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

Citation

Kocarnik, Jonathan M.; Richard, Melissa A.; Graff, Mariaelisa; Haessler, Jeffrey; Bien, Stephanie A.; Carlson, Christopher S.; Carty, Cara L.; Reiner, Alexander P.; Avery, Christy L.; & Ballantyne, Christie M., et al. (2018). 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. Human Molecular Genetics, 27(16), 2940-2953. PMCID: PMC6077792

Abstract

Introduction: 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.
Methods: 30,503 non-European-ancestry participants from six studies participating in the Population Architecture using Genomics and Epidemiology (PAGE) study had serum high-sensitivity CRP measurements and approximately 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 4 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.
Results: 163 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/ethnicity-specific versus overall analyses. Fine-mapping refined the signal in 6 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.
Discussion: 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.

URL

http://dx.doi.org/10.1093/hmg/ddy211

Reference Type

Journal Article

Year Published

2018

Journal Title

Human Molecular Genetics

Author(s)

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

PMCID

PMC6077792

ORCiD

Avery - 0000-0002-1044-8162
Graff - 0000-0001-6380-1735