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

摘要: Whole-genome sequencing (WGS) can improve assessment of low-frequency and rare variants, particularly in non-European populations that have been underrepresented existing genomic studies. The genetic determinants C-reactive protein (CRP), a biomarker chronic inflammation, extensively studied, with genome-wide association studies (GWASs) conducted >200,000 individuals European ancestry. In order to discover novel loci associated CRP levels, we examined multi-ancestry population (n = 23,279) WGS (∼38× coverage) from the Trans-Omics for Precision Medicine (TOPMed) program. We found evidence eight distinct associations at locus, including two variants not identified previously (rs11265259 rs181704186), both which are non-coding more common African ancestry (∼10% ∼1% minor allele frequency, respectively, or monomorphic 1000 Genomes East Asian, South ancestry). show (G) rs181704186 is lower levels decreased transcriptional activity binding in vitro, providing plausible molecular mechanism this ancestry-specific signal. homozygous rs181704186-G mean level 0.23 mg/L, contrast heterozygous 2.97 mg/L major homozygotes 4.11 mg/L. This study demonstrates utility multi-ethnic drive discovery complex trait large effect identify functional alleles noncoding regulatory regions.