A Multi-tissue Transcriptome Analysis of Human Metabolites Guides Interpretability of Associations Based on Multi-SNP Models for Gene Expression
Year: 2020
Type: article
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.
Authors: Anne Ndungu, Anthony Payne, Jason M. Torres, Martijn van de Bunt, Mark I. McCarthy
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,000
Funders: Wellcome Trust, National Institute for Health and Care Research, Rhodes Scholarships, University of Oxford, Novo Nordisk, Natural Sciences and Engineering Research Council of Canada, Biomedical Research Council, NIHR Oxford Biomedical Research Centre, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Large-scale data integration to advance mechanistic inference and precision medicine in type 2 diabetes, Characterising causal alleles for common disease., G3245635901, G3409889404, G3475606702, G3673804865, Identifying variants causal for Type 2 Diabetes in Major human populations, G4850436568, Integrating genome-scale data to reveal causal mechanisms in type 2 diabetes, G5657069725, Human Genetics and Disease Biology: Core Renewal for the Wellcome Trust Centre for Human Genetics, A systematic approach to understanding the biology underpinning GWAS hits., A systematic approach to understanding the biology underpinning GWAS hits., NIHR Senior Investigator Award, G8702410506, G8795285646
OpenAlex ID: W3000509948