Search

The central nervous system is lined by meninges, classically known as dura, arachnoid, and pia mater. We show the existence of a fourth meningeal layer that compartmentalizes the subarachnoid space in the mouse and human brain, designated the subarachnoid lymphatic-like membrane (SLYM). SLYM is morpho- and immunophenotypically similar to the mesothelial membrane lining of peripheral organs and body cavities, and it encases blood vessels and harbors immune cells. Functionally, the close apposition of SLYM with the endothelial lining of the meningeal venous sinus permits direct exchange of small solutes between cerebrospinal fluid and venous blood, thus representing the mouse equivalent of the arachnoid granulations. The functional characterization of SLYM provides fundamental insights into brain immune barriers and fluid transport.

BACKGROUND: Primary membranous nephropathy (MN) is an autoimmune kidney disease in which immune complexes are deposited beneath the epithelium in the glomeruli. The condition introduces a high risk for end-stage kidney disease. Seventy to 80 percent of patients with MN have circulating antibodies against phospholipase A2 receptor 1 (PLA2R1), and levels correlate with treatment response and prognosis. However, experimental evidence that human anti-PLA2R1 antibodies induce MN has been elusive.METHODS: In passive transfer experiments, minipigs received plasma or purified IgG from patients with PLA2R1-associated MN or from healthy controls. Anti-PLA2R1 antibodies and proteinuria were monitored using Western blot, ELISA, and Coomassie staining. Kidney tissues were analyzed using immunohistochemistry, immunofluorescence, electron microscopy, and proteomic analyses.RESULTS: Minipigs, like humans, express PLA2R1 on podocytes. Human anti-PLA2R1 antibodies bound to minipig PLA2R1 in vitro and in vivo. Passive transfer of human anti-PLA2R1 antibodies from patients with PLA2R1-associated MN to minipigs led to histological characteristics of human early-stage MN, activation of components of the complement cascade, and low levels of proteinuria. We observed development of an autologous, later phase of disease.CONCLUSIONS: A translational approach from humans to minipigs showed that human anti-PLA2R1 antibodies are pathogenic in MN, although in the heterologous phase of disease only low-level proteinuria developed.

Identifying genetic determinants of reproductive success may highlight mechanisms underlying fertility and identify alleles under present-day selection. Using data in 785,604 individuals of European ancestry, we identified 43 genomic loci associated with either number of children ever born (NEB) or childlessness. These loci span diverse aspects of reproductive biology, including puberty timing, age at first birth, sex hormone regulation, endometriosis and age at menopause. Missense variants in ARHGAP27 were associated with higher NEB but shorter reproductive lifespan, suggesting a trade-off at this locus between reproductive ageing and intensity. Other genes implicated by coding variants include PIK3IP1, ZFP82 and LRP4, and our results suggest a new role for the melanocortin 1 receptor (MC1R) in reproductive biology. As NEB is one component of evolutionary fitness, our identified associations indicate loci under present-day natural selection. Integration with data from historical selection scans highlighted an allele in the FADS1/2 gene locus that has been under selection for thousands of years and remains so today. Collectively, our findings demonstrate that a broad range of biological mechanisms contribute to reproductive success.

Two trials reported that a high inspiratory oxygen fraction (F io2 ) does not promote myocardial infarction or death. Observational studies can provide larger statistical strength, but associations can be due to unobserved confounding. Therefore, we evaluated the association between intraoperative F io2 and cardiovascular complications in a large international cohort study to see if spurious associations were observed.We included patients from the Vascular events In noncardiac Surgery patIents cOhort evaluatioN (VISION) study, who were ≥45 years of age, scheduled for overnight hospital admission, and had intraoperative F io2 recorded. The primary outcome was myocardial injury after noncardiac surgery (MINS), and secondary outcomes included mortality and pneumonia, all within 30 postoperative days. Data were analyzed with logistic regression, adjusted for many baseline cardiovascular risk factors, and illustrated in relation to findings from 2 recent controlled trials.We included 6588 patients with mean age of 62 years of whom 49% had hypertension. The median intraoperative F io2 was 0.46 (5%-95% range, 0.32-0.94). There were 808 patients (12%) with MINS. Each 0.10 increase in median F io2 was associated with a confounder-adjusted increase in odds for MINS: odds ratio (OR), 1.17 (95% confidence interval [CI], 1.12-1.23; P.0001). MINS occurred in contrast with similar frequencies and no significant difference in controlled trials (2240 patients, 194 events), in which patients were given 80% vs 30% oxygen. Mortality was 2.4% and was not significantly associated with a median F io2 (OR, 1.07; 95% CI, 0.97-1.19 per 0.10 increase; P = .18), and 2.9% of patients had pneumonia (OR, 1.05; 95% CI, 0.95-1.15 per 0.10 increase; P = .34).We observed an association between intraoperative F io2 and risk of myocardial injury within 30 days after noncardiac surgery, which contrasts with recent controlled clinical trials. F io2 was not significantly associated with mortality or pneumonia. Unobserved confounding presumably contributed to the observed association between F io2 and myocardial injury that is not supported by trials.

A CE method was developed and validated for the assessment of the chiral purity of the drug tenofovir applying a quality by design approach. Following selection of a quaternary ammonium β-CD as chiral selector, a fractional factorial resolution V+ design was employed for identification of the critical process parameters, while a central composite design served for method optimization. The final method used a 40/50.2 cm, 50 μm id fused-silica capillary, a BGE composed of a 100 mM sodium phosphate buffer, pH 6.4, containing 45 mg/mL quaternary ammonium β-CD, an applied voltage of 18 kV, and a capillary temperature of 22°C. Robustness was assessed by a Plackett-Burman design. The method was validated according to guideline Q2(R1) of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use and enabled the determination of the (S)-enantiomer of tenofovir at the 0.1% level.

