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

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.

Metabolic control of puberty: 60 years in the footsteps of Kennedy and Mitra's seminal work.

An individual's nutritional status has a powerful effect on sexual maturation. Puberty onset is delayed in response to chronic energy insufficiency and is advanced under energy abundance. The consequences of altered pubertal timing for human health are profound. Late puberty increases the chances of cardiometabolic, musculoskeletal and neurocognitive disorders, whereas early puberty is associated with increased risks of adult obesity, type 2 diabetes mellitus, cardiovascular diseases and various cancers, such as breast, endometrial and prostate cancer. Kennedy and Mitra's trailblazing studies, published in 1963 and using experimental models, were the first to demonstrate that nutrition is a key factor in puberty onset. Building on this work, the field has advanced substantially in the past decade, which is largely due to the impressive development of molecular tools for experimentation and population genetics. In this Review, we discuss the latest advances in basic and translational sciences underlying the nutritional and metabolic control of pubertal development, with a focus on perspectives and future directions.

Genome-wide association study meta-analysis of dizygotic twinning illuminates genetic regulation of female fecundity.

STUDY QUESTION: Which genetic factors regulate female propensity for giving birth to spontaneous dizygotic (DZ) twins? SUMMARY ANSWER: We identified four new loci, GNRH1, FSHR, ZFPM1, and IPO8, in addition to previously identified loci, FSHB and SMAD3. WHAT IS KNOWN ALREADY: The propensity to give birth to DZ twins runs in families. Earlier, we reported that FSHB and SMAD3 as associated with DZ twinning and female fertility measures. STUDY DESIGN, SIZE, DURATION: We conducted a genome-wide association meta-analysis (GWAMA) of mothers of spontaneous dizygotic (DZ) twins (8265 cases, 264 567 controls) and of independent DZ twin offspring (26 252 cases, 417 433 controls). PARTICIPANTS/MATERIALS, SETTING, METHODS: Over 700 000 mothers of DZ twins, twin individuals and singletons from large cohorts in Australia/New Zealand, Europe, and the USA were carefully screened to exclude twins born after use of ARTs. Genetic association analyses by cohort were followed by meta-analysis, phenome wide association studies (PheWAS), in silico and in vivo annotations, and Zebrafish functional validation. MAIN RESULTS AND THE ROLE OF CHANCE: This study enlarges the sample size considerably from previous efforts, finding four genome-wide significant loci, including two novel signals and a further two novel genes that are implicated by gene level enrichment analyses. The novel loci, GNRH1 and FSHR, have well-established roles in female reproduction whereas ZFPM1 and IPO8 have not previously been implicated in female fertility. We found significant genetic correlations with multiple aspects of female reproduction and body size as well as evidence for significant selection against DZ twinning during human evolution. The 26 top single nucleotide polymorphisms (SNPs) from our GWAMA in European-origin participants weakly predicted the crude twinning rates in 47 non-European populations (r = 0.23 between risk score and population prevalence, s.e. 0.11, 1-tail P = 0.058) indicating that genome-wide association studies (GWAS) are needed in African and Asian populations to explore the causes of their respectively high and low DZ twinning rates. In vivo functional tests in zebrafish for IPO8 validated its essential role in female, but not male, fertility. In most regions, risk SNPs linked to known expression quantitative trait loci (eQTLs). Top SNPs were associated with in vivo reproductive hormone levels with the top pathways including hormone ligand binding receptors and the ovulation cycle. LARGE SCALE DATA: The