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.
Bibliographical noteFunding Information:
Analysis of CRP variants was supported by the National Institute of Diabetes and Digestive and Kidney Diseases ( RO1 DK072193 and U01 DK105561 ). A.K.I. and K.L.M. were supported by RO1 DK072193 . L.M.R. was supported by T32 HL129982 . C.N.S. was supported by American Heart Association Postdoctoral Fellowship 15POST24470131 and 17POST33650016 . E.J.B. was supported by HHSN268201500001I , N01-HC 25195 , RO1 HL64753 , R01 HL076784 , and R01 AG028321 . B.E.C. was supported by K01 HL135405 . M.H.K., Y.L., and A.P.R. were supported by R01 HL129132 . A.C. was supported by HHSN268201800010 , HHSN268201800011 , HHSN268201800012 , HHSN268201800013 , HHSN268201800015 , and HHSN268201800015 . J.P.L. was supported by R01 HL137922 . R.P.T. was supported by R01 HL120854 . J.D. was supported by R01 HL128914 . P.L.A. was supported by R01 HL132947 . B.L. was supported by U01HG009086 . S.S. was supported by K01AG059898 .
© 2019 American Society of Human Genetics
- c-reactive protein
- whole-genome sequencing