The state of somatic energy stores in metazoans is communicated to the brain, which regulates key aspects of behaviour, growth, nutrient partitioning and development1. The central melanocortin system acts through melanocortin 4 receptor (MC4R) to control appetite, food intake and energy expenditure2. Here we present evidence that MC3R regulates the timing of sexual maturation, the rate of linear growth and the accrual of lean mass, which are all energy-sensitive processes. We found that humans who carry loss-of-function mutations in MC3R, including a rare homozygote individual, have a later onset of puberty. Consistent with previous findings in mice, they also had reduced linear growth, lean mass and circulating levels of IGF1. Mice lacking Mc3r had delayed sexual maturation and an insensitivity of reproductive cycle length to nutritional perturbation. The expression of Mc3r is enriched in hypothalamic neurons that control reproduction and growth, and expression increases during postnatal development in a manner that is consistent with a role in the regulation of sexual maturation. These findings suggest a bifurcating model of nutrient sensing by the central melanocortin pathway with signalling through MC4R controlling the acquisition and retention of calories, whereas signalling through MC3R primarily regulates the disposition of calories into growth, lean mass and the timing of sexual maturation. MC3R deficiency is associated with a delay in the onset of puberty, and a reduction in growth and lean mass.

Brain tumors cause local structural impairments of the cerebral network. Moreover, brain tumors can also affect functional brain networks more distant from the lesion. In this study, we analyzed the impact of glioma WHO grade II-IV tumors on grey and white matter in relation to impaired language function. In a retrospective analysis of 60 patients, 14 aphasic and 46 non-aphasic, voxel-based lesion-symptom mapping (VLSM) was used to identify tumor induced lesions in grey (GM) and white matter (WM) related to patients' performance in subtests of the Aachen Aphasia Test (AAT). Significant clusters were analyzed for atlas-based grey and white matter involvements in relation to different linguistic modalities. VLSM analysis indicated significant contribution of a posterior perisylvian cluster covering WM and GM to AAT performance averaged across subtests. When considering individual AAT subtests, a substantial overlap between significant clusters for analysis of the token test, picture naming and language comprehension results could be observed. The WM-cluster intersections reflect the overall importance of the perisylvian area in language function, similarly to GM participations. Especially the constant high percentages of Heschl's gyrus, superior temporal gyrus, inferior longitudinal and middle longitudinal fascicles, but also arcuate and inferior fronto-occipital fascicles highlight the importance of the posterior perisylvian area for language function. Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Funder: Department of Health, Mosaic loss of chromosome Y (LOY) in leukocytes is the most common form of clonal mosaicism, caused by dysregulation in cell-cycle and DNA damage response pathways. Previous genetic studies have focussed on identifying common variants associated with LOY, which we now extend to rarer, protein-coding variation using exome sequences from 82,277 male UK Biobank participants. We find that loss of function of two genes-CHEK2 and GIGYF1-reach exome-wide significance. Rare alleles in GIGYF1 have not previously been implicated in any complex trait, but here loss-of-function carriers exhibit six-fold higher susceptibility to LOY (OR = 5.99 [3.04-11.81], p = 1.3 × 10-10). These same alleles are also associated with adverse metabolic health, including higher susceptibility to Type 2 Diabetes (OR = 6.10 [3.51-10.61], p = 1.8 × 10-12), 4 kg higher fat mass (p = 1.3 × 10-4), 2.32 nmol/L lower serum IGF1 levels (p = 1.5 × 10-4) and 4.5 kg lower handgrip strength (p = 4.7 × 10-7) consistent with proposed GIGYF1 enhancement of insulin and IGF-1 receptor signalling. These associations are mirrored by a common variant nearby associated with the expression of GIGYF1. Our observations highlight a potential direct connection between clonal mosaicism and metabolic health.

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5–6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4–14%] for women born in 1940 to 22% [CI = 19–25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.

Achieving optimal HIV outcomes, as measured by global 90-90-90 targets, that is awareness of HIV-positive status, receipt of antiretroviral (ARV) therapy among aware and viral load (VL) suppression among those on ARVs, respectively, is critical. However, few data from sub-Saharan Africa (SSA) are available on older people (50+) living with HIV (OPLWH). We examined 90-90-90 progress by age, 15-49 (as a comparison) and 50+ years, with further analyses among 50+ (55-59, 60-64, 65+ vs. 50-54), in 13 countries (Cameroon, Cote d'Ivoire, Eswatini, Ethiopia, Kenya, Lesotho, Malawi, Namibia, Rwanda, Tanzania, Uganda, Zambia and Zimbabwe).Using data from nationally representative Population-based HIV Impact Assessments, conducted between 2015and 2019, participants from randomly selected households provided demographic and clinical information and whole blood specimens for HIV serology, VL and ARV testing. Survey weighted outcomes were estimated for 90-90-90 targets. Country-specific Poisson regression models examined 90-90-90 variation among OPLWH age strata.Analyses included 24,826 HIV-positive individuals (15-49 years: 20,170; 50+ years: 4656). The first, second and third 90 outcomes were achieved in 1, 10 and 5 countries, respectively, by those aged 15-49, while OPLWH achieved outcomes in 3, 13 and 12 countries, respectively. Among those aged 15-49, women were more likely to achieve 90-90-90 targets than men; however, among OPLWH, men were more likely to achieve first and third 90 targets than women, with second 90 achievement being equivalent. Country-specific 90-90-90 regression models among OPLWH demonstrated minimal variation by age stratum across 13 countries. Among OLPWH, no first 90 target differences were noted by age strata; three countries varied in the second 90 by older age strata but not in a consistent direction; one country showed higher achievement of the third 90 in an older age stratum.While OPLWH in these 13 countries were slightly more likely than younger people to be aware of their HIV-positive status (first 90), this target was not achieved in most countries. However, OPLWH achieved treatment (second 90) and VL suppression (third 90) targets in more countries than PLWH50. Findings support expanded HIV testing, prevention and treatment services to meet ongoing OPLWH health needs in SSA.