full DZT GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/). LIMITATIONS, REASONS FOR CAUTION: Our study only included European ancestry cohorts. Inclusion of data from Africa (with the highest twining rate) and Asia (with the lowest rate) would illuminate further the biology of twinning and female fertility. WIDER IMPLICATIONS OF THE FINDINGS: About one in 40 babies born in the world is a twin and there is much speculation on why twinning runs in families. We hope our results will inform investigations of ovarian response in new and existing ARTs and the causes of female infertility. STUDY FUNDING/COMPETING INTEREST(S): Support for the Netherlands Twin Register came from the Netherlands Organization for Scientific Research (NWO) and The Netherlands Organization for Health Research and Development (ZonMW) grants, 904-61-193, 480-04-004, 400-05-717, Addiction-31160008, 911-09-032, Biobanking and Biomolecular Resources Research Infrastructure (BBMRI.NL, 184.021.007), Royal Netherlands Academy of Science Professor Award (PAH/6635) to DIB, European Research Council (ERC-230374), Rutgers University Cell and DNA Repository (NIMH U24 MH068457-06), the Avera Institute, Sioux Falls, South Dakota (USA) and the National Institutes of Health (NIH R01 HD042157-01A1) and the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health and Grand Opportunity grants 1RC2 MH089951. The QIMR Berghofer Medical Research Institute (QIMR) study was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496610, 496739, 552485, 552498, 1050208, 1075175). L.Y. is funded by Australian Research Council (Grant number DE200100425). The Minnesota Center for Twin and Family Research (MCTFR) was supported in part by USPHS Grants from the National Institute on Alcohol Abuse and Alcoholism (AA09367 and AA11886) and the National Institute on Drug Abuse (DA05147, DA13240, and DA024417). The Women's Genome Health Study (WGHS) was funded by the National Heart, Lung, and Blood Institute (HL043851 and HL080467) and the National Cancer Institute (CA047988 and UM1CA182913), with support for genotyping provided by Amgen. Data collection in the Finnish Twin Registry has been supported by the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, AA-09203, AA15416, and K02AA018755) and the Academy of Finland (grants 100499, 205585, 118555, 141054, 264146, 308248, 312073 and 336823 to J. Kaprio). TwinsUK is funded by the Wellcome Trust, Medical Research Council, Versus Arthritis, European Union Horizon 2020, Chronic Disease Research Foundation (CDRF), Zoe Ltd and the National Institute for Health Research (NIHR) Clinical Research Network (CRN) and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. For NESDA, funding was obtained from the Netherlands Organization for Scientific Research (Geestkracht program grant 10000-1002), the Center for Medical Systems Biology (CSMB, NVVO Genomics), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI-NL), VU University's Institutes for Health and Care Research (EMGO+) and Neuroscience Campus Amsterdam, University Medical Center Groningen, Leiden University Medical Center, National Institutes of Health (NIH, ROI D0042157-01A, MH081802, Grand Opportunity grants 1 RC2 Ml-1089951 and IRC2 MH089995). Part of the genotyping and analyses were funded by the Genetic Association Information Network (GAIN) of the Foundation for the National Institutes of Health. Computing was supported by BiG Grid, the Dutch e-Science Grid, which is financially supported by NWO. Work in the Del Bene lab was supported by the Programme Investissements d'Avenir IHU FOReSIGHT (ANR-18-IAHU-01). C.R. was supported by an EU Horizon 2020 Marie Sklodowska-Curie Action fellowship (H2020-MSCA-IF-2014 #661527). H.S. and K.S. are employees of deCODE Genetics/Amgen. The other authors declare no competing financial interests. TRIAL REGISTRATION NUMBER: N/A.

Rare variants in the MECP2 gene in girls with central precocious puberty: a translational cohort study.

