Accessibility issues or difficulties with this website?
Call 919-962-2073 or email hchsadministration@unc.edu.

Large trans-ethnic meta-analysis identifies AKR1C4 as a novel gene associated with age at menarche

TitleLarge trans-ethnic meta-analysis identifies AKR1C4 as a novel gene associated with age at menarche
Publication TypePublication
Year2021
AuthorsSarnowski C, Cousminer DL, Franceschini N, Raffield LM, Jia G, Fernandez-Rhodes L, Grant SFA, Hakonarson H, Lange LA, Long J, Sofer T, Tao R, Wallace RB, Wong Q, Zirpoli G, Boerwinkle E, Bradfield JP, Correa A, Kooperberg CL, North KE, Palmer JR, Zemel BS, Zheng W, Murabito JM, Lunetta KL
JournalHum Reprod
Volume36
Issue7
Pagination1999-2010
Date Published2021 06 18
ISSN1460-2350
KeywordsAdolescent, Cohort Studies, ethnic groups, Female, genome-wide association study, Humans, Menarche, Polymorphism, Single Nucleotide
Abstract

STUDY QUESTION: Does the expansion of genome-wide association studies (GWAS) to a broader range of ancestries improve the ability to identify and generalise variants associated with age at menarche (AAM) in European populations to a wider range of world populations?

SUMMARY ANSWER: By including women with diverse and predominantly non-European ancestry in a large-scale meta-analysis of AAM with half of the women being of African ancestry, we identified a new locus associated with AAM in African-ancestry participants, and generalised loci from GWAS of European ancestry individuals.

WHAT IS KNOWN ALREADY: AAM is a highly polygenic puberty trait associated with various diseases later in life. Both AAM and diseases associated with puberty timing vary by race or ethnicity. The majority of GWAS of AAM have been performed in European ancestry women.

STUDY DESIGN, SIZE, DURATION: We analysed a total of 38 546 women who did not have predominantly European ancestry backgrounds: 25 149 women from seven studies from the ReproGen Consortium and 13 397 women from the UK Biobank. In addition, we used an independent sample of 5148 African-ancestry women from the Southern Community Cohort Study (SCCS) for replication.

PARTICIPANTS/MATERIALS, SETTING, METHODS: Each AAM GWAS was performed by study and ancestry or ethnic group using linear regression models adjusted for birth year and study-specific covariates. ReproGen and UK Biobank results were meta-analysed using an inverse variance-weighted average method. A trans-ethnic meta-analysis was also carried out to assess heterogeneity due to different ancestry.

MAIN RESULTS AND THE ROLE OF CHANCE: We observed consistent direction and effect sizes between our meta-analysis and the largest GWAS conducted in European or Asian ancestry women. We validated four AAM loci (1p31, 6q16, 6q22 and 9q31) with common genetic variants at P < 5 × 10-7. We detected one new association (10p15) at P < 5 × 10-8 with a low-frequency genetic variant lying in AKR1C4, which was replicated in an independent sample. This gene belongs to a family of enzymes that regulate the metabolism of steroid hormones and have been implicated in the pathophysiology of uterine diseases. The genetic variant in the new locus is more frequent in African-ancestry participants, and has a very low frequency in Asian or European-ancestry individuals.

LARGE SCALE DATA: N/A.

LIMITATIONS, REASONS FOR CAUTION: Extreme AAM (18 years) were excluded from analysis. Women may not fully recall their AAM as most of the studies were conducted many years later. Further studies in women with diverse and predominantly non-European ancestry are needed to confirm and extend these findings, but the availability of such replication samples is limited.

WIDER IMPLICATIONS OF THE FINDINGS: Expanding association studies to a broader range of ancestries or ethnicities may improve the identification of new genetic variants associated with complex diseases or traits and the generalisation of variants from European-ancestry studies to a wider range of world populations.

STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by CHARGE Consortium grant R01HL105756-07: Gene Discovery For CVD and Aging Phenotypes and by the NIH grant U24AG051129 awarded by the National Institute on Aging (NIA). The authors have no conflict of interest to declare.

DOI10.1093/humrep/deab086
Alternate JournalHum Reprod
PubMed ID34021356
PubMed Central IDPMC8213450
Grant ListHHSN268201300005C / HL / NHLBI NIH HHS / United States
HHSN268201800012C / HL / NHLBI NIH HHS / United States
HHSN268201600002C / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
P01 CA151135 / CA / NCI NIH HHS / United States
N01HC65235 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
R01 HL105756 / HL / NHLBI NIH HHS / United States
HHSN268201600004C / HL / NHLBI NIH HHS / United States
HHSN268201800015I / HB / NHLBI NIH HHS / United States
HHSN268201700004C / HL / NHLBI NIH HHS / United States
HHSN268201700003I / HL / NHLBI NIH HHS / United States
R01 CA202981 / CA / NCI NIH HHS / United States
U01 CA164974 / CA / NCI NIH HHS / United States
R01 CA098663 / CA / NCI NIH HHS / United States
HHSN268201600018C / HL / NHLBI NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
N01HC65236 / HL / NHLBI NIH HHS / United States
HHSN268201800014C / HL / NHLBI NIH HHS / United States
N01HC65234 / HL / NHLBI NIH HHS / United States
N01HC65233 / HL / NHLBI NIH HHS / United States
HHSN268201700002C / HL / NHLBI NIH HHS / United States
HHSN268201800013I / MD / NIMHD NIH HHS / United States
HHSN268201700001I / HL / NHLBI NIH HHS / United States
R01 HD056465 / HD / NICHD NIH HHS / United States
N01HC65237 / HL / NHLBI NIH HHS / United States
HHSN268201600003C / HL / NHLBI NIH HHS / United States
HHSN268201700004I / HL / NHLBI NIH HHS / United States
HHSN268201800011C / HL / NHLBI NIH HHS / United States
U24 AG051129 / AG / NIA NIH HHS / United States
K99 HD099330 / HD / NICHD NIH HHS / United States
HHSN268201600001C / HL / NHLBI NIH HHS / United States
HHSN268201700005C / HL / NHLBI NIH HHS / United States
HHSN268201700001C / HL / NHLBI NIH HHS / United States
HHSN268201700003C / HL / NHLBI NIH HHS / United States
HHSN268201700002I / HL / NHLBI NIH HHS / United States
HHSN268201700005I / HL / NHLBI NIH HHS / United States
U01 CA202979 / CA / NCI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
MS#: 
0974B
Manuscript Lead/Corresponding Author Affiliation: 
Coordinating Center - Collaborative Studies Coordinating Center - UNC at Chapel Hill
ECI: 
Yes
Manuscript Affiliation: 
Coordinating Center - Collaborative Studies Coordinating Center - UNC at Chapel Hill
Manuscript Status: 
Published and Public