Purpose: The study aimed to systematically ascertain male sex chromosome abnormalities, 47,XXY (Klinefelter syndrome [KS]) and 47,XYY, and characterize their risks of adverse health outcomes. Methods: We analyzed genotyping array or exome sequence data in 207,067 men of European ancestry aged 40 to 70 years from the UK Biobank and related these to extensive routine health record data. Results: Only 49 of 213 (23%) of men whom we identified with KS and only 1 of 143 (0.7%) with 47,XYY had a diagnosis of abnormal karyotype on their medical records or self-report. We observed expected associations for KS with reproductive dysfunction (late puberty: risk ratio [RR] = 2.7; childlessness: RR = 4.2; testosterone concentration: RR = -3.8 nmol/L, all P < 2 x 10(-8)), whereas XYY men appeared to have normal reproductive function. Despite this difference, we identified several higher disease risks shared across both KS and 47,XYY, including type 2 diabetes (RR = 3.0 and 2.6, respectively), venous thrombosis (RR = 6.4 and 7.4, respectively), pulmonary embolism (RR = 3.3 and 3.7, respectively), and chronic obstructive pulmonary disease (RR = 4.4 and 4.6, respectively) (all P Conclusion: KS and 47,XYY were mostly unrecognized but conferred substantially higher risks for metabolic, vascular, and respiratory diseases, which were only partially explained by higher levels of body mass index, deprivation, and smoking. (C) 2022 The Authors. Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.

Background Insulin resistance predisposes to cardiometabolic disorders, which are commonly comorbid with schizophrenia and are key contributors to the significant excess mortality in schizophrenia. Mechanisms for the comorbidity remain unclear, but observational studies have implicated inflammation in both schizophrenia and cardiometabolic disorders separately. We aimed to examine whether there is genetic evidence that insulin resistance and 7 related cardiometabolic traits may be causally associated with schizophrenia, and whether evidence supports inflammation as a common mechanism for cardiometabolic disorders and schizophrenia. Methods and findings We used summary data from genome-wide association studies of mostly European adults from large consortia (Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) featuring up to 108,557 participants; Diabetes Genetics Replication And Meta-analysis (DIAGRAM) featuring up to 435,387 participants; Global Lipids Genetics Consortium (GLGC) featuring up to 173,082 participants; Genetic Investigation of Anthropometric Traits (GIANT) featuring up to 339,224 participants; Psychiatric Genomics Consortium (PGC) featuring up to 105,318 participants; and Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium featuring up to 204,402 participants). We conducted two-sample uni- and multivariable mendelian randomization (MR) analysis to test whether (i) 10 cardiometabolic traits (fasting insulin, high-density lipoprotein and triglycerides representing an insulin resistance phenotype, and 7 related cardiometabolic traits: low-density lipoprotein, fasting plasma glucose, glycated haemoglobin, leptin, body mass index, glucose tolerance, and type 2 diabetes) could be causally associated with schizophrenia; and (ii) inflammation could be a shared mechanism for these phenotypes. We conducted a detailed set of sensitivity analyses to test the assumptions for a valid MR analysis. We did not find statistically significant evidence in support of a causal relationship between cardiometabolic traits and schizophrenia, or vice versa. However, we report that a genetically predicted inflammation-related insulin resistance phenotype (raised fasting insulin (raised fasting insulin (Wald ratio OR = 2.95, 95% C.I, 1.38–6.34, Holm-Bonferroni corrected p-value (p) = 0.035) and lower high-density lipoprotein (Wald ratio OR = 0.55, 95% C.I., 0.36–0.84; p = 0.035)) was associated with schizophrenia. Evidence for these associations attenuated to the null in multivariable MR analyses after adjusting for C-reactive protein, an archetypal inflammatory marker: (fasting insulin Wald ratio OR = 1.02, 95% C.I, 0.37–2.78, p = 0.975), high-density lipoprotein (Wald ratio OR = 1.00, 95% C.I., 0.85–1.16; p = 0.849), suggesting that the associations could be fully explained by inflammation. One potential limitation of the study is that the full range of gene products from the genetic variants we used as proxies for the exposures is unknown, and so we are unable to comment on potential biological mechanisms of association other than inflammation, which may also be relevant. Conclusions Our findings support a role for inflammation as a common cause for insulin resistance and schizophrenia, which may at least partly explain why the traits commonly co-occur in clinical practice. Inflammation and immune pathways may represent novel therapeutic targets for the prevention or treatment of schizophrenia and comorbid insulin resistance. Future work is needed to understand how inflammation may contribute to the risk of schizophrenia and insulin resistance., In a Mendelian randomization study, Benjamin Perry and colleagues investigate the genetic evidence supporting relationships between inflammation, insulin resistance, and schizophrenia., Author summary Why was this study done? Cardiometabolic disorders such as diabetes are up to 30% more common in people with schizophrenia than in the general population, and are among the predominant causes of a 10- to 15-year shortened life expectancy in people with schizophrenia. Insulin resistance, a precursor to diabetes, is sometimes detectable in young adults suffering their first episode of psychosis, which suggests that chronic lifestyle and clinical factors, such as smoking, physical inactivity, and medication side effects may not fully explain the comorbidity. Inflammation has been consistently associated with schizophrenia and cardiometabolic disorders, and so could be a common mechanism for schizophrenia and cardiometabolic disorders. This could help to at least in part explain why people who have schizophrenia also have higher rates of cardiometabolic disorders, over and above the commonly attributed lifestyle/clinical factors. What did the researchers do and find? To examine whether insulin resistance and 7 related cardiometabolic traits causally influence schizophrenia risk or vice versa, we conducted bidirectional, two-sample, uni- and multivariable mendelian randomizsation (MR) analyses. The MR approach uses genetic variants as proxies for modifiable exposures to untangle the problems of reverse causation and unmeasured confounding. To test a hypothesis that inflammation may be a common mechanism for schizophrenia and cardiometabolic disorders, we also examined a subset of genetic variants which were associated with inflammation as well as the cardiometabolic trait. We also used multivariable MR (MVMR) as a sensitivity analysis to adjust for C-reactive protein (CRP), an archetypal inflammatory marker, as a general downstream marker of systemic inflammation. After correction for multiple testing, overall, there was no significant evidence in support of a causal relationship between cardiometabolic traits and schizophrenia, or vice versa. However, we found evidence that supports a causal relationship of an inflammation-related insulin resistance phenotype with schizophrenia. Evidence for the association of an inflammation-related insulin resistance phenotype with schizophrenia attenuated fully in MVMR analysis after adjusting for CRP, suggesting that these associations may be underpinned by inflammation. What do these findings mean? These results suggest that cardiometabolic traits are unlikely to have a causal role in the pathogenesis of schizophrenia or vice versa. However, our results suggest that inflammation is related to the risk of both schizophrenia and insulin resistance, which may at least partly explain why they commonly occur in clinical practice. Treating or preventing inflammation may be a putative therapeutic option for prevention and/or treatment of both schizophrenia and comorbid insulin resistance. In the future, more research is needed to understand the biological mechanisms underpinning how inflammation may increase the risk of schizophrenia and insulin resistance.

