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

Lauren E. Petty, Heather M. Highland, Eric R. Gamazon, Hao Hu, Mandar Karhade, Hung Hsin Chen, Paul S. De Vries, Megan L. Grove, David Aguilar, Graeme I. Bell, Chad D. Huff, Craig L. Hanis, Harshavardhan Doddapaneni, Donna M. Munzy, Richard A. Gibbs, Jianzhong Ma, Esteban J. Parra, Miguel Cruz, Adan Valladares-Salgado, Dan Arking & 5 others Alvaro Barbeira, Hae Kyung Im, Alanna C. Morrison, Eric Boerwinkle, Jennifer E. Below

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1212-1224
Number of pages13
JournalHuman molecular genetics
Volume28
Issue number7
DOIs
StatePublished - Jan 1 2019

Fingerprint

Gene Expression
Transcriptome
Genes
Phenotype
Factor VII
Health Services Needs and Demand
Genome-Wide Association Study
Platelet Count
Leukocyte Count
Fibrinogen
Population
Fasting
Body Mass Index
Genome
Insulin
Blood Pressure
Lipids
Glucose
Datasets

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Petty, L. E., Highland, H. M., Gamazon, E. R., Hu, H., Karhade, M., Chen, H. H., ... Below, J. E. (2019). Functionally oriented analysis of cardiometabolic traits in a trans-ethnic sample. Human molecular genetics, 28(7), 1212-1224. https://doi.org/10.1093/hmg/ddy435

Functionally oriented analysis of cardiometabolic traits in a trans-ethnic sample. / 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; Barbeira, Alvaro; Im, Hae Kyung; Morrison, Alanna C.; Boerwinkle, Eric; Below, Jennifer E.

In: Human molecular genetics, Vol. 28, No. 7, 01.01.2019, p. 1212-1224.

Research output: Contribution to journalArticle

Petty, LE, Highland, HM, Gamazon, ER, Hu, H, Karhade, M, Chen, HH, De Vries, PS, Grove, ML, Aguilar, D, Bell, GI, Huff, CD, Hanis, CL, Doddapaneni, H, Munzy, DM, Gibbs, RA, Ma, J, Parra, EJ, Cruz, M, Valladares-Salgado, A, Arking, D, Barbeira, A, Im, HK, Morrison, AC, Boerwinkle, E & Below, JE 2019, 'Functionally oriented analysis of cardiometabolic traits in a trans-ethnic sample', Human molecular genetics, vol. 28, no. 7, pp. 1212-1224. https://doi.org/10.1093/hmg/ddy435
Petty LE, Highland HM, Gamazon ER, Hu H, Karhade M, Chen HH et al. Functionally oriented analysis of cardiometabolic traits in a trans-ethnic sample. Human molecular genetics. 2019 Jan 1;28(7):1212-1224. https://doi.org/10.1093/hmg/ddy435
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 ; Barbeira, Alvaro ; Im, Hae Kyung ; Morrison, Alanna C. ; Boerwinkle, Eric ; Below, Jennifer E. / Functionally oriented analysis of cardiometabolic traits in a trans-ethnic sample. In: Human molecular genetics. 2019 ; Vol. 28, No. 7. pp. 1212-1224.
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