ESPE Abstracts

Background: Age at menarche in girls varies widely between individuals, is a heritable trait and is associated with risks for adult obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality.

Objective and Hypotheses: The mechanisms that determine pubertal timing and underlie its links to later disease remain unclear.

Method: We performed a genome-wide association study meta-analysis of genome-wide or dense custom-genotyping arrays in up to 182 416 women of European descent from 57 individual studies. Evidence for parent-of-origin specific allelic associations at imprinted loci was tested in a unique cohort of 35 377 women whose allelic parental origins had been determined by a combination of genealogy and long-range phasing.

Results: We found robust evidence (P<5×10⁻⁸) for 123 independent signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in BMI and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted gene regions compared to published genome-wide-significant signals for all other traits (6/123, 4.8% vs 75/4332, 1.7%; P=0.017). Three imprinted menarche loci (DLK1/WDR25, MKRN3/MAGEL2, and KCNK9) demonstrated parent-of-origin specific associations concordant with their known parental expression patterns. Other findings implicated lysine-specific histone demethylases and nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans.

Conclusion: Our findings indicate both BMI-related and BMI-independent mechanisms that could underlie the epidemiological associations between early menarche and higher risks of adult disease. Of note, only few parent-of-origin specific allelic associations at imprinted loci have been described for complex traits. Our findings implicate differential pubertal timing, a trait with putative selection advantages, as a potential additional target for the evolution of genomic imprinting.