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

TOPMed Inflammation Working Group, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)112-120
Number of pages9
JournalAmerican Journal of Human Genetics
Volume106
Issue number1
DOIs
StatePublished - Jan 2 2020

Fingerprint

C-Reactive Protein
Genome
Alleles
Population
Precision Medicine
Nucleic Acid Regulatory Sequences
Genome-Wide Association Study
Homozygote
Protein Binding
Gene Frequency
Biomarkers
Inflammation

Keywords

  • c-reactive protein
  • whole-genome sequencing

Cite this

TOPMed Inflammation Working Group, & NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium (2020). Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts. American Journal of Human Genetics, 106(1), 112-120. https://doi.org/10.1016/j.ajhg.2019.12.002

Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts. / TOPMed Inflammation Working Group; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium.

In: American Journal of Human Genetics, Vol. 106, No. 1, 02.01.2020, p. 112-120.

Research output: Contribution to journalArticle

TOPMed Inflammation Working Group & NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium 2020, 'Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts', American Journal of Human Genetics, vol. 106, no. 1, pp. 112-120. https://doi.org/10.1016/j.ajhg.2019.12.002
TOPMed Inflammation Working Group, NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium. Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts. American Journal of Human Genetics. 2020 Jan 2;106(1):112-120. https://doi.org/10.1016/j.ajhg.2019.12.002
TOPMed Inflammation Working Group ; NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium. / Allelic Heterogeneity at the CRP Locus Identified by Whole-Genome Sequencing in Multi-ancestry Cohorts. In: American Journal of Human Genetics. 2020 ; Vol. 106, No. 1. pp. 112-120.
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AU - Raffield, Laura M.

AU - Iyengar, Apoorva K.

AU - Wang, Biqi

AU - Gaynor, Sheila M.

AU - Spracklen, Cassandra N.

AU - Zhong, Xue

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AU - Cruz, Pedro

AU - Doddapaneni, Harsha

AU - Durda, Peter

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AU - Jain, Deepti

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AU - Kral, Brian G.

AU - Lange, Leslie A.

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AU - Yanek, Lisa R.

AU - Zhao, Lue Ping

AU - Lin, Xihong

AU - Li, Bingshan

AU - Li, Yun

AU - Dupuis, Josée

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