Discovery, fine-mapping, and conditional analyses of genetic variants associated with C-reactive protein in multiethnic populations using the Metabochip in the Population Architecture using Genomics and Epidemiology (PAGE) study

Jonathan M. Kocarnik*, Melissa Richard, Misa Graff, Jeffrey Haessler, Stephanie Bien, Chris Carlson, Cara L. Carty, Alexander P. Reiner, Christy L. Avery, Christie M. Ballantyne, Andrea Z. LaCroix, Themistocles L. Assimes, Maja Barbalic, Nathan Pankratz, Weihong Tang, Ran Tao, Dongquan Chen, Gregory A. Talavera, Martha L. Daviglus, Diana A. Chirinos-MedinaRocio Pereira, Katie Nishimura, Petra Bůžková, Lyle G. Best, José Luis Ambite, Iona Cheng, Dana C. Crawford, Lucia A. Hindorff, Myriam Fornage, Gerardo Heiss, Kari E. North, Christopher A. Haiman, Ulrike Peters, Loic Le Marchand, Charles Kooperberg

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

C-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30 503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and ~200 000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value<2.5E-7. Three loci have no (HACL1, OLFML2B) or only limited (PLA2G6) previous associations with CRP levels. Six loci had different top hits in race/ethnicityspecific versus overall analyses. Fine-mapping refined the signal in six loci, particularly in HNF1A. Conditional analyses provided evidence for secondary signals in LEPR, IL1RN and HNF1A, and for multiple independent signals in CRP and APOE. We identified novel variants and loci associated with CRP levels, generalized known CRP associations to a multiethnic study population, refined association signals at several loci and found evidence for multiple independent signals at several well-known loci. This study demonstrates the benefit of conducting inclusive genetic association studies in large multiethnic populations.

Original languageEnglish (US)
Pages (from-to)2940-2953
Number of pages14
JournalHuman molecular genetics
Volume27
Issue number16
DOIs
StatePublished - Aug 15 2018

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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