BACKGROUND: Identification of genetic causes of central precocious puberty have revealed epigenetic mechanisms as regulators of human pubertal timing. MECP2, an X-linked gene, encodes a chromatin-associated protein with a role in gene transcription. MECP2 loss-of-function mutations usually cause Rett syndrome, a severe neurodevelopmental disorder. Early pubertal development has been shown in several patients with Rett syndrome. The aim of this study was to explore whether MECP2 variants are associated with an idiopathic central precocious puberty phenotype. METHODS: In this translational cohort study, participants were recruited from seven tertiary centres from five countries (Brazil, Spain, France, the USA, and the UK). Patients with idiopathic central precocious puberty were investigated for rare potentially damaging variants in the MECP2 gene, to assess whether MECP2 might contribute to the cause of central precocious puberty. Inclusion criteria were the development of progressive pubertal signs (Tanner stage 2) before the age of 8 years in girls and 9 years in boys and basal or GnRH-stimulated LH pubertal concentrations. Exclusion criteria were the diagnosis of peripheral precocious puberty and the presence of any recognised cause of central precocious puberty (CNS lesions, known monogenic causes, genetic syndromes, or early exposure to sex steroids). All patients included were followed up at the outpatient clinics of participating academic centres. We used high-throughput sequencing in 133 patients and Sanger sequencing of MECP2 in an additional 271 patients. Hypothalamic expression of Mecp2 and colocalisation with GnRH neurons were determined in mice to show expression of Mecp2 in key nuclei related to pubertal timing regulation. FINDINGS: Between Jun 15, 2020, and Jun 15, 2022, 404 patients with idiopathic central precocious puberty (383 [95%] girls and 21 [5%] boys; 261 [65%] sporadic cases and 143 [35%] familial cases from 134 unrelated families) were enrolled and assessed. We identified three rare heterozygous likely damaging coding variants in MECP2 in five girls: a de novo missense variant (Arg97Cys) in two monozygotic twin sisters with central precocious puberty and microcephaly; a de novo missense variant (Ser176Arg) in one girl with sporadic central precocious puberty, obesity, and autism; and an insertion (Ala6_Ala8dup) in two unrelated girls with sporadic central precocious puberty. Additionally, we identified one rare heterozygous 3'UTR MECP2 insertion (36_37insT) in two unrelated girls with sporadic central precocious puberty. None of them manifested Rett syndrome. Mecp2 protein colocalised with GnRH expression in hypothalamic nuclei responsible for GnRH regulation in mice. INTERPRETATION: We identified rare MECP2 variants in girls with central precocious puberty, with or without mild neurodevelopmental abnormalities. MECP2 might have a role in the hypothalamic control of human pubertal timing, adding to the evidence of involvement of epigenetic and genetic mechanisms in this crucial biological process. FUNDING: Fundação de Amparo à Pesquisa do Estado de São Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnológico, and the Wellcome Trust.

Newborn body composition and child cardiovascular risk markers: a prospective multi-ethnic Asian cohort study.

BACKGROUND: Early epidemiological studies have associated low birthweight with increased cardiovascular risk. We aimed to examine whether the fat and fat-free components of birthweight have differing relationships with childhood cardiovascular risk markers. METHODS: In the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort, air displacement plethysmography was conducted within 24 h after delivery in 290 naturally conceived singletons. We investigated associations of newborn cohort-specific standardized z-score of fat mass, fat-free mass, body fat percentage and birthweight on child (at 6 years of age) carotid intima-media thickness, pulse wave velocity, blood pressure, prehypertension/hypertension (>110/70 mmHg) and standardized systolic and diastolic blood pressure (SBP and DBP) trajectories (at 3-6 years of age), taking account of maternal education, height, tobacco exposure, parity, ethnicity, child's sex, gestational age, age at follow-up, and other maternal factors. RESULTS: Clear inverse associations were seen for blood pressure with z-score of fat mass [SBP, ß (95% CI): -1.31 mmHg (-2.57, -0.06); DBP: -0.79 mmHg (-1.74, 0.15)] and body fat percentage [SBP: -1.46 mmHg (-2.73, -0.19); DBP: -0.80 mmHg (-1.75, 0.16)], but not with fat-free mass [SBP: 0.27 mmHg (-1.29, 1.83)]; DBP: -0.14 mmHg (-1.30, 1.03)]. Being in the lowest tertile of fat mass or body fat percentage was associated with higher blood pressure trajectories and prehypertension/hypertension risk [OR (95% CI), fat mass: 4.23 (1.41, 12.68); body fat percentage: 3.22 (1.09, 9.53)] without concomitantly higher overweight/obesity risk. CONCLUSIONS: At birth, low adiposity was associated with increased childhood blood pressure. Low newborn adiposity might serve as a marker of poor fetal growth or suboptimal intrauterine conditions associated with hypertension risk later in life.

