C Sarnowski1,2, D L Cousminer3,4,5, N Franceschini6, L M Raffield7, G Jia8, L Fernández-Rhodes9, S F A Grant3,4,10,11, H Hakonarson3,4,10,12, L A Lange13, J Long8, T Sofer14,15, R Tao16,17, R B Wallace18, Q Wong19, G Zirpoli20,21, E Boerwinkle22, J P Bradfield3,4,23, A Correa24,25,26, C L Kooperberg27, K E North6,28, J R Palmer20,21, B S Zemel10,29, W Zheng8, J M Murabito30,31, K L Lunetta1. 1. Boston University School of Public Health, Boston, MA, USA. 2. Department of Epidemiology, Human Genetics and Environmental Sciences, The University of Texas Health Science Center at Houston School of Public Health, Houston, TX, USA. 3. Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. 4. Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. 5. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 6. Department of Epidemiology, University of North Carolina at Chapel Hill Gillings School of Global Public Health, Chapel Hill, NC, USA. 7. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. 8. Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. 9. Department of Biobehavioral Health, College of Health and Human Development, Pennsylvania State University, University Park, PA, USA. 10. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 11. Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. 12. Division of Pulmonary Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. 13. Department of Medicine, University of Colorado Denver, Anschutz Medical Campus, Aurora, CO, USA. 14. Departments of Medicine and of Biostatistics, Harvard University, Boston, MA, USA. 15. Division of Sleep and Circadian Disorders, Departments of Medicine and Neurology, Brigham and Women's Hospital, Boston, MA, USA. 16. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA. 17. Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA. 18. University of Iowa College of Public Health, Iowa City, IA, USA. 19. Department of Biostatistics, University of Washington, Seattle, WA, USA. 20. Slone Epidemiology Center at Boston University, Boston, MA, USA. 21. Section of Hematology/Oncology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA. 22. Human Genetic Center and Department of Epidemiology, The University of Texas School of Public Health, Houston, TX, USA. 23. Quantinuum Research, LLC, Wayne, PA, USA. 24. Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA. 25. Department of Pediatrics, University of Mississippi Medical Center, Jackson, MS, USA. 26. Department of Population Health Science, University of Mississippi Medical Center, Jackson, MS, USA. 27. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 28. Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC, USA. 29. Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. 30. National Heart Lung and Blood Institute and Boston University's Framingham Heart Study, Framingham, MA, USA. 31. Section of General Internal Medicine, Department of Medicine, Boston University School of Medicine, Boston, MA, USA.
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 (<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. 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.
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 (<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. 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.
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