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGGoverall) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGGoverall. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E–06), PCDH7 (P = 2.0E–06), and IPO13 (P = 2.5E–06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (rg) among rater-specific assessment of AGG ranged from rg = 0.46 between self- and teacher-assessment to rg = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rgs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range $$\left| {r_g} \right|$$ r g : 0.19–1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (rg = ~−0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range $$\left| {r_g} \right|$$ r g : 0.46–0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.

OBJECTIVE Given the interindividual variance of functional language anatomy, risk prediction based merely on anatomical data is insufficient in language area–related brain tumor surgery, suggesting the need for direct cortical and subcortical mapping during awake surgery. Reliable, noninvasive preoperative methods of language localization hold the potential for reducing the necessity for awake procedures and may improve patient counseling and surgical planning. Repetitive navigated transcranial magnetic stimulation (rnTMS) is an evolving tool for localizing language-eloquent areas. The aim of this study was to investigate the reliability of rnTMS in locating cortical language sites. METHODS Twenty-five patients with brain tumors in speech-related areas were prospectively evaluated with preoperative rnTMS (5 Hz, train of five, average 105% resting motor threshold) and navigated direct cortical stimulation (DCS; bipolar, 50 Hz, 6–8 mA, 200-μsec pulse width) during awake surgeries employing a picture-naming task. Positive and negative stimulation spots within the craniotomy were documented in the same MRI data set. TMS and DCS language-positive areas were compared with regard to their spatial overlap, their allocation in a cortical parcellation system, and their linguistic qualities. RESULTS There were over twofold more positive language spots within the exposed area on rnTMS than on DCS. The comparison of positive rnTMS and DCS (ground truth) overlaps revealed low sensitivity (35%) and low positive predictive value (16%) but high specificity (90%) and high negative predictive value (96%). Within the overlaps, there was no correlation in error quality. On DCS, 73% of language-positive spots were located in the pars opercularis and pars triangularis of the frontal operculum and 24% within the supramarginal gyrus and dorsal portion of the superior temporal gyrus, while on rnTMS language positivity was distributed more evenly over a large number of gyri. CONCLUSIONS The current protocol for rnTMS for language mapping identified language-negative sites with good dependability but was unable to reliably detect language-positive spots. Further refinements of the technique will be needed to establish rnTMS language mapping as a useful clinical tool.

Age at first sexual intercourse and age at first birth have implications for health and evolutionary fitness. In this genome-wide association study (age at first sexual intercourse, N = 387,338; age at first birth, N = 542,901), we identify 371 single-nucleotide polymorphisms, 11 sex-specific, with a 5-6% polygenic score prediction. Heritability of age at first birth shifted from 9% [CI = 4-14%] for women born in 1940 to 22% [CI = 19-25%] for those born in 1965. Signals are driven by the genetics of reproductive biology and externalising behaviour, with key genes related to follicle stimulating hormone (FSHB), implantation (ESR1), infertility and spermatid differentiation. Our findings suggest that polycystic ovarian syndrome may lead to later age at first birth, linking with infertility. Late age at first birth is associated with parental longevity and reduced incidence of type 2 diabetes and cardiovascular disease. Higher childhood socioeconomic circumstances and those in the highest polygenic score decile (90%+) experience markedly later reproductive onset. Results are relevant for improving teenage and late-life health, understanding longevity and guiding experimentation into mechanisms of infertility.

Human rabies remains a globally significant public health problem. Replacement of polyclonal anti-rabies immunoglobulin (RIG), a passive component of rabies post-exposure prophylaxis (PEP), with a monoclonal antibody (MAb), would eliminate the cost and availability constraints associated with RIG. Our team has developed and licensed a human monoclonal antibody RAB1 (Rabishield©), as the replacement for RIG where canine rabies is enzootic. However, for the highly diverse rabies viruses of North America, a cocktail containing two or more MAbs targeting different antigenic sites of the rabies glycoprotein should be included to ensure neutralization of all variants of the virus. In this study, two MAb cocktails, R172 (RAB1-RAB2) and R173 (RAB1-CR57), were identified and evaluated against a broad range of rabies variants from North America. R173 was found to be the most potent cocktail, as it neutralized all the tested North American RABV isolates and demonstrated broad coverage of isolates from both terrestrial and bat species. R173 could be a promising candidate as an alternative or replacement for RIG PEP in North America.