Adverse Effects of Early Puberty Timing in Girls and Potential Solutions.

Given the global secular declining trends of the age at puberty and its relevant mechanisms, as illustrated in the first part of this series, the present part will discuss the public health implications of early puberty and potential clinical and public health measures. Although the major effect of earlier maturation impacts adolescents' mental health and likelihood of engaging in risky behaviors, there are also effects in adulthood on cardiometabolic health, especially type 2 diabetes, and an increased risk of certain cancers, especially hormone-related cancers such as breast cancer. The paper ends with recommendations for clinical management, especially for girls who should receive further evaluation, as well as recommendations for the patient and her family and public health considerations.

Detection and characterization of male sex chromosome abnormalities in the UK Biobank study.

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 × 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 < 7 × 10-6). 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.

Associations between maternal iron supplementation in pregnancy and offspring growth and cardiometabolic risk outcomes in infancy and childhood.

It was previously observed that maternal iron supplementation in pregnancy was associated with increased offspring size and adiposity at birth, possibly mediated through increased risk of gestational diabetes. In this study we investigated potential long-term associations of maternal iron supplementation in pregnancy with offspring growth in infancy, and growth and cardiometabolic risk factors in mid-childhood to seek evidence of nutritional programming. Using a nested case-control format, markers of growth and adiposity were measured at 3, 12 and 24 months of age in 341 infants from the Cambridge Baby Growth Study whose mothers supplemented with iron in pregnancy and 222 infants whose mothers did not. Measures of growth, glucose tolerance (using a 30 minute 1.75 g glucose/kg body weight oral glucose tolerance test), insulin sensitivity (HOMA IR) and blood pressure were collected in 122 and 79 of these children, respectively, at around 9.5 years of age. In infancy adiposity-promoting associations with maternal iron supplementation in pregnancy were evident at 3 months of age (e.g. mean difference in skinfold thickness: ß = +0.15 mm, p = 0.02, in n = 341 whose mothers supplemented versus 222 that did not; waist circumference: ß = +0.7 cm, p = 0.04, in n = 159 and 78, respectively) but differences lessened after this time (e.g. 3-12 month change in mean difference in skinfold thickness: ß = -0.2 mm, p = 0.03, in n = 272 and 178, respectively). At ~9.5 years of age children whose mothers supplemented with iron in pregnancy had lower mean arterial blood pressures (ß = -1.0 mmHg, p = 0.03, in n = 119 and 78, respectively). There were no apparent differences in markers of growth or other cardiometabolic factors. These results suggest that most of the associations of maternal iron supplementation in pregnancy on growth and adiposity evident at birth disappear during infancy, but there may be some evidence of long-term nutritional programming of blood pressure in mid-childhood.

ImprintSeq, a novel tool to interrogate DNA methylation at human imprinted regions and diagnose multilocus imprinting disturbance.

PURPOSE: Disruptions of genomic imprinting are associated with congenital imprinting disorders (CIDs) and other disease states, including cancer. CIDs are most often associated with altered methylation at imprinted differentially methylated regions (iDMRs). In some cases, multiple iDMRs are affected causing multilocus imprinting disturbances (MLIDs). The availability of accurate, quantitative, and scalable high-throughput methods to interrogate multiple iDMRs simultaneously would enhance clinical diagnostics and research. METHODS: We report the development of a custom targeted methylation sequencing panel that covered most relevant 63 iDMRs for CIDs and the detection of MLIDs. We tested it in 70 healthy controls and 147 individuals with CIDs. We distinguished loss and gain of methylation per differentially methylated region and classified high and moderate methylation alterations. RESULTS: Across a range of CIDs with a variety of molecular mechanisms, ImprintSeq performed at 98.4% sensitivity, 99.9% specificity, and 99.9% accuracy (when compared with previous diagnostic testing). ImprintSeq was highly sensitive for detecting MLIDs and enabled diagnostic criteria for MLID to be proposed. In a child with extreme MLID profile a probable genetic cause was identified. CONCLUSION: ImprintSeq provides a novel assay for clinical diagnostic and research studies of CIDs, MLIDs, and the role of disordered imprinting in human disease states.

