Journal article
Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts
American journal of human genetics, Vol.106(1), pp.112-120
01/02/2020
DOI: 10.1016/j.ajhg.2019.12.002
PMCID: PMC7042494
PMID: 31883642
Abstract
Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented in existing genomic studies. The genetic determinants of C-reactive protein (CRP), a biomarker of chronic inflammation, have been extensively studied, with existing genome-wide association studies (GWASs) conducted in >200,000 individuals of European ancestry. In order to discover novel loci associated with CRP levels, we examined a multi-ancestry population (n = 23,279) with WGS (similar to 38x coverage) from the Trans-Omics for Precision Medicine (TOPMed) program. We found evidence for eight distinct associations at the CRP locus, including two variants that have not been identified previously (rs11265259 and rs181704186), both of which are non-coding and more common in individuals of African ancestry (similar to 10% and similar to 1% minor allele frequency, respectively, and rare or monomorphic in 1000 Genomes populations of East Asian, South Asian, and European ancestry). We show that the minor (G) allele of rs181704186 is associated with lower CRP levels and decreased transcriptional activity and protein binding in vitro, providing a plausible molecular mechanism for this African ancestry-specific signal. The individuals homozygous for rs181704186-G have a mean CRP level of 0.23 mg/L, in contrast to individuals heterozygous for rs181704186 with mean CRP of 2.97 mg/L and major allele homozygotes with mean CRP of 4.11 mg/L. This study demonstrates the utility of WGS in multi-ethnic populations to drive discovery of complex trait associations of large effect and to identify functional alleles in noncoding regulatory regions.
Details
- Title: Subtitle
- Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts
- Creators
- Laura M. Raffield - University of North Carolina at Chapel HillApoorva K. Iyengar - University of North Carolina at Chapel HillBiqi Wang - Boston UniversitySheila M. Gaynor - Harvard UniversityCassandra N. Spracklen - University of North Carolina at Chapel HillXue Zhong - Vanderbilt UniversityMadeline H. Kowalski - University of North Carolina at Chapel HillShabnam Salimi - University of Maryland, BaltimoreLinda M. Polfus - University of Southern CaliforniaEmelia J. Benjamin - Boston UniversityJoshua C. Bis - University of WashingtonRussell Bowler - University of Colorado DenverBrian E. Cade - Brigham and Women's HospitalWon Jung Choi - MacroGenicsAlejandro P. Comellas - University of IowaAdolfo Correa - University of Mississippi Medical CenterPedro Cruz - IlluminaHarsha Doddapaneni - Baylor College of MedicinePeter Durda - University of VermontStephanie M. Gogarten - University of WashingtonDeepti Jain - University of WashingtonRyan W. Kim - MacroGenicsBrian G. Kral - Johns Hopkins MedicineLeslie A. Lange - University of Colorado DenverMartin G. Larson - Boston UniversityCecelia Laurie - University of WashingtonJiwon Lee - Brigham and Women's HospitalSeonwook Lee - MacroGenicsJoshua P. Lewis - University of Maryland, BaltimoreGinger A. Metcalf - Baylor College of MedicineBraxton D. Mitchell - University of Maryland, BaltimoreZeineen Momin - Baylor College of MedicineDonna M. Muzny - Baylor College of MedicineNathan Pankratz - University of MinnesotaCheol Joo Park - MacroGenicsStephen S. Rich - University of VirginiaJerome I. Rotter - The Lundquist InstituteKathleen Ryan - University of Maryland, BaltimoreDaekwan Seo - MacroGenicsRussell P. Tracy - University of VermontKarine A. Viaud-Martinez - IlluminaLisa R. Yanek - Johns Hopkins MedicineLue Ping Zhao - Fred Hutch Cancer CenterXihong Lin - Harvard UniversityBingshan Li - Vanderbilt UniversityYun Li - University of North Carolina at Chapel HillJose Prime E. Dupuis - Boston UniversityAlexander P. Reiner - University of WashingtonKaren L. Mohlke - University of North Carolina at Chapel HillPaul L. Auer - University of Wisconsin–MilwaukeeTrans-Omics for Precision Medicine (TOPMed) Working Group
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.106(1), pp.112-120
- Publisher
- Elsevier
- DOI
- 10.1016/j.ajhg.2019.12.002
- PMID
- 31883642
- PMCID
- PMC7042494
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Number of pages
- 9
- Grant note
- RO1 DK072193; U01 DK105561 / National Institute of Diabetes and Digestive and Kidney Diseases; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) 15POST24470131; 17POST33650016 / American Heart Association
- Language
- English
- Date published
- 01/02/2020
- Academic Unit
- Pulmonary, Critical Care, and Occupational Medicine; ICTS; Internal Medicine
- Record Identifier
- 9984359823402771
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