Abstract P158: Evidence for Shared Genetic Loci between Body Mass Index and Menarche Timing among 2,073 African American Women in the Atherosclerosis Risk in Communities (ARIC) Study
Authors: Lindsay Fernández-Rhodes
Journal: Circulation (2013)

Obesity is an important cardiovascular risk factor. Body mass index (BMI) is a proxy measure of obesity often used in large epidemiological studies. Age at menarche has marked historical secular trends in female pubertal timing. A recent study has found overlapping obesity and age at menarche genetic loci among women of European descent. Interestingly, the association findings at these loci conform to the expected epidemiologic relationship, in which the same susceptibility allele is associated with both early menarche and obesity. Yet to date this relationship has not been investigated among individuals of diverse ancestry with a high prevalence of both early menarche and obesity, such as African American women. We therefore selected 25 validated BMI genetic loci available on the MetaboChip array and interrogated their association with age at menarche among 2,073 unrelated African American women in the Atherosclerosis Risk in Communities (ARIC) Study. Self-reported menarche ages (in years) beyond three standard deviations from the mean were excluded. Given the complexity of linkage disequilibrium structure among African Americans, we defined regions to be within 500kb of each validated single nucleotide polymorphisms (SNPs) and comprising at least 100 SNPs. Assuming an additive genetic model, we performed linear regression of the association between age of menarche and each SNP in the region while adjusting for birth year, study site, and the first 10 principal components to measure global ancestry. We adjusted for multiple testing using a Bonferroni threshold for the number loci tested. The mean (SD) age at menarche and BMI in our sample was 12.9 (1.7) years and 30.8 (6.6) kg/m 2 . Of the 25 BMI loci available, all contained at least one SNP with nominally significant association with age at menarche (p&lt;0.05). However, nine of these loci contained at least one SNP that remained significant after multiple testing adjustment (p&lt;0.002; NEGR1, SEC16B, ETV5, GNPDA2, TFAP2B, PRKD1, GP2, SH2B1, MC4R ). PRKD1 and MC4R contained the strongest evidence of association with menarche (p&lt;0.0002). Significant SNPs at the MC4R locus were in weak linkage disequilibrium with the index SNPs reported to associate with BMI in the literature (r 2 &lt;0.28 in HapMap CEU). All other significant SNP associations were unavailable in HapMap or beyond 500kb from previously reported index SNP(s). In conclusion, a number of BMI loci showed evidence for association with age at menarche among African American women. As part of the Population Architecture using Genomics and Epidemiology consortium, we are currently analyzing ~30,000 additional women of African, Asian, and Hispanic ancestry within the consortium to determine if the same loci are informative for menarche across ancestrally diverse populations. The conclusions of this work may help illucidate the underlying genetic mechanisms of female growth and development.