Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts.

TitleAllelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts.
Publication TypeJournal Article
Year of Publication2020
AuthorsRaffield LM, Iyengar AK, Wang B, Gaynor SM, Spracklen CN, Zhong X, Kowalski MH, Salimi S, Polfus LM, Benjamin EJ, Bis JC, Bowler R, Cade BE, Choi WJung, Comellas AP, Correa A, Cruz P, Doddapaneni H, Durda P, Gogarten SM, Jain D, Kim RW, Kral BG, Lange LA, Larson MG, Laurie C, Lee J, Lee S, Lewis JP, Metcalf GA, Mitchell BD, Momin Z, Muzny DM, Pankratz N, Park CJoo, Rich SS, Rotter JI, Ryan K, Seo D, Tracy RP, Viaud-Martinez KA, Yanek LR, Zhao LPing, Lin X, Li B, Li Y, Dupuis J, Reiner AP, Mohlke KL
Secondary AuthorsAuer PL
Corporate AuthorsTOPMed Inflammation Working Group, NHLBI Trans-Omics for Precision Medicine(TOPMed) Consortium
JournalAm J Hum Genet
Volume106
Issue1
Pagination112-120
Date Published2020 01 02
ISSN1537-6605
KeywordsAfrican Continental Ancestry Group, Asian Continental Ancestry Group, C-Reactive Protein, Cohort Studies, European Continental Ancestry Group, Gene Frequency, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Whole Genome Sequencing
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 (∼38× 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 (∼10% and ∼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.

DOI10.1016/j.ajhg.2019.12.002
Alternate JournalAm J Hum Genet
PubMed ID31883642
PubMed Central IDPMC7042494
Grant ListK01 AG059898 / AG / NIA NIH HHS / United States
R01 HG006703 / HG / NHGRI NIH HHS / United States
HHSN268201500001C / HL / NHLBI NIH HHS / United States
R01 HL137922 / HL / NHLBI NIH HHS / United States
R01 HL076784 / HL / NHLBI NIH HHS / United States
R01 HL120854 / HL / NHLBI NIH HHS / United States
R01 HL128914 / HL / NHLBI NIH HHS / United States
T32 HL129982 / HL / NHLBI NIH HHS / United States
HHSN268201800013I / MD / NIMHD NIH HHS / United States
HHSN268201500001I / HL / NHLBI NIH HHS / United States
HHSN268201800011C / HL / NHLBI NIH HHS / United States
K01 HL135405 / HL / NHLBI NIH HHS / United States
R01 HL132947 / HL / NHLBI NIH HHS / United States
HHSN268201800012C / HL / NHLBI NIH HHS / United States
R01 DK072193 / DK / NIDDK NIH HHS / United States
R01 HL129132 / HL / NHLBI NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
HHSN268201800015I / HB / NHLBI NIH HHS / United States
U01 DK105561 / DK / NIDDK NIH HHS / United States
U01 HG009086 / HG / NHGRI NIH HHS / United States
R01 AG028321 / AG / NIA NIH HHS / United States