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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.

TitleThe 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.
Publication TypePublication
Year2018
AuthorsFernández-Rhodes L, Malinowski JR, Wang Y, Tao R, Pankratz N, Jeff JM, Yoneyama S, Carty CL, V Setiawan W, Le Marchand L, Haiman C, Corbett S, Demerath E, Heiss G, Gross M, Buzkova P, Crawford DC, Hunt SC, Rao DC, Schwander K, Chakravarti A, Gottesman O, Abul-Husn NS, Bottinger EP, Loos RJF, Raffel LJ, Yao J, Guo X, Bielinski SJ, Rotter JI, Vaidya D, Chen Y-DIda, Castañeda SF, Daviglus M, Kaplan R, Talavera GA, Ryckman KK, Peters U, Ambite JLuis, Buyske S, Hindorff L, Kooperberg C, Matise T, Franceschini N, North KE
JournalPLoS One
Volume13
Issue7
Paginatione0200486
Date Published2018
ISSN1932-6203
KeywordsAge Factors, Alleles, Biological Variation, Population, Female, Genetic Loci, Genotype, Humans, Menarche, Menopause, Phenotype, Polymorphism, Single Nucleotide
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.

DOI10.1371/journal.pone.0200486
Alternate JournalPLoS One
PubMed ID30044860
PubMed Central IDPMC6059436
Grant ListU01 HG007419 / HG / NHGRI NIH HHS / United States
R01 HL071251 / HL / NHLBI NIH HHS / United States
R01 HL071259 / HL / NHLBI NIH HHS / United States
UL1 TR001420 / TR / NCATS NIH HHS / United States
R01 HL071258 / HL / NHLBI NIH HHS / United States
UL1 TR000040 / TR / NCATS NIH HHS / United States
HHSN268201100008C / HL / NHLBI NIH HHS / United States
U01 HG007417 / HG / NHGRI NIH HHS / United States
U01 HG004798 / HG / NHGRI NIH HHS / United States
R01 HD057194 / HD / NICHD NIH HHS / United States
U01 HG004802 / HG / NHGRI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
HHSN263201500003I / NH / NIH HHS / United States
U01 HG004801 / HG / NHGRI NIH HHS / United States
HHSN268201300028C / HL / NHLBI NIH HHS / United States
UL1 TR001881 / TR / NCATS NIH HHS / United States
HHSN268201300027C / HL / NHLBI NIH HHS / United States
HHSN268201100007C / HL / NHLBI NIH HHS / United States
U01 HG007416 / HG / NHGRI NIH HHS / United States
HHSN268200900041C / HL / NHLBI NIH HHS / United States
HHSN268201100011C / HL / NHLBI NIH HHS / United States
R01 DK089256 / DK / NIDDK NIH HHS / United States
U01 HG007376 / HG / NHGRI NIH HHS / United States
/ RA / ARRA NIH HHS / United States
R01 HL071051 / HL / NHLBI NIH HHS / United States
R01 HL071205 / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
HHSN268201300029C / HL / NHLBI NIH HHS / United States
HHSN268201300025C / HL / NHLBI NIH HHS / United States
R56 HG010297 / HG / NHGRI NIH HHS / United States
U01 CA136792 / CA / NCI NIH HHS / United States
HHSN268201100012C / HL / NHLBI NIH HHS / United States
UL1 RR033176 / RR / NCRR NIH HHS / United States
HHSN268201100005C / HL / NHLBI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
HHSN268201100009C / HL / NHLBI NIH HHS / United States
UL1 TR001079 / TR / NCATS NIH HHS / United States
S10 OD020069 / OD / NIH HHS / United States
HHSN268201100006C / HL / NHLBI NIH HHS / United States
R01 DK101855 / DK / NIDDK NIH HHS / United States
P2C HD050924 / HD / NICHD NIH HHS / United States
T32 HL007055 / HL / NHLBI NIH HHS / United States
R01 HL071250 / HL / NHLBI NIH HHS / United States
P30 CA071789 / CA / NCI NIH HHS / United States
HHSN268201300026C / HL / NHLBI NIH HHS / United States
U01 HG004790 / HG / NHGRI NIH HHS / United States
U01 HG004803 / HG / NHGRI NIH HHS / United States
HHSN268201100010C / HL / NHLBI NIH HHS / United States
P50 ES015915 / ES / NIEHS NIH HHS / United States
R01 CA063464 / CA / NCI NIH HHS / United States
UL1 TR000445 / TR / NCATS NIH HHS / United States
MS#: 
0281
ECI: 
Manuscript Status: 
Published