Assessing the outcomes of chemical reactions in a quantitative fashion has been a cornerstone across all synthetic disciplines. Classically approached through empirical optimization, data-driven modelling bears an enormous potential to streamline this process. However, such predictive models require significant quantities of high-quality data, the availability of which is limited: Main reasons for this include experimental errors and, importantly, human biases regarding experiment selection and result reporting. In a series of case studies, we investigate the impact of these biases for drawing general conclusions from chemical reaction data, revealing the utmost importance of "negative" examples. Eventually, case studies into data expansion approaches showcase directions to circumvent these limitations-and demonstrate perspectives towards a long-term data quality enhancement in chemistry.

Aims/hypothesis Type 2 diabetes is a complex metabolic disease with increasing prevalence worldwide. Improving the prediction of incident type 2 diabetes using epigenetic markers could help tailor prevention efforts to those at the highest risk. The aim of this study was to identify predictive methylation markers for incident type 2 diabetes by combining epigenome-wide association study (EWAS) results from five prospective European cohorts. Methods We conducted a meta-analysis of EWASs in blood collected 7–10 years prior to type 2 diabetes diagnosis. DNA methylation was measured with Illumina Infinium Methylation arrays. A total of 1250 cases and 1950 controls from five longitudinal cohorts were included: Doetinchem, ESTHER, KORA1, KORA2 and EPIC-Norfolk. Associations between DNA methylation and incident type 2 diabetes were examined using robust linear regression with adjustment for potential confounders. Inverse-variance fixed-effects meta-analysis of cohort-level individual CpG EWAS estimates was performed using METAL. The methylGSA R package was used for gene set enrichment analysis. Confirmation of genome-wide significant CpG sites was performed in a cohort of Indian Asians (LOLIPOP, UK). Results The meta-analysis identified 76 CpG sites that were differentially methylated in individuals with incident type 2 diabetes compared with control individuals (p values −7). Sixty-four out of 76 (84.2%) CpG sites were confirmed by directionally consistent effects and p values 1c) showed no improvement (AUC 0.757 vs 0.753). Gene set enrichment analysis of the full epigenome-wide results clearly showed enrichment of processes linked to insulin signalling, lipid homeostasis and inflammation. Conclusions/interpretation By combining results from five European cohorts, and thus significantly increasing study sample size, we identified 76 CpG sites associated with incident type 2 diabetes. Replication of 64 CpGs in an independent cohort of Indian Asians suggests that the association between DNA methylation levels and incident type 2 diabetes is robust and independent of ethnicity. Our data also indicate that BMI partly explains the association between DNA methylation and incident type 2 diabetes. Further studies are required to elucidate the underlying biological mechanisms and to determine potential causal roles of the differentially methylated CpG sites in type 2 diabetes development. Graphical abstract

Background Prior research suggested a differential association of 25-hydroxyvitamin D (25(OH)D) metabolites with type 2 diabetes (T2D), with total 25(OH)D and 25(OH)D3 inversely associated with T2D, but the epimeric form (C3-epi-25(OH)D3) positively associated with T2D. Whether or not these observational associations are causal remains uncertain. We aimed to examine the potential causality of these associations using Mendelian randomisation (MR) analysis. Methods and findings We performed a meta-analysis of genome-wide association studies for total 25(OH)D (N = 120,618), 25(OH)D3 (N = 40,562), and C3-epi-25(OH)D3 (N = 40,562) in participants of European descent (European Prospective Investigation into Cancer and Nutrition [EPIC]–InterAct study, EPIC-Norfolk study, EPIC-CVD study, Ely study, and the SUNLIGHT consortium). We identified genetic variants for MR analysis to investigate the causal association of the 25(OH)D metabolites with T2D (including 80,983 T2D cases and 842,909 non-cases). We also estimated the observational association of 25(OH)D metabolites with T2D by performing random effects meta-analysis of results from previous studies and results from the EPIC-InterAct study. We identified 10 genetic loci associated with total 25(OH)D, 7 loci associated with 25(OH)D3 and 3 loci associated with C3-epi-25(OH)D3. Based on the meta-analysis of observational studies, each 1–standard deviation (SD) higher level of 25(OH)D was associated with a 20% lower risk of T2D (relative risk [RR]: 0.80; 95% CI 0.77, 0.84; p < 0.001), but a genetically predicted 1-SD increase in 25(OH)D was not significantly associated with T2D (odds ratio [OR]: 0.96; 95% CI 0.89, 1.03; p = 0.23); this result was consistent across sensitivity analyses. In EPIC-InterAct, 25(OH)D3 (per 1-SD) was associated with a lower risk of T2D (RR: 0.81; 95% CI 0.77, 0.86; p < 0.001), while C3-epi-25(OH)D3 (above versus below lower limit of quantification) was positively associated with T2D (RR: 1.12; 95% CI 1.03, 1.22; p = 0.006), but neither 25(OH)D3 (OR: 0.97; 95% CI 0.93, 1.01; p = 0.14) nor C3-epi-25(OH)D3 (OR: 0.98; 95% CI 0.93, 1.04; p = 0.53) was causally associated with T2D risk in the MR analysis. Main limitations include the lack of a non-linear MR analysis and of the generalisability of the current findings from European populations to other populations of different ethnicities. Conclusions Our study found discordant associations of biochemically measured and genetically predicted differences in blood 25(OH)D with T2D risk. The findings based on MR analysis in a large sample of European ancestry do not support a causal association of total 25(OH)D or 25(OH)D metabolites with T2D and argue against the use of vitamin D supplementation for the prevention of T2D., Using both observational and genetic analyses, Ju-Sheng Zheng and colleagues investigate the relationship between vitamin D metabolites and type 2 diabetes among European individuals., Author summary Why was this study done? There is ongoing uncertainty on whether the body’s vitamin D status indicated by blood 25-hydroxyvitamin D (25(OH)D) is relevant to the prevention of type 2 diabetes. There are conflicting findings from observational studies and a limited number of randomised controlled trials. Prior research did not distinguish between different metabolites of total 25(OH)D, including 25(OH)D3 and C3-epi-25(OH)D3, an isomer of 25(OH)D3. It is not clear whether the associations of 25(OH)D metabolites with type 2 diabetes are causal, with conflicting findings from prior Mendelian randomisation studies of total 25(OH)D and no previous Mendelian randomisation studies appraising 25(OH)D metabolites. What did the researchers do and find? The current research compared observational estimates of the association between 25(OH)D metabolites and incident type 2 diabetes with Mendelian randomisation estimates based on genetic instruments. Using multiple data sources, we performed genome-wide association studies among 120,618 individuals for total 25(OH)D, and among 40,562 individuals for the other vitamin D metabolites. Among participants of European descent, 10 genetic loci were identified for total 25(OH)D, 7 loci for 25(OH)D3 and 3 loci for C3-epi-25(OH)D3. In meta-analysis of observational studies, we found that each 1–standard deviation higher level of total 25(OH)D was associated with 20% lower risk of type 2 diabetes. The result was similar for 25(OH)D3, but for C3-epi-25(OH)D3, a positive association with type 2 diabetes was found. With up to 80,983 type 2 diabetes cases and 842,909 controls, we assessed the association of genetically predicted differences in total 25(OH)D and its metabolites with type 2 diabetes. Neither genetically predicted higher total 25(OH)D level nor genetically predicted higher levels of 25(OH)D metabolites were significantly associated with type 2 diabetes. What do these findings mean? There were conflicting findings for a link with type 2 diabetes for the observational analysis of biochemically measured 25(OH)D metabolites versus the genetically predicted levels of these metabolites. The null findings based on Mendelian randomisation analysis indicate that blood levels of 25(OH)D or its metabolites are not likely to be causal factors for the development of type 2 diabetes. The current findings together with other evidence from randomised controlled trials do not support the use of vitamin D supplementation for the prevention of type 2 diabetes.

