Search

Analyses of whole-exome sequencing data identify rare loss-of-function variants in BSN associated with adult-onset obesity, type 2 diabetes and fatty liver disease, with stronger effect sizes than those observed for variants in known obesity risk genes such as MC4R.

John Perry and colleagues identify genetic variants at 19 genomic regions associated with mosaic loss of the Y chromosome (mLOY) in blood. They further highlight a shared genetic architecture between mLOY and cancer susceptibility, and infer a causal effect of smoking on mLOY.

John Perry, Ken Ong and colleagues perform a genome-wide association study for reproductive ability, behavior and success to determine underlying genetic factors. They find 38 variants associated with age of first sexual intercourse and show that both physical and neurobehavioral traits influence the onset of reproductive activity.

John Perry and colleagues report the results of a large genome-wide association study meta-analysis to identify variants influencing age at natural menopause. They identify 54 independent signals and find enrichment near genes involved in delayed puberty and DNA damage response.

John Perry, Ken Ong and colleagues analyze genotype data on ∼370,000 women and identify 389 independent signals that associate with age at menarche, implicating ∼250 genes. Their analyses suggest causal inverse associations, independent of BMI, between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men.

Types of clonal hematopoiesis (CH) differ in frequency and fitness. These findings uncover shared genetic architecture, suggest evolutionary trade-offs between CH types, and detail elevated leukemia risk in individuals with overlapping types of CH.

Little is known about the genetic determinants of social isolation and loneliness despite their well-established importance for health. Here, using multi-trait GWAS, Day et al. identify 15 genomic loci for loneliness and further show a bidirectional causal relationship between BMI and loneliness by MR.

Using exome sequencing data from 104,733 postmenopausal women in the UK Biobank, an analysis of 105 gene variants previously reported as associated with premature ovarian insufficiency reveals that most cases are not monogenic.

Age at voice-breaking is used to determine puberty timing in men, recall of which is considered less accurate than age at first menarche in women. Here, the authors perform multi-trait GWAS for male puberty timing by including both age at voice breaking and age of first facial hair for improved phenotype definition and power.

Mathieson et al. carried out a genome-wide association study of reproductive success (number of children born) in humans, revealing the importance of diverse neuro-endocrine and behavioural factors.

Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

Mosaic loss of chromosome Y (LOY) is a common form of clonal mosaicism in leukocytes. Here, the authors extend genetic association analyses to rare variation using exome-sequence data from 82,277 males, finding that loss-of-function alleles in GIGYF1 are associated with six-fold higher susceptibility to both LOY and Type 2 Diabetes.

Genetic analyses identify widespread sex-differential participation bias in population-based studies and show how this bias can lead to incorrect inferences. These findings highlight new challenges for association studies as sample sizes continue to grow.

Previous studies have linked over 100 genomic loci to age-at-menarche but that work was restricted to common autosomal variation. Here, Lunetta et al. identify associations with rare protein-coding and X-linked variants, implicating new mechanisms that regulate puberty timing.

This paper describes the largest genome-wide association study to date on polycystic ovary syndrome (PCOS), a common reproductive disorder in women. Six genetic loci—including known targets of cancer chemotherapy—were identified, and the authors infer causal and balancing selection mechanisms involved in PCOS risk and susceptibility.

Past studies on genetics of puberty relied on rare disorders or age of menarche in women. Here, Dayet al. examine puberty timing in men by the age of voice breaking, and find some loci with sexually dimorphic effects and genetic architectures shared with other health conditions.

Genetic analysis of data from over 400,000 participants in the UK Biobank Study shows that circulating testosterone levels have sex-specific implications for cardiometabolic diseases and cancer outcomes.

A genome-wide association study of mosaic loss of chromosome Y (LOY) in UK Biobank participants identifies 156 genetic determinants of LOY, showing that LOY is associated with cancer and non-haematological health outcomes.

The timing of female reproductive capacity is influenced by genetic and environmental factors. Here, in genome-wide association studies, the authors identify genetic loci for age at menarche and onset of menopause in Japanese women, and highlight differences with European populations.

Here 106 genomic loci associated with age at menarche, a marker of puberty timing in females, are identified; these loci show enrichment for genes involved in nuclear hormone receptor function, body mass index, and rare disorders of puberty, and for genes located in imprinted regions, with parent-of-origin specific effects at several loci.

Genetic studies have identified dozens of mutations that are associated with reproductive disorders, including common variants associated with the timing of puberty and/or menopause. This Review discusses the contribution of such genetic findings to our understanding of the molecular regulation of reproductive timing and the biological basis of the epidemiological links between reproductive ageing and disease risk.