Associations between Maternal Iron Supplementation in Pregnancy and Changes in Offspring Size at Birth Reflect Those of Multiple Micronutrient Supplementation.

It was previously observed that in a population of a high-income country, dietary multiple micronutrient supplementation in pregnancy was associated with an increased risk of gestational diabetes (GDM) and increased offspring size at birth. In this follow-up study, we investigated whether similar changes are observed with dietary iron supplementation. For this we used the prospective Cambridge Baby Growth Study with records of maternal GDM status, nutrient supplementation, and extensive offspring birth size measurements. Maternal iron supplementation in pregnancy was associated with GDM development (risk ratio 1.67 (1.01-2.77), p = 0.048, n = 677) as well as offspring size and adiposity (n = 844-868) at birth in terms of weight (ß' = 0.078 (0.024-0.133); p = 0.005), head circumference (ß' = 0.060 (0.012-0.107); p = 0.02), body mass index (ß' = 0.067 (0.014-0.119); p = 0.01), and various skinfold thicknesses (ß' = 0.067-0.094; p = 0.03-0.003). In a subset of participants for whom GDM statuses were available, all these associations were attenuated by adjusting for GDM. Iron supplementation also attenuated the associations between multiple micronutrient supplementation and these same measures. These results suggest that iron supplementation may mediate the effects associated with multiple micronutrient supplementation in pregnancy in a high-income country, possibly through the increased risk of developing GDM.

Meta-analysis of epigenome-wide association studies of carotid intima-media thickness.

Common carotid intima-media thickness (cIMT) is an index of subclinical atherosclerosis that is associated with ischemic stroke and coronary artery disease (CAD). We undertook a cross-sectional epigenome-wide association study (EWAS) of measures of cIMT in 6400 individuals. Mendelian randomization analysis was applied to investigate the potential causal role of DNA methylation in the link between atherosclerotic cardiovascular risk factors and cIMT or clinical cardiovascular disease. The CpG site cg05575921 was associated with cIMT (beta = -0.0264, p value = 3.5 × 10-8) in the discovery panel and was replicated in replication panel (beta = -0.07, p value = 0.005). This CpG is located at chr5:81649347 in the intron 3 of the aryl hydrocarbon receptor repressor gene (AHRR). Our results indicate that DNA methylation at cg05575921 might be in the pathway between smoking, cIMT and stroke. Moreover, in a region-based analysis, 34 differentially methylated regions (DMRs) were identified of which a DMR upstream of ALOX12 showed the strongest association with cIMT (p value = 1.4 × 10-13). In conclusion, our study suggests that DNA methylation may play a role in the link between cardiovascular risk factors, cIMT and clinical cardiovascular disease.

Association between perinatal factors, genetic susceptibility to obesity and age at adiposity rebound in children of the EDEN mother-child cohort.

