TY - JOUR
T1 - 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
AU - Kocarnik, Jonathan M.
AU - Richard, Melissa
AU - Graff, Misa
AU - Haessler, Jeffrey
AU - Bien, Stephanie
AU - Carlson, Chris
AU - Carty, Cara L.
AU - Reiner, Alexander P.
AU - Avery, Christy L.
AU - Ballantyne, Christie M.
AU - LaCroix, Andrea Z.
AU - Assimes, Themistocles L.
AU - Barbalic, Maja
AU - Pankratz, Nathan
AU - Tang, Weihong
AU - Tao, Ran
AU - Chen, Dongquan
AU - Talavera, Gregory A.
AU - Daviglus, Martha L.
AU - Chirinos-Medina, Diana A.
AU - Pereira, Rocio
AU - Nishimura, Katie
AU - Bůžková, Petra
AU - Best, Lyle G.
AU - Ambite, José Luis
AU - Cheng, Iona
AU - Crawford, Dana C.
AU - Hindorff, Lucia A.
AU - Fornage, Myriam
AU - Heiss, Gerardo
AU - North, Kari E.
AU - Haiman, Christopher A.
AU - Peters, Ulrike
AU - Marchand, Loic Le
AU - Kooperberg, Charles
N1 - Publisher Copyright:
© The Author(s) 2018.
PY - 2018/8/15
Y1 - 2018/8/15
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddy211
DO - 10.1093/hmg/ddy211
M3 - Article
C2 - 29878111
AN - SCOPUS:85054997249
SN - 0964-6906
VL - 27
SP - 2940
EP - 2953
JO - Human molecular genetics
JF - Human molecular genetics
IS - 16
ER -