African-American (AA) women have earlier menarche on average than women of European ancestry (EA), and earlier menarche is a risk factor for obesity and type 2 diabetes among other chronic diseases. Identification ofcommongeneticvariants associated withageatmenarchehasapotential value inpointing to the geneticpathways underlying chronic disease risk, yet comprehensive genome-wide studies of age at menarche are lacking for AA women. In this study, we tested the genome-wide association of self-reported age at menarche with common single-nucleotide polymorphisms (SNPs) in a total of 18 089 AA women in 15 studies using an additive genetic linear regression model, adjusting for year of birth and population stratification, followed by inversevariance weighted meta-analysis (Stage 1). Top meta-analysis results were then tested in an independent sample of 2850 women (Stage 2). First, while no SNP passed the pre-specified P < 5 × 10-8 threshold for significance in Stage 1, suggestive associations were found for variants near FLRT2 and PIK3R1, and conditional analysis identified two independent SNPs (rs339978 and rs980000) in or near RORA, strengthening the support for this suggestive locus identified inEAwomen. Secondly, an investigation of SNPs in 42 previously identifiedmenarche loci in EA women demonstrated that 25 (60%) of them contained variants significantly associated with menarche in AA women. The findings provide the first evidence of cross-ethnic generalization of menarche loci identified to date, and suggest a number of novel biological links to menarche timing in AA women.
Bibliographical noteFunding Information:
Bogalusa Heart Study (BHS): E.N.S., N.J.S. and S.S.M. are supported in part by National Institutes of Health (grant 1U54RR025204-01). W.C., S.R.S. and G.S.B. are supported from National Institute of Environmental Health Science (ES-021724); from the National Institute of Child Health and Human Development (HD-061437 and HD-062783) and from the National Institute on Aging (AG-16592). E.N.S., S.S.M. and N.J.S. are supported in part by National Institute of Health/National Center for Research Resources Grant (UL1RR025774).
AABC Studies (CARE, CBCS, MEC, NBHS, NC-BCFR/ SFBCS, PLCO, WCHS, WFBC): This work was supported by a Department of Defense Breast Cancer Research Program Era of Hope Scholar Award to C.A.H. and the Norris Foundation. Each of the participating studies was supported by the following grants: CARE - National Institute for Child Health and Development grant (NO1-HD-3-3175), CBCS – National Institutes of Health Specialized Program of Research Excellence in Breast Cancer (P50-CA58223) and Center for Environmental Health and Susceptibility, National Institute of Environmental Health Sciences, National Institutes of Health, grant (P30-ES10126); MEC – National Institutes of Health grants (R01-CA63464 and R37-CA54281); NHBS – National Institutes of Health grant (R01-CA100374); NC-BCFR - National Institutes of Health grant (U01-CA69417). SFBCS - National Institutes of Health grant (R01-CA77305) and United States Army Medical Research Program grant (DAMD17-96-6071). The Breast Cancer Family Registry (BCFR) was supported by the National Cancer Institute, National Institutes of Health (RFA CA-95-011) and through cooperative agreements with members of the Breast Cancer Family Registry and Principal Investigators; PLCO - Intramural Research Program, National Cancer Institute, National Institutes of Health; WCHS - U.S. Army Medical Research and Material Command (USAMRMC) grant (DAMD-17-01-0-0334), the National Institutes of Health grant (R01-CA100598) and the Breast Cancer Research Foundation; and WFBC—National Institutes of Health grant (R01-CA73629).
Black Women’s Health Study (BWHS): BWHS. research was supported from the National Cancer Institute, Division of Cancer Control and Population Science (R01 CA058420 and R01 CA098663); and by a grant from the Susan G. Komen for the Cure Foundation.
Nine parent studies contributed parent study data, ancillary study data and DNA samples through the Massachusetts Institute of Technology-Broad Institute (N01-HC-65226) to create the Candidate Gene Association Resource (CARe) genotype/phenotype database for wide dissemination to the biomedical research community. Of these, four parent studies (ARIC, CARDIA, CFS and JHS) participated in this study of age at menarche. Analysis support came through National Institutes of Health (HHSN268200900055C and 5215810-550000234). Additional support for this menarche project came from R21AG032598. Information on the CARe parent studies follows here. The Atherosclerosis Risk in Communities Study (ARIC) is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268 201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268 201100011C, and HHSN268201100012C), (R01HL087641), (R01HL59367 and R01HL086694); National Human Genome Research Institute (U01HG004402); and National Institutes of Health contract (HHSN268200625226C). Infrastructure was partly supported by a component of the National Institutes of Health and NIH Roadmap for Medical Research Grant (UL1RR025005). Coronary Artery Risk in Young Adults (CARDIA): Work on this manuscript was supported (or partially supported) by contracts from the National Heart, Lung and Blood Institute (NHLBI): University of Alabama at Birmingham, Coordinating Center (N01-HC-95095); University of Alabama at Birmingham, Field Center (N01-HC-48047); University of Minnesota, Field Center (N01-HC-48048); North-western University, Field Center (N01-HC-48049); Kaiser Foundation Research Institute (N01-HC-48050); Harbor-UCLA Research and Education Institute (N01-HC-05187), University of California, Irvine (N01-HC-45134, N01-HC-95100); Wake Forest University (Year 20 Exam) (N01-HC-45205); New England Medical Center (Year 20 Exam) (N01-HC-45204). M.W.’s effort is supported by the National Heart, Lung and Blood Institute (K23-HL-87114). Cleveland Family Study (CFS): The Cleveland Family Study was supported by the National Heart, Lung and Blood Institute (RO1-HL46380, M01-RR-00080). Jackson Heart Study (JHS): The Jackson Heart Study is supported by the National Heart, Lung, and Blood Institute and the National Center on Minority Health and Health Disparities through National Institutes of Health contracts (N01-HC-95170, N01-HC-95171 and N01-HC-95172).
Health Across the Lifespan (HANDLS): This research was supported by the Intramural Research Program of the National Institute of Health, National Institute on Aging and the National Center on Minority Health and Health Disparities (Z01-AG000513) and human subjects protocol (# 2009-149).
Women’s Health Initiative (WHI): The WHI program is supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services (HHSN268201100046C, HHSN268201100001C, HHSN 268201100002C, HHSN268201100003C, HHSN2682011 00004C and HHSN271201100004C). Funding for WHI SHARe genotyping was provided by the National Heart, Lung, and Blood Institute Contract (N02-HL-64278).