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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.

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.

SUBMITTER: Fernandez-Rhodes L

PROVIDER: S-EPMC6059436 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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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.

Fernández-Rhodes Lindsay L Malinowski Jennifer R JR Wang Yujie Y Tao Ran R Pankratz Nathan N Jeff Janina M JM Yoneyama Sachiko S Carty Cara L CL Setiawan V Wendy VW Le Marchand Loic L Haiman Christopher C Corbett Steven S Demerath Ellen E Heiss Gerardo G Gross Myron M Buzkova Petra P Crawford Dana C DC Hunt Steven C SC Rao D C DC Schwander Karen K Chakravarti Aravinda A Gottesman Omri O Abul-Husn Noura S NS Bottinger Erwin P EP Loos Ruth J F RJF Raffel Leslie J LJ Yao Jie J Guo Xiuqing X Bielinski Suzette J SJ Rotter Jerome I JI Vaidya Dhananjay D Chen Yii-Der Ida YI Castañeda Sheila F SF Daviglus Martha M Kaplan Robert R Talavera Gregory A GA Ryckman Kelli K KK Peters Ulrike U Ambite Jose Luis JL Buyske Steven S Hindorff Lucia L Kooperberg Charles C Matise Tara T Franceschini Nora N North Kari E KE

PloS one 20180725 7

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 w ...[more]

PMID: 30044860

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Project description:STUDY QUESTIONDo 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 ANSWERWe 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 ALREADYMenarche 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, DURATIONA total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM.MATERIALS, SETTING, METHODSSNPs 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.MAIN RESULTS AND THE ROLE OF CHANCEWe 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 CAUTIONLack 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 FINDINGSThe 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.

Project description:By relating hundreds of thousands of genotypes to only a few phenotypes, mostly in individuals of one ancestry, genome-wide association (GWA) studies are identifying a rapidly growing number of associations. The Population Architecture using Genomics and Epidemiology (PAGE) Study is designed to further characterize the most promising variants along an epidemiological dimension that is substantial in its sample size, ethnic diversity, breadth of phenotypes, and exposures. PAGE includes scientists and population samples from large ongoing cohort studies: CALiCo (Causal Variants Across the Life Course, a consortium of ARIC, CARDIA, CHS, HCHS/SOL, Strong Heart Cohort Study, Strong Heart Family Study), EAGLE (Epidemiologic Architecture for Genes Linked to Environment, based on 3 National Health and Nutrition Examination Surveys (NHANES), MEC (Multiethnic Cohort) and WHI (Women's Health Initiative), with logistical and scientific support contributed by a Coordinating Center and the NHGRI Office of Population Genomics. These studies combined include over 270,000 participants, and populations represented include Asian Americans, African Americans, European Americans, Hispanic Americans, Native Hawaiians and American Indians. Health outcomes and traits of interest are prioritized, followed by replication of trait-genotype associations and generalization of their effects across population groups and environmental contexts. The first phase of genotyping focused on 901 high-profile SNPs having replicated associations with phenotypes related to diabetes, obesity, cardiovascular disease, lipids, cancers, menopause/menarche, inflammation and autoimmunity that are being genotyped in over 121,000 participants, as available for trait-specific analyses. SNP genotyping, quality control and population-specific association analyses are performed within each cohort, followed by meta-analyses using harmonized phenotypes and standardized analytic methods. The second phase of genotyping will be done using the Metabochip. The Metabochip is a custom large-scale (~200K SNPs) Illumina chip designed for association testing of several metabolic-related phenotypes. Genotyping will be performed at each study site and centralized analysis will be managed through the coordinating center. PAGE is generating 3 types of data: tier 1 (minimally curated phenotypes and analyses, all SNPs by all available phenotypes, used for Phenome-wide association study (PheWAS analysis)), tier 2 (carefully curated analyses of phenotypes available at only one of the four PAGE sites) and tier 3 (carefully curated phenotypes for multi-site analyses, data specifically generated for manuscripts). All tiers of data are submitted to the CC, where they undergo QC prior to submission to dbGaP.

Project description:Using a phenome-wide association study (PheWAS) approach, we comprehensively tested genetic variants for association with phenotypes available for 70,061 study participants in the Population Architecture using Genomics and Epidemiology (PAGE) network. Our aim was to better characterize the genetic architecture of complex traits and identify novel pleiotropic relationships. This PheWAS drew on five population-based studies representing four major racial/ethnic groups (European Americans (EA), African Americans (AA), Hispanics/Mexican-Americans, and Asian/Pacific Islanders) in PAGE, each site with measurements for multiple traits, associated laboratory measures, and intermediate biomarkers. A total of 83 single nucleotide polymorphisms (SNPs) identified by genome-wide association studies (GWAS) were genotyped across two or more PAGE study sites. Comprehensive tests of association, stratified by race/ethnicity, were performed, encompassing 4,706 phenotypes mapped to 105 phenotype-classes, and association results were compared across study sites. A total of 111 PheWAS results had significant associations for two or more PAGE study sites with consistent direction of effect with a significance threshold of p<0.01 for the same racial/ethnic group, SNP, and phenotype-class. Among results identified for SNPs previously associated with phenotypes such as lipid traits, type 2 diabetes, and body mass index, 52 replicated previously published genotype-phenotype associations, 26 represented phenotypes closely related to previously known genotype-phenotype associations, and 33 represented potentially novel genotype-phenotype associations with pleiotropic effects. The majority of the potentially novel results were for single PheWAS phenotype-classes, for example, for CDKN2A/B rs1333049 (previously associated with type 2 diabetes in EA) a PheWAS association was identified for hemoglobin levels in AA. Of note, however, GALNT2 rs2144300 (previously associated with high-density lipoprotein cholesterol levels in EA) had multiple potentially novel PheWAS associations, with hypertension related phenotypes in AA and with serum calcium levels and coronary artery disease phenotypes in EA. PheWAS identifies associations for hypothesis generation and exploration of the genetic architecture of complex traits.

Dataset Information

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.

Publications

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.

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