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Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study.

TitleReplication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study.
Publication TypeJournal Article
Year of Publication2013
AuthorsCarty CL, Spencer KL, Setiawan VW, Fernández-Rhodes L, Malinowski J, Buyske S, Young A, Jorgensen NW, Cheng I, Carlson CS, Brown-Gentry K, Goodloe R, Park A, Parikh NI, Henderson B, Le Marchand L, Wactawski-Wende J, Fornage M, Matise TC, Hindorff LA, Arnold AM, Haiman CA, Franceschini N, Peters U
Secondary AuthorsCrawford DC
JournalHum Reprod
Volume28
Issue6
Pagination1695-706
Date Published2013 Jun
ISSN1460-2350
KeywordsAge Factors, Cross-Sectional Studies, Female, Genome-Wide Association Study, Genotype, Humans, Menarche, Menopause, Polymorphism, Single Nucleotide
Abstract

STUDY QUESTION: Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study?

SUMMARY ANSWER: We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry.

WHAT IS KNOWN ALREADY: Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations.

STUDY DESIGN, SIZE, DURATION: A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM.

MATERIALS, SETTING, METHODS: SNPs previously associated with ANM (n = 5 SNPs) and AM (n = 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P

MAIN RESULTS AND THE ROLE OF CHANCE: We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends.

LIMITATIONS, REASONS FOR CAUTION: Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings.

WIDER IMPLICATIONS OF THE FINDINGS: The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research.

DOI10.1093/humrep/det071
Alternate JournalHum Reprod
PubMed ID23508249
PubMed Central IDPMC3657124
Grant ListUL1RR025005 / RR / NCRR NIH HHS / United States
N01-HC-45205 / HC / NHLBI NIH HHS / United States
UL1TR000124 / TR / NCATS NIH HHS / United States
N01WH22110 / WH / WHI NIH HHS / United States
N01-HC-05187 / HC / NHLBI NIH HHS / United States
U01CA98758 / CA / NCI NIH HHS / United States
U01 HL65520 / HL / NHLBI NIH HHS / United States
N01WH42129-32 / WH / WHI NIH HHS / United States
HHHSN268201100005C / / PHS HHS / United States
N01-HC-85085 / HC / NHLBI NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
T32 GM080178 / GM / NIGMS NIH HHS / United States
5T32HL007055 / HL / NHLBI NIH HHS / United States
U01 HG004790 / HG / NHGRI NIH HHS / United States
N01-HC-48047 / HC / NHLBI NIH HHS / United States
U01 HL65521 / HL / NHLBI NIH HHS / United States
N01-HC-85081 / HC / NHLBI NIH HHS / United States
U01 HL41642 / HL / NHLBI NIH HHS / United States
HL105756 / HL / NHLBI NIH HHS / United States
N01WH32100-2 / WH / WHI NIH HHS / United States
HHSN268201100009C / / PHS HHS / United States
U01CA136792 / CA / NCI NIH HHS / United States
N01WH32108-9 / WH / WHI NIH HHS / United States
U01HG004803 / HG / NHGRI NIH HHS / United States
N01-HC-95095 / HC / NHLBI NIH HHS / United States
HHSN268200625226C / / PHS HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
U01HG004802 / HG / NHGRI NIH HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
N01WH42107-26 / WH / WHI NIH HHS / United States
HHSN268201100010C / / PHS HHS / United States
N01-HC-15103 / HC / NHLBI NIH HHS / United States
N01-HC-48050 / HC / NHLBI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
U01 HL41654 / HL / NHLBI NIH HHS / United States
N01-HC-85082 / HC / NHLBI NIH HHS / United States
N01-HC-35129 / HC / NHLBI NIH HHS / United States
N01-HC-45134 / HC / NHLBI NIH HHS / United States
N01 HC-55222 / HC / NHLBI NIH HHS / United States
HHSN268201100008C / / PHS HHS / United States
HHSN268201100012C / / PHS HHS / United States
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N01WH32122 / WH / WHI NIH HHS / United States
U54 MD007584 / MD / NIMHD NIH HHS / United States
N01-HC-48049 / HC / NHLBI NIH HHS / United States
U01HG004798-01 / HG / NHGRI NIH HHS / United States
U01HG004798 / HG / NHGRI NIH HHS / United States
N01-HC-85083 / HC / NHLBI NIH HHS / United States
N01-HC-75150 / HC / NHLBI NIH HHS / United States
N01-HC-85080 / HC / NHLBI NIH HHS / United States
HHSN268201100007C / / PHS HHS / United States
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P01CA33619 / CA / NCI NIH HHS / United States
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R01HL086694 / HL / NHLBI NIH HHS / United States
R01 CA63 / CA / NCI NIH HHS / United States