Association of adiposity genetic variants with menarche timing in 92,105 women of European descent

Abstract

Obesity is of global health concern. There are well-described inverse relationships between female pubertal timing and obesity. Recent genome-wide association studies of age at menarche identified several obesity-related variants. Using data from the ReproGen Consortium, we employed meta-analytical techniques to estimate the associations of 95 a priori and recently identified obesity-related (body mass index (weight (kg)/height (m)(2)), waist circumference, and waist:hip ratio) single-nucleotide polymorphisms (SNPs) with age at menarche in 92,116 women of European descent from 38 studies (1970-2010), in order to estimate associations between genetic variants associated with central or overall adiposity and pubertal timing in girls. Investigators in each study performed a separate analysis of associations between the selected SNPs and age at menarche (ages 9-17 years) using linear regression models and adjusting for birth year, site (as appropriate), and population stratification. Heterogeneity of effect-measure estimates was investigated using meta-regression. Six novel associations of body mass index loci with age at menarche were identified, and 11 adiposity loci previously reported to be associated with age at menarche were confirmed, but none of the central adiposity variants individually showed significant associations. These findings suggest complex genetic relationships between menarche and overall obesity, and to a lesser extent central obesity, in normal processes of growth and development.

Keywords: adiposity; body mass index; genetic association studies; menarche; obesity; waist circumference; waist:hip ratio; women's health.

Figure 1.

Secular trends in mean age at menarche among 38 studies of women of European descent in the ReproGen Consortium, by continent of origin (Europe (n = 28; white circles) or United States/Australia (n = 10; black diamonds)). The ReproGen Consortium studies were conducted in Europe, the United States, and Australia between 1970 and 2010 (see Web Table 1). The best-fit line includes all studies and corresponds to an 11.2-day decline in age at menarche per decade.

Figure 2.

Effect estimates for the association between overall and central adiposity genetic risk scores (GRS) and age at menarche in the Atherosclerosis Risk in Communities (ARIC) Study (n = 4,775; bars with vertical thin stripes) (52), the Women's Genome Health Study (WGHS) (n = 22,863; white bars) (53), and 38 studies in the ReproGen Consortium, using SNP-level fixed-effect estimates from a sample of up to 92,105 women (bars with diagonal thick stripes) (for references, see Web Appendix). The ARIC and WGHS studies were conducted in the United States in 1987–1989 and 1992–1994, respectively; other ReproGen studies included in the SNP-level fixed-effect estimates were conducted in Europe, the United States, and Australia between 1970 and 2010 (see Web Table 1). Cumulative genetic risk was defined as the sum of the menarche risk alleles per individual. Genetic risk scores were calculated for overall (BMI) and central adiposity (WC/WHR) variants separately. Adjustments were made for birth year, population stratification, and center (appropriate for the ARIC Study only). Further details about the use of SNP-level fixed-effect estimates can be found in the Web Appendix. Bars, 95% confidence interval. BMI, body mass index; SNP, single-nucleotide polymorphism; WC, waist circumference; WHR, waist:hip ratio.