Review of mendelian randomization studies on age at natural menopause

Abstract

Menopause marks the end of the reproductive phase of life. Based on epidemiological studies, abnormal age at natural menopause (ANM) is thought to contribute to a number of adverse outcomes, such as osteoporosis, cardiovascular disease, and cancer. However, the causality of these associations remains unclear. A powerful epidemiological method known as Mendelian randomization (MR) can be used to clarify the causality between ANM and other diseases or traits. The present review describes MR studies that included ANM as an exposure, outcome and mediator. The findings of MR analyses on ANM have revealed that higher body mass index, poor educational level, early age at menarche, early age at first live birth, early age at first sexual intercourse, and autoimmune thyroid disease appear to be involved in early ANM etiology. The etiology of late ANM appears to be influenced by higher free thyroxine 4 and methylene tetrahydrofolate reductase gene mutations. Furthermore, early ANM has been found to be causally associated with an increased risk of osteoporosis, fracture, type 2 diabetes mellitus, glycosylated hemoglobin, and the homeostasis model of insulin resistance level. In addition, late ANM has been found to be causally associated with an increased systolic blood pressure, higher risk of breast cancer, endometrial cancer, endometrioid ovarian carcinoma, lung cancer, longevity, airflow obstruction, and lower risk of Parkinson's disease. ANM is also a mediator for breast cancer caused by birth weight and childhood body size. However, due to the different instrumental variables used, some results of studies are inconsistent. Future studies with more valid genetic variants are needed for traits with discrepancies between MRs or between MR and other types of epidemiological studies.

Keywords: age at natural menopause; causality; early menopause; genome-wide association study; late menopause; mendelian randomization.

Figure 1

Methods of Mendelian randomization (MR). (A) One-sample/Two-sample MR; (B) Mediation MR; (C) Multivariable MR. SNPs, single nucleotide polymorphisms.

Figure 2

Relationship with evidence of causation identified in mediation MR studies. AAM, age at menarche; ANM, age at natural menopause; (+) indicates a positive relationship; (–) indicates a negative relationship; solid arrow indicates the presence of association; dot arrow indicates the absence of association; the color of arrows, lines, and symbols is consistent with that for maternal-specific birthweight, fetal-specific birthweight, and childhood body size.

Figure 3

Study selection of literature search. ANM, age at natural menopause.

Figure 4

Brief overview of Mendelian randomization (MR) studies in age at natural menopause. EM, early menopause; LM, late menopause; T2DM, type 2 diabetes mellitus; HbA1c, glycosylated hemoglobin A1c; HOMA-IR, homeostasis model of insulin resistance; AITD, autoimmune thyroid disease; BMI, body mass index; AAM, age at menarche; AFS, age first had sexual intercourse; AFB, age at first birth; fT4, free thyroxine 4; MTHFR, methylene tetrahydrofolate reductase; PD, Parkinson’s disease; LC, lung cancer; SBP, systolic blood pressure; BC, breast cancer; EC, endometrial cancer; OC, ovarian cancer; AD, Alzheimer’s disease; ADHD, attention-deficit/hyperactivity disorder; BIP, bipolar disorder; SCZ, schizophrenia; TSH, thyroid stimulating hormone; CHD, coronary heart disease; TC, total cholesterol; LDLC, low-density lipoprotein cholesterol; DBP, diastolic blood pressure; ALB, age at last birth; NLB, number of live births; LNS, lifetime number of sexual partners; EPS, ever being parous; aSAH, aneurysmal subarachnoid hemorrhage; AF, atrial fibrillation; CAD, coronary artery disease; HF, heart failure; IS, ischemic stroke; FI, fasting insulin; FPG, fasting plasma glucose; HOMA-B, homeostasis model of B-cell function; CRP, C reactive protein; ALP, alkaline phosphatase; ALT, alanine transaminase; CRC, colorectal cancer; OA, osteoarthritis; RA, rheumatoid arthritis; The red up arrow indicates a higher incidence or a higher degree, and green down arrow the opposite; the question mark indicates that there are still inconsistencies in MR studies; ^* indicates ER+ BC ()?\ER- BC ()?\luminal A-like BC\luminal B-like BC\HER2-enriched-like BC; ^** indicates abnormal level of total cholesterol\high-density lipoprotein cholesterol\low-density lipoprotein cholesterol\triglycerides\apolipoprotein A1\apolipoprotein B; ^*** indicates invasive epithelial OC, high grade serous OC, low grade serous OC, clear cell OC, low malignant potential OC; ^**** indicates AAM\AFS\AFB\ALB\NLB\LNS\EPS.