BACKGROUND: Early adiposity rebound (AR) has been associated with increased risk of overweight or obesity in adulthood. However, little is known about early predictors of age at AR. We aimed to study the role of perinatal factors and genetic susceptibility to obesity in the kinetics of AR. METHODS: Body mass index (BMI) curves were modelled by using mixed-effects cubic models, and age at AR was estimated for 1415 children of the EDEN mother-child cohort study. A combined obesity risk-allele score was calculated from genotypes for 27 variants identified by genome-wide association studies of adult BMI. Perinatal factors of interest were maternal age at delivery, parental education, parental BMI, gestational weight gain, maternal smoking during pregnancy, and newborn characteristics (sex, prematurity, and birth weight). We used a hierarchical level approach with multivariable linear regression model to investigate the association between these factors, obesity risk-allele score, and age at AR. RESULTS: A higher genetic susceptibility to obesity score was associated with an earlier age at AR. At the most distal level of the hierarchical model, maternal and paternal educational levels were positively associated with age at AR. Children born to parents with higher BMI were more likely to exhibit earlier age at AR. In addition, higher gestational weight gain was related to earlier age at AR. For children born small for gestational age, the average age at AR was 88 [±39] days lower than for children born appropriate for gestational age and 91 [±56] days lower than for children born large for gestational age. CONCLUSION: The timing of AR seems to be an early childhood manifestation of the genetic susceptibility to adult obesity. We further identified low birth weight and gestational weight gain as novel predictors of early AR, highlighting the role of the intrauterine environment in the kinetics of adiposity.

Factors associated with breast cancer screening intention in Kathmandu Valley, Nepal.

BACKGROUND: Breast cancer burden is increasing in low-income countries (LICs). Increasing incidence and delayed presentation of breast cancer are mainly responsible for this burden. Many women do not participate in breast cancer screening despite its effectiveness. Moreover, studies are limited on the barriers associated with low utilization of breast cancer screening in LICs. This study identified breast cancer screening behavior and factors associated with breast cancer screening intention among women in Kathmandu Valley, Nepal. METHODS: A cross-sectional study was conducted among 500 women living in five municipalities of Kathmandu Valley, Nepal. Data were collected from July to September 2018, using a structured questionnaire. Interviews were conducted among women selected through proportionate random household sampling. This study was conceptualized using the theory of planned behavior, fatalism, perceived susceptibility, and perceived severity. The outcome variables included: the intention to have mammography (MMG) biennially, the intention to have clinical breast examination (CBE) annually, and the intention to perform breast self-examination (BSE) monthly. Analysis was conducted separately for each outcome variable using partial proportional odds model. RESULTS: Out of 500 women, 3.4% had undergone MMG biennially, 7.2% CBE annually, and 14.4% BSE monthly. Women with a positive attitude, high subjective norms, and high perceived behavioral control were more likely to have the intention to undergo all three screening methods. Similarly, women were more likely to have intention to undergo CBE and MMG when they perceived themselves susceptible to breast cancer. Conversely, women were less likely to have intention to undergo CBE when they had high fatalistic beliefs towards breast cancer. CONCLUSION: Women in this study had poor screening behavior. The practice of breast self-examination was comparatively higher than clinical breast examination and mammography. Multidimensional culturally sensitive interventions are needed to enhance screening intentions. Efforts should be directed to improve attitude, family support, and fatalistic belief towards cancer. Furthermore, the proper availability of screening methods should be ensured while encouraging women to screen before the appearance of symptoms.

Positive maternal attitudes to following healthy infant feeding guidelines attenuate the associations between infant appetitive traits and both infant milk intake and weight.

Appetitive traits influence food intake and weight gain throughout the life-course. Here, we investigated whether maternal attitudes to following healthy infant feeding guidelines could modify this association. Baseline data from 544 mother-infant formula-feeding dyads recruited to the Baby Milk Trial were included in this observational, cross-sectional analysis. Infant appetitive traits (food responsiveness and satiety responsiveness), maternal attitudes to following healthy infant feeding guidelines (self-efficacy, outcome-expectancy, intentions) and infant milk intakes were reported by mothers through questionnaires. Infant weight was measured using standard procedures. Associations between the maternal attitudes score or infant appetitive traits with infant milk intake and infant weight were evaluated in linear regression models adjusted for infant sex and age. To identify effect modification, the interaction term between the maternal attitudes score and infant appetitive trait was added to the model. Infants' mean age and weight were 2.3 months (SD = 0.9) and 5.5 kg (SD = 0.9), respectively. The mean daily infant milk intake reported by mothers was 895 ml/day (SD = 215). Higher maternal attitudes score was associated with lower infant milk intake (Beta = -68.4 ml/day/unit (95% CI: 96.6, -40.2)) and infant weight (Beta = -0.13 SD/unit (-0.25, -0.02)). The maternal attitudes score showed interactions with infant food responsiveness on infant milk intake (p = 0.049), and with infant satiety responsiveness on infant weight (p = 0.01). In both cases, a higher maternal attitudes score attenuated the associations between infant appetitive traits and those outcomes. This analysis provides evidence that positive maternal attitudes to following healthy infant feeding guidelines attenuate the effects of infant appetitive traits on infant milk intake and body weight.

