Shared Genetics Between Age at Menopause, Early Menopause, POI and Other Traits

Abstract

Reproductive ageing leading to menopause is characterized by depletion of follicles and its regulating mechanisms are only partly understood. Early age at menopause and premature ovarian insufficiency (POI) are associated with several other traits such as cardiovascular disease, dyslipidemia, osteoporosis and diabetes. In large cohorts of Northern European women hundreds of Single Nucleotide Polymorphisms (SNPs) have been identified to be associated with age at menopause. These SNPs are located in genes enriched for immune and mitochondrial function as well as DNA repair and maintenance processes. Genetic predisposition to earlier menopause might also increase the risk of other associated traits. Increased risk for cardiovascular disease in women has been associated with age at menopause lowering SNPs. Pleiotropy between early age at menopause and increased mortality from coronary artery disease has been observed, implicating that genetic variants affecting age at menopause also affect the risk for coronary deaths. This review will discuss the shared genetics of age at menopause with other traits. Mendelian Randomization studies implicate causal genetic association between age at menopause and age at menarche, breast cancer, ovarian cancer, BMD and type 2 diabetes. Although the shared biological pathways remain to be determined, mechanisms that regulate duration of estrogen exposure remain an important focus.

Association of parity with body mass index and cardiometabolic risk in high-parous women

“…In the Coronary Artery Risk Development in Young Adults Study, primiparas had increased waist-to-hip ratio compared with women who remained nulliparous during a 5-year follow-up, 26 although the mechanisms for this are unclear as others have reported that the effects of increased accretion of visceral fat on transient insulin resistance becomes resolved shortly postpartum 27 . Low parity has also been associated with an earlier age at natural menopause, which may lead to higher risk of cardiovascular disease in later life, 28 or impact different aspects of the aging process based on pleiotropic genetic influences 29 . In our study, we found that a one-child increase in parity was associated with an increase in BMI that persisted, although with smaller effect size, in the postmenopausal years, and this was not accompanied by an elevation in conventional cardiometabolic risk.…”

Sohlh1loss of function male and female infertility model impacts overall health beyond gonadal dysfunction in mice

“…Epidemiological studies have shown that early menopause and loss of ovarian function are strongly correlated with shorter life span and elevated risk of metabolic, cardiovascular, and osteoporosis disease, among others [3][4][5]. GWAS and WES studies have identified 290 loci that associate with age at natural menopause [9], some of which overlap with the >100 genes currently linked to POI [35,36].…”

“…Primary ovarian insufficiency (POI) is a condition that affects 1-5% of women and is defined by the cessation of menstruation before the age of 40 [1,2]. Early menopause is linked to shorter life span, increased risk of diabetes mellitus, heart disease, cardiovascular disease, and osteoporosis [3][4][5]. Similarly, lower sperm counts are an independent predictor of comorbidity and mortality [6,7].…”

Lipid Profile in Patients With Primary Ovarian Insufficiency: A Systematic Review and Meta-Analysis

“…This meta-analysis indicated that levels of serum lipid profile were remarkably altered in patients with primary ovarian insufficiency: levels of serum TC, TG and LDL in women with POI were significantly higher than that in healthy controls, however, no significant difference was observed regarding the level of serum HDL between women with POI and healthy controls. Women with POI present several risk factors for the occurrence and development of CVD: autonomic and endothelial dysfunction, insulin dysfunction, abnormal lipid profile (33), genetic variants associated with early menopause (34,35). Diminished ovarian response to FSH is thought to cause the occurrence and development of atherosclerosis based on non-human primate models (36) and studies of hypothalamic angiography (37).…”