Background Emerging studies have investigated the association between puberty timing, particularly age at menarche (AAM), and type 2 diabetes. However, whether this association is independent of adiposity is unclear. We aimed to systematically review published evidence on the association between puberty timing and type 2 diabetes (T2D) or impaired glucose tolerance (IGT), with and without adjustment for adiposity, and to estimate the potential contribution of puberty timing to the burden of T2D in the United Kingdom (UK). Methods and findings We searched PubMed, Medline, and Embase databases for publications until February 2019 on the timing of any secondary sexual characteristic in boys or girls in relation to T2D/IGT. Inverse-variance-weighted random-effects meta-analysis was used to pool reported estimates, and meta-regression was used to explore sources of heterogeneity. Twenty-eight observational studies were identified. All assessed AAM in women (combined N = 1,228,306); only 1 study additionally included men. In models without adjustment for adult adiposity, T2D/IGT risk was lower per year later AAM (relative risk [RR] = 0.91, 95% CI 0.89–0.93, p < 0.001, 11 estimates, n = 833,529, I2 = 85.4%) and higher for early versus later menarche (RR = 1.39, 95% CI 1.25–1.55, p < 0.001, 23 estimates, n = 1,185,444, I2 = 87.8%). Associations were weaker but still evident in models adjusted for adiposity (AAM: RR = 0.97 per year, 95% CI 0.95–0.98, p < 0.001, 12 estimates, n = 852,268, I2 = 51.8%; early menarche: RR = 1.19, 95% CI 1.11–1.28, p < 0.001, 21 estimates, n = 890,583, I2 = 68.1%). Associations were stronger among white than Asian women, and in populations with earlier average AAM. The estimated population attributable risk of T2D in white UK women due to early menarche unadjusted and adjusted for adiposity was 12.6% (95% CI 11.0–14.3) and 5.1% (95% CI 3.6–6.7), respectively. Findings in this study are limited by residual and unmeasured confounding, and self-reported AAM. Conclusions Earlier AAM is consistently associated with higher T2D/IGT risk, independent of adiposity. More importantly, this research has identified that a substantial proportion of T2D in women is related to early menarche, which would be expected to increase in light of global secular trends towards earlier puberty timing. These findings highlight the need to identify the underlying mechanisms linking early menarche to T2D/IGT risk., Tuck Seng Cheng and colleagues examine the literature on the association between puberty timing and Type 2 diabetes., Author summary Why was this study done? Secular trends towards earlier puberty timing have led to interest in its long-term disease consequences, particularly the association between early age at menarche in women and the development of type 2 diabetes. An earlier pooled analysis of the association between puberty timing and risk of type 2 diabetes was limited to findings adjusted for adulthood adiposity and included studies mainly among Western women. The present study aimed to evaluate whether puberty timing is associated with type 2 diabetes/impaired glucose tolerance, independent of adiposity. What did the researchers do and find? This systematic review identified 28 observational studies that analysed age at menarche among women and type 2 diabetes/impaired glucose tolerance; 1 study additionally included age at voice breaking in men. Meta-analysis showed that risk for type 2 diabetes and impaired glucose tolerance is higher among women with early than later menarche, independent of adiposity. The risk for type 2 diabetes and impaired glucose tolerance among women with early menarche is even higher in white than Asian women and in populations with younger average age at menarche. What do these findings mean? Girls who experience earlier menarche than their peers within and between populations have a higher risk for type 2 diabetes in adulthood. Preventive strategies that avoid early puberty timing might reduce future risk of type 2 diabetes.

