-QTLs) involved true causal genes. These results guide the interpretation of TWAS and highlight the need for corroborative data to provide confident assignment of causality.

Keywords: GWAS; S-PrediXcan; TWAS; colocalization; eQTLs; gene expression; gene regulation; metabolites; multi-tissue GTEx; transcriptome wide association studies.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Gene Expression Regulation*
Genetic Predisposition to Disease*
Genome-Wide Association Study
Humans
Metabolome*
Models, Genetic*
Phenotype
Polymorphism, Single Nucleotide*
Quantitative Trait Loci*
Transcriptome*

Abstract

Publication types

MeSH terms

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