Using human genetics to understand the disease impacts of testosterone in men and women.

Testosterone supplementation is commonly used for its effects on sexual function, bone health and body composition, yet its effects on disease outcomes are unknown. To better understand this, we identified genetic determinants of testosterone levels and related sex hormone traits in 425,097 UK Biobank study participants. Using 2,571 genome-wide significant associations, we demonstrate that the genetic determinants of testosterone levels are substantially different between sexes and that genetically higher testosterone is harmful for metabolic diseases in women but beneficial in men. For example, a genetically determined 1 s.d. higher testosterone increases the risks of type 2 diabetes (odds ratio (OR) = 1.37 (95% confidence interval (95% CI): 1.22-1.53)) and polycystic ovary syndrome (OR = 1.51 (95% CI: 1.33-1.72)) in women, but reduces type 2 diabetes risk in men (OR = 0.86 (95% CI: 0.76-0.98)). We also show adverse effects of higher testosterone on breast and endometrial cancers in women and prostate cancer in men. Our findings provide insights into the disease impacts of testosterone and highlight the importance of sex-specific genetic analyses.

Genetic predisposition to mosaic Y chromosome loss in blood.

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.

Comparison of smoking-related DNA methylation between newborns from prenatal exposure and adults from personal smoking.

Aim: Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for in utero exposure in newborns is unknown. Materials & methods: We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Results & conclusion: Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring.

Epigenome-Wide Association Study of Incident Type 2 Diabetes in a British Population: EPIC-Norfolk Study.

Epigenetic changes may contribute substantially to risks of diseases of aging. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset, to investigate the role of methylation in the etiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM and robustly confirmed three MVPs identified previously (near to TXNIP, ABCG1, and SREBF1). All 18 MVPs showed directionally consistent associations with incident and prevalent T2DM in independent studies. Further conditional analyses suggested that the identified epigenetic signals appear related to T2DM via glucose and obesity-related pathways acting before the collection of baseline samples. We integrated genome-wide genetic data to identify methylation-associated quantitative trait loci robustly associated with 16 of the 18 MVPs and found one MVP, cg00574958 at CPT1A, with a possible direct causal role in T2DM. None of the implicated genes were previously highlighted by genetic association studies, suggesting that DNA methylation studies may reveal novel biological mechanisms involved in tissue responses to glycemia.

Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.

Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.

Genome-wide association study for risk taking propensity indicates shared pathways with body mass index.

Risk-taking propensity is a trait of significant public health relevance but few specific genetic factors are known. Here we perform a genome-wide association study of self-reported risk-taking propensity among 436,236 white European UK Biobank study participants. We identify genome-wide associations at 26 loci (P < 5 × 10-8), 24 of which are novel, implicating genes enriched in the GABA and GABA receptor pathways. Modelling the relationship between risk-taking propensity and body mass index (BMI) using Mendelian randomisation shows a positive association (0.25 approximate SDs of BMI (SE: 0.06); P = 6.7 × 10-5). The impact of individual SNPs is heterogeneous, indicating a complex relationship arising from multiple shared pathways. We identify positive genetic correlations between risk-taking and waist-hip ratio, childhood obesity, ever smoking, attention-deficit hyperactivity disorder, bipolar disorder and schizophrenia, alongside a negative correlation with women's age at first birth. These findings highlight that behavioural pathways involved in risk-taking propensity may play a role in obesity, smoking and psychiatric disorders.