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PLoS One. 2018 Jul 25;13(7):e0200486. doi: 10.1371/journal.pone.0200486. eCollection 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.

Author information

1
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
2
Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
3
Write InSciTe, LLC, Hebron, Connecticut, United States of America.
4
Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
5
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, United States of America.
6
Genotyping Arrays Division, Illumina, Inc., San Diego, California, United States of America.
7
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
8
Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America.
9
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, United States of America.
10
Kansas Health Institute, Topeka, Kansas, United States of America.
11
Division of Epidemiology & Community Health, University of Minnesota, Minneapolis, Minnesota, United States of America.
12
Department of Biostatistics, School of Public Health, University of Washington, Seattle, Washington, United States of America.
13
Institute for Computational Biology, Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio, United States of America.
14
Department of Genetic Medicine, Weill Cornell Medical College in Qatar, Doha, Qatar.
15
Division of Biostatistics, Washington University in St. Louis, St. Louis, Michigan, United States of America.
16
Center for Complex Disease Genomics, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
17
Division of General Internal Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
18
The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
19
Division of Genetic and Genomic Medicine, University of California-Irvine, Irvine, California, United States of America.
20
Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute and Department of Pediatrics at Harbor-UCLA Medical Center, Torrance, California, United States of America.
21
College of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
22
Department of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
23
South Bay Latino Research Center, Graduate School of Public Health, San Diego State University, San Diego, California, United States of America.
24
Institute of Minority Health Research, University of Illinois at Chicago, Chicago, Illinois, United States of America.
25
Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York, United States of America.
26
Departments of Epidemiology and Pediatrics, University of Iowa, Iowa City, Iowa, United States of America.
27
Information Sciences Institute, University of Southern California, Marina del Rey, California, United States of America.
28
Department of Genetics, Rutgers University, Piscataway, New Jersey, United States of America.
29
Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

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-valuesbinomial≤0.01). 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.

PMID:
30044860
PMCID:
PMC6059436
DOI:
10.1371/journal.pone.0200486
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Two coauthors were affiliated with commercial organizations (JRM at Write InSciTe, LLC, and JMJ at the Genotyping Arrays Division at Illumina, Inc.) at the time of the completion of this manuscript. These affiliations did not alter our adherence to PLOS ONE policies on sharing and data materials. Therefore, the coauthors collectively have declared that no competing interests exist.

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