Both extrinsic and intrinsic factors predispose older people to fall. We performed a genome-wide association analysis to investigate how much of an individual’s fall susceptibility can be attributed to genetics in 89,076 cases and 362,103 controls from the UK Biobank Study. The analysis revealed a small, but significant SNP-based heritability (2.7%) and identified three novel fall-associated loci (Pcombined ≤ 5 × 10−8). Polygenic risk scores in two independent settings showed patterns of polygenic inheritance. Risk of falling had positive genetic correlations with fractures, identifying for the first time a pathway independent of bone mineral density. There were also positive genetic correlations with insomnia, neuroticism, depressive symptoms, and different medications. Negative genetic correlations were identified with muscle strength, intelligence and subjective well-being. Brain, and in particular cerebellum tissue, showed the highest gene expression enrichment for fall-associated variants. Overall, despite the highly heterogenic nature underlying fall risk, a proportion of the susceptibility can be attributed to genetics., Katerina Trajanoska et al. report a genome-wide association study of self-reported falls in UK Biobank participants. They identify three novel fall-associated loci and find that risk of falling shows patterns of polygenic inheritance and a SNP-based heritability of 2.7%.

OBJECTIVE Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. RESEARCH DESIGN AND METHODS We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants. RESULTS We identified 11 genomic regions associated with plasma vitamin C (P < 5 × 10−8), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1, and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10). CONCLUSIONS These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.

Chromatin-remodelling complexes of the SWI/SNF family function in the formation of nucleosome-depleted, transcriptionally active promoter regions (NDRs)1,2. In the yeast Saccharomyces cerevisiae, the essential SWI/SNF complex RSC3 contains 16 subunits, including the ATP-dependent DNA translocase Sth14,5. RSC removes nucleosomes from promoter regions6,7 and positions the specialized +1 and -1 nucleosomes that flank NDRs8,9. Here we present the cryo-electron microscopy structure of RSC in complex with a nucleosome substrate. The structure reveals that RSC forms five protein modules and suggests key features of the remodelling mechanism. The body module serves as a scaffold for the four flexible modules that we call DNA-interacting, ATPase, arm and actin-related protein (ARP) modules. The DNA-interacting module binds extra-nucleosomal DNA and is involved in the recognition of promoter DNA elements8,10,11 that influence RSC functionality12. The ATPase and arm modules sandwich the nucleosome disc with the Snf2 ATP-coupling (SnAC) domain and the finger helix, respectively. The translocase motor of the ATPase module engages with the edge of the nucleosome at superhelical location +2. The mobile ARP module may modulate translocase-nucleosome interactions to regulate RSC activity5. The RSC-nucleosome structure provides a basis for understanding NDR formation and the structure and function of human SWI/SNF complexes that are frequently mutated in cancer13.

Context As many as 75% of patients with polycystic ovary syndrome (PCOS) are estimated to be unidentified in clinical practice. Objective Utilizing polygenic risk prediction, we aim to identify the phenome-wide comorbidity patterns characteristic of PCOS to improve accurate diagnosis and preventive treatment. Design, Patients, and Methods Leveraging the electronic health records (EHRs) of 124 852 individuals, we developed a PCOS risk prediction algorithm by combining polygenic risk scores (PRS) with PCOS component phenotypes into a polygenic and phenotypic risk score (PPRS). We evaluated its predictive capability across different ancestries and perform a PRS-based phenome-wide association study (PheWAS) to assess the phenomic expression of the heightened risk of PCOS. Results The integrated polygenic prediction improved the average performance (pseudo-R2) for PCOS detection by 0.228 (61.5-fold), 0.224 (58.8-fold), 0.211 (57.0-fold) over the null model across European, African, and multi-ancestry participants respectively. The subsequent PRS-powered PheWAS identified a high level of shared biology between PCOS and a range of metabolic and endocrine outcomes, especially with obesity and diabetes: “morbid obesity”, “type 2 diabetes”, “hypercholesterolemia”, “disorders of lipid metabolism”, “hypertension”, and “sleep apnea” reaching phenome-wide significance. Conclusions Our study has expanded the methodological utility of PRS in patient stratification and risk prediction, especially in a multifactorial condition like PCOS, across different genetic origins. By utilizing the individual genome–phenome data available from the EHR, our approach also demonstrates that polygenic prediction by PRS can provide valuable opportunities to discover the pleiotropic phenomic network associated with PCOS pathogenesis.

Despite advances in clinical care and modest improvement in mortality rates for extreme prematurity, morbidity remains a significant challenge. The ideal environment to support prematurity would be fluidic and rely on natural fetal circulation to mimic the natural fetal amniotic environment, yet such an environment has been unsuccessful in long-term support until recently. Our group has succeeded in developing such a support system to foster fetal growth in the premature lamb model that shows promise for clinical translation. Here, we describe the EXTrauterine Environment for Neonatal Development (EXTEND) from its conception onwards, review published literature on fetal development and support of the premature lamb model in EXTEND, and discuss future applications.

Genetic association results are often interpreted with the assumption that study participation does not affect downstream analyses. Understanding the genetic basis of participation bias is challenging since it requires the genotypes of unseen individuals. Here we demonstrate that it is possible to estimate comparative biases by performing a genome-wide association study contrasting one subgroup versus another. For example, we showed that sex exhibits artifactual autosomal heritability in the presence of sex-differential participation bias. By performing a genome-wide association study of sex in approximately 3.3 million males and females, we identified over 158 autosomal loci spuriously associated with sex and highlighted complex traits underpinning differences in study participation between the sexes. For example, the body mass index-increasing allele at FTO was observed at higher frequency in males compared to females (odds ratio = 1.02, P = 4.4 × 10-36). Finally, we demonstrated how these biases can potentially lead to incorrect inferences in downstream analyses and propose a conceptual framework for addressing such biases. Our findings highlight a new challenge that genetic studies may face as sample sizes continue to grow.

