The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic meta-analysis

Lindsay Fernández-Rhodes, Jennifer R. Malinowski, Yujie Wang, Ran Tao, Nathan Pankratz, Janina M. Jeff, Sachiko Yoneyama, Cara L. Carty, V. Wendy Setiawan, Loic Le Marchand, Christopher Haiman, Steven Corbett, Ellen Demerath, Gerardo Heiss, Myron Gross, Petra Buzkova, Dana C. Crawford, Steven C. Hunt, D. C. Rao, Karen SchwanderAravinda Chakravarti, Omri Gottesman, Noura S. Abul-Husn, Erwin P. Bottinger, Ruth J.F. Loos, Leslie J. Raffel, Jie Yao, Xiuqing Guo, Suzette J. Bielinski, Jerome I. Rotter, Dhananjay Vaidya, Yii Der Ida Chen, Sheila F. Castañeda, Martha Daviglus, Robert Kaplan, Gregory A. Talavera, Kelli K. Ryckman, Ulrike Peters, Jose Luis Ambite, Steven Buyske, Lucia Hindorff, Charles Kooperberg, Tara Matise, Nora Franceschini, Kari E. North

Research output: Contribution to journalArticle

Abstract

Current knowledge of the genetic architecture of key reproductive events across the female life course is largely based on association studies of European descent women. The relevance of known loci for age at menarche (AAM) and age at natural menopause (ANM) in diverse populations remains unclear. We investigated 32 AAM and 14 ANM previously-identified loci and sought to identify novel loci in a trans-ethnic array-wide study of 196,483 SNPs on the MetaboChip (Illumina, Inc.). A total of 45,364 women of diverse ancestries (African, Hispanic/Latina, Asian American and American Indian/Alaskan Native) in the Population Architecture using Genomics and Epidemiology (PAGE) Study were included in cross-sectional analyses of AAM and ANM. Within each study we conducted a linear regression of SNP associations with self-reported or medical record-derived AAM or ANM (in years), adjusting for birth year, population stratification, and center/region, as appropriate, and meta-analyzed results across studies using multiple meta-analytic techniques. For both AAM and ANM, we observed more directionally consistent associations with the previously reported risk alleles than expected by chance (p-valuesbinomial0.01). Eight densely genotyped reproductive loci generalized significantly to at least one non-European population. We identified one trans-ethnic array-wide SNP association with AAM and two significant associations with ANM, which have not been described previously. Additionally, we observed evidence of independent secondary signals at three of six AAM trans-ethnic loci. Our findings support the transferability of reproductive trait loci discovered in European women to women of other race/ethnicities and indicate the presence of additional trans-ethnic associations both at both novel and established loci. These findings suggest the benefit of including diverse populations in future studies of the genetic architecture of female growth and development.

Original languageEnglish (US)
Article numbere0200486
JournalPloS one
Volume13
Issue number7
DOIs
StatePublished - Jul 2018

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Fernández-Rhodes, L., Malinowski, J. R., Wang, Y., Tao, R., Pankratz, N., Jeff, J. M., Yoneyama, S., Carty, C. L., Setiawan, V. W., Le Marchand, L., Haiman, C., Corbett, S., Demerath, E., Heiss, G., Gross, M., Buzkova, P., Crawford, D. C., Hunt, S. C., Rao, D. C., ... North, K. E. (2018). The genetic underpinnings of variation in ages at menarche and natural menopause among women from the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) Study: A trans-ethnic meta-analysis. PloS one, 13(7), [e0200486]. https://doi.org/10.1371/journal.pone.0200486