Functionally oriented analysis of cardiometabolic traits in a trans-ethnic sample

• Published in: Human molecular genetics Vol. 28; no. 7; pp. 1212 - 1224
• Main Authors: Petty, Lauren E, Highland, Heather M, Gamazon, Eric R, Hu, Hao, Karhade, Mandar, Chen, Hung-Hsin, de Vries, Paul S, Grove, Megan L, Aguilar, David, Bell, Graeme I, Huff, Chad D, Hanis, Craig L, Doddapaneni, HarshaVardhan, Munzy, Donna M, Gibbs, Richard A, Ma, Jianzhong, Parra, Esteban J, Cruz, Miguel, Valladares-Salgado, Adan, Arking, Dan E, Barbeira, Alvaro, Im, Hae Kyung, Morrison, Alanna C, Boerwinkle, Eric, Below, Jennifer E
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-04-2019
• Subjects: Adult; Aged; Association Studies; Blood Pressure; Body Mass Index; Chromosome Mapping - methods; Ethnic Groups - genetics; European Continental Ancestry Group - genetics; Female; Forecasting - methods; Genetic Association Studies - methods; Genome-Wide Association Study - methods; Humans; Male; Metabolome - genetics; Metabolome - physiology; Middle Aged; Multifactorial Inheritance - genetics; Phenotype; Polymorphism, Single Nucleotide - genetics; Transcriptome - genetics
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/ddy435

Abstract
Interpretation of genetic association results is difficult because signals often lack biological context. To generate hypotheses of the functional genetic etiology of complex cardiometabolic traits, we estimated the genetically determined component of gene expression from common variants using PrediXcan (1) and determined genes with differential predicted expression by trait. PrediXcan imputes tissue-specific expression levels from genetic variation using variant-level effect on gene expression in transcriptome data. To explore the value of imputed genetically regulated gene expression (GReX) models across different ancestral populations, we evaluated imputed expression levels for predictive accuracy genome-wide in RNA sequence data in samples drawn from European-ancestry and African-ancestry populations and identified substantial predictive power using European-derived models in a non-European target population. We then tested the association of GReX on 15 cardiometabolic traits including blood lipid levels, body mass index, height, blood pressure, fasting glucose and insulin, RR interval, fibrinogen level, factor VII level and white blood cell and platelet counts in 15 755 individuals across three ancestry groups, resulting in 20 novel gene-phenotype associations reaching experiment-wide significance across ancestries. In addition, we identified 18 significant novel gene-phenotype associations in our ancestry-specific analyses. Top associations were assessed for additional support via query of S-PrediXcan (2) results derived from publicly available genome-wide association studies summary data. Collectively, these findings illustrate the utility of transcriptome-based imputation models for discovery of cardiometabolic effect genes in a diverse dataset.