Birth weight (BW) variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. These associations have been proposed to reflect the lifelong consequences of an adverse intrauterine environment. In earlier work, we demonstrated that much of the negative correlation between BW and adult cardio-metabolic traits could instead be attributable to shared genetic effects. However, that work and other previous studies did not systematically distinguish the direct effects of an individual’s own genotype on BW and subsequent disease risk from indirect effects of their mother’s correlated genotype, mediated by the intrauterine environment. Here, we describe expanded genome-wide association analyses of own BW (n=321,223) and offspring BW (n=230,069 mothers), which identified 278 independent association signals influencing BW (214 novel). We used structural equation modelling to decompose the contributions of direct fetal and indirect maternal genetic influences on BW, implicating fetal- and maternal-specific mechanisms. We used Mendelian randomization to explore the causal relationships between factors influencing BW through fetal or maternal routes, for example, glycemic traits and blood pressure. Direct fetal genotype effects dominate the shared genetic contribution to the association between lower BW and higher type 2 diabetes risk, whereas the relationship between lower BW and higher later blood pressure (BP) is driven by a combination of indirect maternal and direct fetal genetic effects: indirect effects of maternal BP-raising genotypes act to reduce offspring BW, but only direct fetal genotype effects (once inherited) increase the offspring’s later BP. Instrumental variable analysis using maternal BW-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring BP. In successfully separating fetal from maternal genetic effects, this work represents an important advance in genetic studies of perinatal outcomes, and shows that the association between lower BW and higher adult BP is attributable to genetic effects, and not to intrauterine programming.

The timing of puberty is highly variable and is associated with long-term health outcomes. To date, understanding of the genetic control of puberty timing is based largely on studies in women. Here, we report a multi-trait genome-wide association study for male puberty timing with an effective sample size of 205,354 men. We find moderately strong genomic correlation in puberty timing between sexes (rg = 0.68) and identify 76 independent signals for male puberty timing. Implicated mechanisms include an unexpected link between puberty timing and natural hair colour, possibly reflecting common effects of pituitary hormones on puberty and pigmentation. Earlier male puberty timing is genetically correlated with several adverse health outcomes and Mendelian randomization analyses show a genetic association between male puberty timing and shorter lifespan. These findings highlight the relationships between puberty timing and health outcomes, and demonstrate the value of genetic studies of puberty timing in both sexes., 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.

The negative impacts of social isolation and loneliness on health are well documented. However, little is known about their possible biological determinants. In up to 452,302 UK Biobank study participants, we perform genome-wide association study analyses for loneliness and regular participation in social activities. We identify 15 genomic loci (P −8) for loneliness, and demonstrate a likely causal association between adiposity and increased susceptibility to loneliness and depressive symptoms. Further loci were identified for regular attendance at a sports club or gym (N = 6 loci), pub or social club (N = 13) or religious group (N = 18). Across these traits there was strong enrichment for genes expressed in brain regions that control emotional expression and behaviour. We demonstrate aetiological mechanisms specific to each trait, in addition to identifying loci that are pleiotropic across multiple complex traits. Further study of these traits may identify novel modifiable risk factors associated with social withdrawal and isolation.

Context Biological and translational insights from large-scale, array-based genetic studies of fat distribution, a key determinant of metabolic health, have been limited by the difficulty in linking predominantly noncoding variants to specific gene targets. Rare coding variant analyses provide greater confidence that a specific gene is involved, but do not necessarily indicate whether gain or loss of function (LoF) would be of most therapeutic benefit. Objective This work aimed to identify genes/proteins involved in determining fat distribution. Methods We combined the power of genome-wide analysis of array-based rare, nonsynonymous variants in 450 562 individuals in the UK Biobank with exome-sequence-based rare LoF gene burden testing in 184 246 individuals. Results The data indicate that the LoF of 4 genes (PLIN1 [LoF variants, P = 5.86 × 10–7], INSR [LoF variants, P = 6.21 × 10–7], ACVR1C [LoF + moderate impact variants, P = 1.68 × 10–7; moderate impact variants, P = 4.57 × 10–7], and PDE3B [LoF variants, P = 1.41 × 10–6]) is associated with a beneficial effect on body mass index–adjusted waist-to-hip ratio and increased gluteofemoral fat mass, whereas LoF of PLIN4 (LoF variants, P = 5.86 × 10–7 adversely affects these parameters. Phenotypic follow-up suggests that LoF of PLIN1, PDE3B, and ACVR1C favorably affects metabolic phenotypes (eg, triglycerides [TGs] and high-density lipoprotein [HDL] cholesterol concentrations) and reduces the risk of cardiovascular disease, whereas PLIN4 LoF has adverse health consequences. INSR LoF is associated with lower TG and HDL levels but may increase the risk of type 2 diabetes. Conclusion This study robustly implicates these genes in the regulation of fat distribution, providing new and in some cases somewhat counterintuitive insight into the potential consequences of targeting these molecules therapeutically.

During mammalian pregnancy, immune cells are vertically transferred from mother to fetus. The functional role of these maternal microchimeric cells (MMc) in the offspring is mostly unknown. Here we show a mouse model in which MMc numbers are either normal or low, which enables functional assessment of MMc. We report a functional role of MMc in promoting fetal immune development. MMc induces preferential differentiation of hematopoietic stem cells in fetal bone marrow towards monocytes within the myeloid compartment. Neonatal mice with higher numbers of MMc and monocytes show enhanced resilience against cytomegalovirus infection. Similarly, higher numbers of MMc in human cord blood are linked to a lower number of respiratory infections during the first year of life. Our data highlight the importance of MMc in promoting fetal immune development, potentially averting the threats caused by early life exposure to pathogens., Maternal immune cells seed into the foetus during mammalian pregnancy, yet the functional role of these cells is unclear. Here the authors show that maternal immune cells in foetal bone marrow stimulate immune development, subsequently reducing the risk or severity of infections in newborns.

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. 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) in circulating white blood cells is the most common form of clonal mosaicism1–5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases. 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.