Evaluation of GWAS-identified genetic variants for age at menarche among Chinese women

Human Reproduction, Apr 2013

STUDY QUESTION Do genetic polymorphisms which influence age at menarche in women of European ancestry also influence women of Chinese ancestry?

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Evaluation of GWAS-identified genetic variants for age at menarche among Chinese women

R.J. Delahanty 2 A. Beeghly-Fadiel 2 J.R. Long 2 Y.T. Gao 1 W. Lu 0 Y.B. Xiang 1 Y. Zheng 0 B.T. Ji 3 W.Q. Wen 2 Q.Y. Cai 2 W. Zheng 2 X.O. Shu 2 0 Shanghai Municipal Center for Disease Prevention and Control, Shanghai Institute of Preventive Medicine , 1380 Zhong Shan Road (W), Shanghai 200336, China 1 Department of Epidemiology, Shanghai Cancer Institute , 2200/25 Xie Tu Road, Shanghai 200032, China 2 Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center , 2525 West End Avenue, Suite 600 (IMPH), Nashville, TN 37203-1738, USA 3 Division of Cancer Epidemiology and Genetics, National Cancer Institute , Bethesda, MD 20892, USA study question: Do genetic polymorphisms which influence age at menarche in women of European ancestry also influence women of Chinese ancestry? summary answer: Many genetic variants influencing age at menarche in European populations appear to impact Chinese populations in a similar manner. what is known and what this paper adds: Prior genome-wide association studies have uncovered 42 SNPs associated with age at menarche in European populations. This study is the first to demonstrate that many of the genetic determinants of age at menarche are shared between European and Chinese women. participants and setting: We evaluated 37 of 42 SNPs identified as associated with age at menarche from a recent, large metaanalysis, consisting primarily of women of European ancestry, in a population of 6929 Chinese women from Shanghai, China. We also constructed weighted genetic risk scores (GRSs) combining the number of effect variants for all 37 SNPs, or only the SNPs associated with age at menarche among our study population, to evaluate their joint influence on age at menarche. main results: For 32 of the 37 evaluated variants, the direction of the allele associations were the same between women of European ancestry and women of Chinese ancestry (P 3.71 1026, binomial sign test); 9 of these were statistically significant. Subjects in the highest quintile of GRSs began menarche 5 months later than those in the lowest quintile. bias, limitations and generalizability to other populations: Age at menarche was obtained by self-report, which can be subject to recall errors. The current analysis was restricted to loci which met or approached GWAS significance thresholds and did not evaluate loci which may act predominantly or exclusively in the Chinese population. The smaller sample size for our meta-analysis compared with meta-analyses conducted in European populations reduced the power to detect significant results. study funding/competing interests: This study was supported, in part, by grants from US National Institutes of Health (grants R01CA124558, R01CA090899, R01CA070867; R01CA064277 and R01CA092585 and UL1 RR024975), Ingram professorship funds and Allen Foundation funds. There are no competing interests to declare. Background As with other measures of growth and development, recent investigations into the genetics of age at menarche have uncovered several loci associated with its timing, including single nucleotide polymorphisms (SNPs) on chromosome 6q16.3 near the LIN28B gene (He et al., 2009; Ong et al., 2009; Perry et al., 2009; Sulem et al., 2009; ) and a locus in an intergenic region at 9q31.28 (He et al., 2009; Perry et al., 2009). A large meta-analysis of women of European ancestry by the ReproGen Consortium has recently reported 42 loci associated with age at menarche, including both the LIN28B and 9q loci (Elks et al., 2010). Earlier onset of puberty in girls may also be related to diet and fat accumulation (Dietz, 1998). Improved economic standards and access to nutrition in Europe has corresponded with a decrease in the average age at menarche from 17 in 1830 to 13 in 1960 (Education and Science and Plowden, 1967). The recent rapid development of economies in East Asia has likewise lead to increased standards of living and greater access to nutrition (Shen et al., 1996; Mason et al., 2001). With these improvements, age at menarche among Asian women has decreased following a pattern similar to that seen in Europe (Parent et al., 2003; Graham et al., 1999). In 1979, the mean age at menarche in China was 13.5; among girls surveyed from 2003 to 2005, it had decreased to 12.3 (Ma et al., 2009). Early menarche has been associated with several important clinical outcomes. Women who mature early are at increased risk later in life for breast (Kelsey et al., 1993) and endometrial (Weiderpass et al., 1999) cancer, obesity (Adair and Gordon-Larsen, 2001), type 2 diabetes (Lakshman et al., 2008) and cardiovascular disease (Okasha et al., 2001). They are also at higher risk of teenage pregnancy and a number of psychosocial problems, including depression, anxiety and substance abuse (Stice et al., 2001; Harlow et al., 2004). No genome-wide association study (GWAS) to date has evaluated age at m (...truncated)


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R.J. Delahanty, A. Beeghly-Fadiel, J.R. Long, Y.T. Gao, W. Lu, Y.B. Xiang, Y. Zheng, B.T. Ji, W.Q. Wen, Q.Y. Cai, W. Zheng, X.O. Shu. Evaluation of GWAS-identified genetic variants for age at menarche among Chinese women, Human Reproduction, 2013, pp. 1135-1143, 28/4, DOI: 10.1093/humrep/det011