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

Research output: Contribution to journalArticlepeer-review

6 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

Bibliographical note

Funding Information:
The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI) with co-funding from the National Institute on Minority Health and Health Disparities (NIMHD), supported by U01HG007416 (CALiCo), U01HG007417 (ISMMS), U01HG007397 (MEC), U01HG007376 (WHI), and U01HG007419 (Coordinating Center). Dr Kocarnik was supported by KL2TR000421 from the National Center for Advancing Translational Sciences (NCATS). The contents of this paper are solely the responsibility of the authors and do not necessarily

Funding Information:
represent the official views of the National Institutes of Health (NIH). The PAGE consortium thanks the staff and participants of all PAGE studies for their important contributions. The complete list of PAGE members can be found at http:// www.pagestudy.org; date last accessed June 18, 2018. The data and materials included in this report result from collaboration between the following studies and organizations: Coordinating Center: Assistance with data management, data integration, data dissemination, genotype imputation, ancestry deconvolution, population genetics, analysis pipelines and general study coordination was provided by the PAGE Coordinating Center (U01HG007419 and U01HG004801). CALiCo: Funding support for the Genetic Epidemiology of Causal Variants Across the Life Course (CALiCo) program was provided through the NHGRI PAGE program (U01 HG007416, U01 HG004803). The following studies contributed to this manuscript and are funded by the following agencies: The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201 100005C, HHSN268201100006C, HHSN268201100007C, HHSN268 201100008C, HHSN268201100009C, HHSN268201100010C, HHSN 268201100011C and HHSN268201100012C). The Hispanic Community Health Study/Study of Latinos was carried out as a collaborative study supported by contracts from the National Heart, Lung, and Blood Institute (NHLBI) to the University of North Carolina (N01-HC65233), University of Miami (N01-HC65234), Albert Einstein College of Medicine (N01-HC65235), Northwestern University (N01-HC65236), and San Diego State University (N01-HC65237). The following Institutes/Centers/ Offices contribute to the HCHS/SOL through a transfer of funds to the NHLBI: National Institute on Minority Health and Health Disparities, National Institute on Deafness and Other Communication Disorders, National Institute of Dental and Craniofacial Research, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, NIH Institution-Office of Dietary Supplements. The Coronary Artery Risk Development in Young Adults Study (CARDIA) is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham (HHSN268201300025C & HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C) and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging. Cardiovascular Health Study (CHS) research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295 and U01HL130114 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The Strong Heart Study (SHS) is supported by NHLBI grants U01 HL65520, U01 HL41642, U01 HL41652, U01 HL41654, U01 HL65521 and R01 HL109301. The datasets used for the analyses described in this manuscript were obtained from dbGaP under accession phs000223 (ARIC), phs000236, (CARDIA), phs000301 (CHS), phs000555 (HCHS/SOL). MEC: The Multiethnic Cohort study (MEC) characterization of epidemiological architecture is funded through the NHGRI Population Architecture Using Genomics and Epidemiology (PAGE) program (U01 HG007397, U01HG004802 and its NHGRI ARRA supplement). The MEC study is funded through the National Cancer Institute (R37CA54281, R01 CA63, P01CA33619, U01CA136792, and U01CA98758). The datasets used for the analyses described in this manuscript were obtained from dbGaP under accession phs000220. WHI: Funding support for the ‘Exonic variants and their relation to complex traits in minorities of the WHI’ study is provided through the NHGRI PAGE program (U01HG007376, U01HG004790). The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN26820 1100002C, HHSN268201100003C, HHSN268201100004C and HHSN271201100004C.

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