The attached article describes an excellent example of what today’s genome-wide association studies (GWAS) are able to do –– finding genetic loci (throughout the genome) that are statistically significantly associated with very complicated multifactorial traits. In this case, the very complex multifactorial phenotype is “onset of menarche, i.e. age at which girls have their first menstrual period. Moreover, the timing of puberty, a highly polygenic childhood trait, is known to be epidemiologically associated with various adult diseases.
Using 1000 Genomes Project–imputed genotype data in as many as ~370,000 women, authors [attached] identified 389 independent signals (P <5.0 x 10–8) that were correlated with age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ~7.4% of the population variance in age at menarche, corresponding to ~25% of estimated heritability. Authors implicated ~250 genes via coding variation or associated expression –– demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses also suggested causal inverse associations, independent of body mass index (BMI), between puberty timing and risk for breast and endometrial cancers in women and prostate cancer in men. In agreement with other studies, earlier puberty is associated with increased risk of breast and prostate cancer. Altogether, these data highlight the complexity of genetic regulation of puberty timing and support causal links with cancer susceptibility. Nat Genet June 2o17; 49: 834–841