Genomic analyses for age at menarche identify 389 independent signals and indicate BMI-independent effects of puberty timing on cancer susceptibility

Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Here, we analyse 1000-Genome reference panel imputed genotype data on up to ~370,000 women and identify 389 independent signals (all P<5×10 -8 ) for age at menarche, a notable milestone in female pubertal development. In Icelandic data from deCODE, these signals explain ~7.4% of the population variance in age at menarche, corresponding to one quarter of the estimated heritability. We implicate over 250 genes via coding variation or associated gene expression, and demonstrate enrichment across genes active in neural tissues. We identify multiple rare variants near the imprinted genes MKRN3 and DLK1 that exhibit large effects on menarche only when paternally inherited. Disproportionate effects of variants on early or late puberty timing are observed: single variant and heritability estimates are larger for early than late puberty timing in females. The opposite pattern is seen in males, with larger estimates for late than early puberty timing. Mendelian randomization analyses indicate causal inverse associations, independent of BMI, between puberty timing and risks for breast and endometrial cancers in women, and prostate cancer in men. In aggregate, our findings reveal new complexity in the genetic regulation of puberty timing and support new causal links with adult cancer risks.

Genetically Determined Later Puberty Impacts Lowered Bone Mineral Density in Childhood and Adulthood

“…Additionally, one genetic locus at chromosome 12q13 is genome-wide associated with both AAM 17 and adult BMD 13 , although the lead variants differ and are in partial LD (rs1054442 (AAM) and rs12821008 (BMD), r 2 = 0.57), and the causal gene(s) is unknown. Further work is needed to identify the key genes at these loci that mediate links between pubertal timing and bone acquisition.…”

“…Imputation was performed using the Haplotype Reference Consortium panel (r1.1 2016, https://imputationserver.sph.umich.edu/index.html) 27 . In this study, we included 333 common, well-imputed autosomal puberty-associated variants 17 . To define ancestry, we used principal component analysis and ADMIXTURE (> 50% European ancestry) 16 .…”

“…We calculated two puberty-delaying GRS, which represent a sum of puberty-delaying alleles weighted on their effect sizes on pubertal timing derived from large-scale GWASs, using PLINK, a whole-genome association analysis toolset (28) : (i) female-GRS: a GRS summed across 333 AAM alleles, weighted on AAMdelaying effect estimates derived from a large-scale GWAS performed by the ReproGen Consortium (http://www.reprogen. org/; Supporting Table 2) (17) ; and (ii) male-GRS: a GRS summing 49 alleles that were genomewide significant for AAM but also associated with AVB (p < 0.05), weighted on the AVM-delaying effect estimates (Supporting Table 3). All of the male effect estimates for AVB were directionally concordant with those for AAM.…”

“…For pubertal timing, 380 variants have been associated with AAM in females and/or AVB in males 17 . Recent co-heritability studies using LD-score regression found that pubertal timing and adult aBMD share a common genetic etiology; this genetic correlation suggests that some of the same genetic variants impact both traits 18,19 .…”

“…(14)(15)(16) For pubertal timing, 380 variants have been associated with AAM in females and/or AVB in males. (17) Recent co-heritability studies using linkage disequilibrium score regression (LDSC) score regression found that pubertal timing and adult aBMD share a common genetic etiology; this genetic correlation suggests that some of the same genetic variants impact both traits. (18,19) In addition, in disorders of absent puberty, such as Turner and Kallmann syndromes, there are clear skeletal defects.…”