title: Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study.
abstract: OBJECTIVE
  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?
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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.
  
  
  METHODS
  A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM.
  
  
  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 < 0.01 for ANM analyses and P < 0.017 for AM analyses.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. ccarty@fhcrc.org
authors.forename: C L
authors.initials: CL
authors.lastname: Carty
authors.forename: K L
authors.initials: KL
authors.lastname: Spencer
authors.forename: V W
authors.initials: VW
authors.lastname: Setiawan
authors.forename: L
authors.initials: L
authors.lastname: Fernandez-Rhodes
authors.forename: J
authors.initials: J
authors.lastname: Malinowski
authors.forename: S
authors.initials: S
authors.lastname: Buyske
authors.forename: A
authors.initials: A
authors.lastname: Young
authors.forename: N W
authors.initials: NW
authors.lastname: Jorgensen
authors.forename: I
authors.initials: I
authors.lastname: Cheng
authors.forename: C S
authors.initials: CS
authors.lastname: Carlson
authors.forename: K
authors.initials: K
authors.lastname: Brown-Gentry
authors.forename: R
authors.initials: R
authors.lastname: Goodloe
authors.forename: A
authors.initials: A
authors.lastname: Park
authors.forename: N I
authors.initials: NI
authors.lastname: Parikh
authors.forename: B
authors.initials: B
authors.lastname: Henderson
authors.forename: L
authors.initials: L
authors.lastname: Le Marchand
authors.forename: J
authors.initials: J
authors.lastname: Wactawski-Wende
authors.forename: M
authors.initials: M
authors.lastname: Fornage
authors.forename: T C
authors.initials: TC
authors.lastname: Matise
authors.forename: L A
authors.initials: LA
authors.lastname: Hindorff
authors.forename: A M
authors.initials: AM
authors.lastname: Arnold
authors.forename: C A
authors.initials: CA
authors.lastname: Haiman
authors.forename: N
authors.initials: N
authors.lastname: Franceschini
authors.forename: U
authors.initials: U
authors.lastname: Peters
authors.forename: D C
authors.initials: DC
authors.lastname: Crawford
mesh_terms: D000367:Age Factors; D003430:Cross-Sectional Studies; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008572:Menarche / Q000208:ethnology / Q000235:genetics*; D008593:Menopause / Q000208:ethnology / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide
keywords: genome-wide association study; menarche; menopause; race/ethnicity; single nucleotide polymorphism