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

Ellen W. Demerath, Ching Ti Liu, Nora Franceschini, Gary Chen, Julie R. Palmer, Erin N. Smith, Christina T.L. Chen, Christine B. Ambrosone, Alice M. Arnold, Elisa V. Bandera, Gerald S. Berenson, Leslie Bernstein, Angela Britton, Anne R. Cappola, Christopher S. Carlson, Stephen J. Chanock, Wei Chen, Zhao Chen, Sandra L. Deming, Cathy E. ElksMichelle K. Evans, Zofia Gajdos, Brian E. Henderson, Jennifer J. Hu, Sue Ingles, Esther M. John, Kathleen F. Kerr, Laurence N. Kolonel, Loic Le Marchand, Xiaoning Lu, Robert C. Millikan, Solomon K. Musani, Nora L. Nock, Kari North, Sarah Nyante, Michael F. Press, Jorge L. Rodriquez-Gil, Edward A. Ruiz-Narvaez, Nicholas J. Schork, Sathanur R. Srinivasan, Nancy F. Woods, Wei Zheng, Regina G. Ziegler, Alan Zonderman, Gerardo Heiss, B. Gwen Windham, Melissa Wellons, Sarah S. Murray, Michael Nalls, Tomi Pastinen, Aleksandar Rajkovic, Joel Hirschhorn, L. Adrienne Cupples, Charles Kooperberg, Joanne M. Murabito, Christopher A. Haiman

Research output: Contribution to journalArticle

30 Scopus citations

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 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.

Original languageEnglish (US)
Article numberddt181
Pages (from-to)3329-3346
Number of pages18
JournalHuman molecular genetics
Volume22
Issue number16
DOIs
StatePublished - Aug 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Demerath, E. W., Liu, C. T., Franceschini, N., Chen, G., Palmer, J. R., Smith, E. N., Chen, C. T. L., Ambrosone, C. B., Arnold, A. M., Bandera, E. V., Berenson, G. S., Bernstein, L., Britton, A., Cappola, A. R., Carlson, C. S., Chanock, S. J., Chen, W., Chen, Z., Deming, S. L., ... Haiman, C. A. (2013). Genome-wide association study of age at menarche in African-American women. Human molecular genetics, 22(16), 3329-3346. [ddt181]. https://doi.org/10.1093/hmg/ddt181