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Genome-wide association study of age at menarche in African-American women.

ABSTRACT: 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 of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways 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 inverse-variance 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 in EA women. Secondly, an investigation of SNPs in 42 previously identified menarche 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.

SUBMITTER: Demerath EW

PROVIDER: S-EPMC3723312 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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Genome-wide association study of age at menarche in African-American women.

Demerath Ellen W EW Liu Ching-Ti CT Franceschini Nora N Chen Gary G Palmer Julie R JR Smith Erin N EN Chen Christina T L CT Ambrosone Christine B CB Arnold Alice M AM Bandera Elisa V EV Berenson Gerald S GS Bernstein Leslie L Britton Angela A Cappola Anne R AR Carlson Christopher S CS Chanock Stephen J SJ Chen Wei W Chen Zhao Z Deming Sandra L SL Elks Cathy E CE Evans Michelle K MK Gajdos Zofia Z Henderson Brian E BE Hu Jennifer J JJ Ingles Sue S John Esther M EM Kerr Kathleen F KF Kolonel Laurence N LN Le Marchand Loic L Lu Xiaoning X Millikan Robert C RC Musani Solomon K SK Nock Nora L NL North Kari K Nyante Sarah S Press Michael F MF Rodriquez-Gil Jorge L JL Ruiz-Narvaez Edward A EA Schork Nicholas J NJ Srinivasan Sathanur R SR Woods Nancy F NF Zheng Wei W Ziegler Regina G RG Zonderman Alan A Heiss Gerardo G Gwen Windham B B Wellons Melissa M Murray Sarah S SS Nalls Michael M Pastinen Tomi T Rajkovic Aleksandar A Hirschhorn Joel J Adrienne Cupples L L Kooperberg Charles C Murabito Joanne M JM Haiman Christopher A CA

Human molecular genetics 20130417 16

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 of common genetic variants associated with age at menarche has a potential value in pointing to the genetic pathways 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 ...[more]

PMID: 23599027

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Project description:BackgroundOsteoporosis is a major public health problem associated with excess disability and mortality. It is estimated that 50-70% of the variation in osteoporotic fracture risk is attributable to genetic factors. The purpose of this hypothesis-generating study was to identify possible genetic determinants of fracture among African American (AA) women in a GWAS meta-analysis.MethodsData on clinical fractures (all fractures except fingers, toes, face, skull or sternum) were analyzed among AA female participants in the Women's Health Initiative (WHI) (N = 8155), Cardiovascular Health Study (CHS) (N = 504), BioVU (N = 704), Health ABC (N = 651), and the Johnston County Osteoarthritis Project (JoCoOA) (N = 291). Affymetrix (WHI) and Illumina (Health ABC, JoCoOA, BioVU, CHS) GWAS panels were used for genotyping, and a 1:1 ratio of YRI:CEU HapMap haplotypes was used as an imputation reference panel. We used Cox proportional hazard models or logistic regression to evaluate the association of ~ 2.5 million SNPs with fracture risk, adjusting for ancestry, age, and geographic region where applicable. We conducted a fixed-effects, inverse variance-weighted meta-analysis. Genome-wide significance was set at P < 5 × 10- 8.ResultsOne SNP, rs12775980 in an intron of SVIL on chromosome 10p11.2, reached genome-wide significance (P = 4.0 × 10- 8). Although this SNP has a low minor allele frequency (0.03), there was no evidence for heterogeneity of effects across the studies (I2 = 0). This locus was not reported in any previous osteoporosis-related GWA studies. We also interrogated previously reported GWA-significant loci associated with fracture or bone mineral density in our data. One locus (SMOC1) generalized, but overall there was not substantial evidence of generalization. Possible reasons for the lack of generalization are discussed.ConclusionThis GWAS meta-analysis of fractures in African American women identified a potentially novel locus in the supervillin gene, which encodes a platelet-associated factor and was previously associated with platelet thrombus formation in African Americans. If validated in other populations of African descent, these findings suggest potential new mechanisms involved in fracture that may be particularly important among African Americans.

Dataset Information

Genome-wide association study of age at menarche in African-American women.

Publications

Genome-wide association study of age at menarche in African-American women.

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