Journal article
Large trans-ethnic meta-analysis identifies AKRIC4 as a novel gene associated with age at menarche
Human reproduction (Oxford), Vol.36(7), pp.1999-2010
07/01/2021
DOI: 10.1093/humrep/deab086
PMCID: PMC8213450
PMID: 34021356
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 x 10(-7). We detected one new association (10p15) at P < 5 x 10(-8) with a low-frequency genetic variant lying in AKRIC4, 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 (<9 years or > 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.
Details
- Title: Subtitle
- Large trans-ethnic meta-analysis identifies AKRIC4 as a novel gene associated with age at menarche
- Creators
- C. Sarnowski - Boston UniversityD. L. Cousminer - University of PennsylvaniaN. Franceschini - University of North Carolina at Chapel HillL. M. Raffield - University of North Carolina at Chapel HillG. Jia - Vanderbilt University Medical CenterL. Fernandez-Rhodes - Pennsylvania State UniversityS. F. A. Grant - Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USAH. Hakonarson - Center for Applied GenomicsL. A. Lange - University of Colorado DenverJ. Long - Vanderbilt University Medical CenterT. Sofer - Brigham and Women's HospitalR. Tao - Vanderbilt University Medical CenterR. B. Wallace - University of IowaQ. Wong - University of WashingtonG. Zirpoli - Boston UniversityE. Boerwinkle - Human Genetic Center and Department of Epidemiology, The University of Texas School of Public Health, Houston, TX, USA.J. P. Bradfield - Children's Hospital of PhiladelphiaA. Correa - University of Mississippi Medical CenterC. L. Kooperberg - Fred Hutch Cancer CenterK. E. North - Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27515 USAJ. R. Palmer - Boston UniversityB. S. Zemel - University of PennsylvaniaW. Zheng - Vanderbilt University Medical CenterJ. M. Murabito - Boston UniversityK. L. Lunetta - Boston University
- Resource Type
- Journal article
- Publication Details
- Human reproduction (Oxford), Vol.36(7), pp.1999-2010
- DOI
- 10.1093/humrep/deab086
- PMID
- 34021356
- PMCID
- PMC8213450
- NLM abbreviation
- Hum Reprod
- ISSN
- 0268-1161
- eISSN
- 1460-2350
- Publisher
- Oxford Univ Press
- Number of pages
- 12
- Grant note
- R01HL105756-07 / CHARGE Consortium grant U24AG051129 / NIH - National Institute on Aging (NIA); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA)
- Language
- English
- Date published
- 07/01/2021
- Academic Unit
- Epidemiology; Injury Prevention Research Center; Internal Medicine
- Record Identifier
- 9984364408902771
Metrics
8 Record Views