Mendelian randomization identifies circulating proteins as biomarkers for age at menarche and age at natural menopause

Abstract

Age at menarche (AAM) and age at natural menopause (ANM) are highly heritable traits and have been linked to various health outcomes. We aimed to identify circulating proteins associated with altered ANM and AAM using an unbiased two-sample Mendelian randomization (MR) and colocalization approach. By testing causal effects of 1,271 proteins on AAM, we identified 22 proteins causally associated with AAM in MR, among which 13 proteins (GCKR, FOXO3, SEMA3G, PATE4, AZGP1, NEGR1, LHB, DLK1, ANXA2, YWHAB, DNAJB12, RMDN1 and HPGDS) colocalized. Among 1,349 proteins tested for causal association with ANM using MR, we identified 19 causal proteins among which 7 proteins (CPNE1, TYMP, DNER, ADAMTS13, LCT, ARL and PLXNA1) colocalized. Follow-up pathway and gene enrichment analyses demonstrated links between AAM-related proteins and obesity and diabetes, and between AAM and ANM-related proteins and various types of cancer. In conclusion, we identified proteomic signatures of reproductive ageing in women, highlighting biological processes at both ends of the reproductive lifespan.

Pre-diagnosis blood DNA methylation profiling of twin pairs discordant for breast cancer points to the importance of environmental risk

“…Most of the identified DNAm sites associated with BC risk independent of genetic effects, and may reflect within-pair differences in exposures to environmental BC risk factors, such as alcohol consumption, exposure to sex hormones [24], and risk factors previously identified in twin studies such as age at first birth, number of children and age at menopause [60] and BMI [61]. Identification of genes related to estrogen signaling ( TDRD1 [62], SCMH1 [31], PXDNL [63], GNAS [64] and RMDN1 [65]) suggests that subtle within-pair differences in hormonal exposures may have resulted in the observed within-pair differences in DNAm patterns associated with future BC diagnosis. In particular, identification of BC–associated DNAm in SCMH1 , which has been associated with lifetime exposure to sex hormones [31], reinforce this.…”