Loss of transient receptor potential channel 5 causes obesity and postpartum depression.

Hypothalamic neural circuits regulate instinctive behaviors such as food seeking, the fight/flight response, socialization, and maternal care. Here, we identified microdeletions on chromosome Xq23 disrupting the brain-expressed transient receptor potential (TRP) channel 5 (TRPC5). This family of channels detects sensory stimuli and converts them into electrical signals interpretable by the brain. Male TRPC5 deletion carriers exhibited food seeking, obesity, anxiety, and autism, which were recapitulated in knockin male mice harboring a human loss-of-function TRPC5 mutation. Women carrying TRPC5 deletions had severe postpartum depression. As mothers, female knockin mice exhibited anhedonia and depression-like behavior with impaired care of offspring. Deletion of Trpc5 from oxytocin neurons in the hypothalamic paraventricular nucleus caused obesity in both sexes and postpartum depressive behavior in females, while Trpc5 overexpression in oxytocin neurons in knock-in mice reversed these phenotypes. We demonstrate that TRPC5 plays a pivotal role in mediating innate human behaviors fundamental to survival, including food seeking and maternal care.

Maternal obesity increases hypothalamic miR-505-5p expression in mouse offspring leading to altered fatty acid sensing and increased intake of high-fat food.

In utero exposure to maternal obesity programs increased obesity risk. Animal models show that programmed offspring obesity is preceded by hyperphagia, but the mechanisms that mediate these changes are unknown. Using a mouse model of maternal obesity, we observed increased intake of a high-fat diet (HFD) in offspring of obese mothers that precedes the development of obesity. Through small RNA sequencing, we identified programmed overexpression of hypothalamic miR-505-5p that is established in the fetus, lasts to adulthood and is maintained in hypothalamic neural progenitor cells cultured in vitro. Metabolic hormones and long-chain fatty acids associated with obesity increase miR-505-5p expression in hypothalamic neurons in vitro. We demonstrate that targets of miR-505-5p are enriched in fatty acid metabolism pathways and overexpression of miR-505-5p decreased neuronal fatty acid metabolism in vitro. miR-505-5p targets are associated with increased BMI in human genetic studies. Intra-cerebroventricular injection of miR-505-5p in wild-type mice increased HFD intake, mimicking the phenotype observed in offspring exposed to maternal obesity. Conversely, maternal exercise intervention in an obese mouse pregnancy rescued the programmed increase of hypothalamic miR-505-5p in offspring of obese dams and reduced HFD intake to control offspring levels. This study identifies a novel mechanism by which maternal obesity programs obesity in offspring via increased intake of high-fat foods.

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.

Using genetic variation to disentangle the complex relationship between food intake and health outcomes.

Diet is considered as one of the most important modifiable factors influencing human health, but efforts to identify foods or dietary patterns associated with health outcomes often suffer from biases, confounding, and reverse causation. Applying Mendelian randomization in this context may provide evidence to strengthen causality in nutrition research. To this end, we first identified 283 genetic markers associated with dietary intake in 445,779 UK Biobank participants. We then converted these associations into direct genetic effects on food exposures by adjusting them for effects mediated via other traits. The SNPs which did not show evidence of mediation were then used for MR, assessing the association between genetically predicted food choices and other risk factors, health outcomes. We show that using all associated SNPs without omitting those which show evidence of mediation, leads to biases in downstream analyses (genetic correlations, causal inference), similar to those present in observational studies. However, MR analyses using SNPs which have only a direct effect on the exposure on food exposures provided unequivocal evidence of causal associations between specific eating patterns and obesity, blood lipid status, and several other risk factors and health outcomes.

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.

Ultra-processed food consumption in UK adolescents: distribution, trends, and sociodemographic correlates using the National Diet and Nutrition Survey 2008/09 to 2018/19.

PURPOSE: We quantified levels of ultra-processed food (UPF) consumption and investigated consumption patterns in a representative sample of UK adolescents. METHODS: We used data from 4-day food diaries from adolescents in the UK National Diet and Nutrition Survey (NDNS) (2008/09-2018/19). UPF were identified using the NOVA classification. We estimated the percentage of Total Energy Intake (%TEI) and the absolute weight (grams). Linear regression models quantified differences in UPF consumption across survey years and its association with participant's individual characteristics. This was an analysis of the repeated cross-sectional data from the UK NDNS Rolling Programme waves 1-11 (2008/09-2018/19). A total of 2991 adolescents (11-18y) with complete information on dietary intake were included. RESULTS: Mean UPF consumption was 861 (SD 442) g/d and this accounted for 65.9% (SD 13.4%) of TEI. Between 2008 and 2019, mean UPF consumption decreased from 996 to 776 g/d [ - 211 (95%CI - 302; - 120)] and from 67.7% to 62.8% of TEI [ - 4.8% (95%CI - 8.1; - 1.5)]. Higher %TEI was consumed by adolescents with lower socioeconomic status; white ethnicity and living in England North. A higher weight of UPF consumption (g/d) was associated with being male, white, age 18y, having parents with routine or manual occupation, living in England North, and living with obesity. CONCLUSION: Average energy intake from UPF has decreased over a decade in UK adolescents. We observed a social and regional patterning of UPF consumption, with higher consumption among adolescents from lower socioeconomic backgrounds, from a white ethnicity and living in England North. Our findings suggest inequalities associated with UPF intake and factors that might lie beyond individual choice.

Adaptation and application of the Parent Attitudes About Childhood Vaccines survey tool in the Vietnamese language: a cross-sectional study.

BACKGROUND: Parental vaccine hesitancy could lead to outbreaks of vaccine-preventable diseases. Although parental vaccine hesitancy exists in the Vietnamese community, no research has directly investigated this social phenomenon in Vietnam. Among the validated measures, the 15-item Parent Attitudes About Childhood Vaccines survey tool (PACV) was reliable for predicting vaccine-hesitant parents. However, the PACV was not available in Vietnamese. This study aimed to develop a Vietnamese version of the PACV and examine factors associated with parental vaccine hesitancy in Hue city, Vietnam. METHODS: This study was a cross-sectional study. The English PACV was translated into Vietnamese with content and face validation. Self-administered questionnaires were distributed to 400 parents at ten commune health centres in Hue city, Vietnam. The parents were asked to answer the questionnaire again after two weeks for the test-retest reliability. The Vietnamese PACV reliability was assessed using Cronbach's alpha and McDonald's omega, and the intra-class correlation (ICC) coefficients were used for the test-retest reliability. The construct validity was tested by the hypothesis that parental vaccine hesitancy would be related to the intention of getting the children vaccinated. Exploratory factor analysis was also undertaken to determine the construct validity. Bivariate and multivariable logistic regression were used to identify the factors associated with parental vaccine hesitancy. RESULTS: The Vietnamese PACV final version (PACV-Viet) contained 14 items. Three hundred and fifteen parents returned completed questionnaires, giving a response rate of 78.8%. The Cronbach's alpha and McDonald's omega were 0.72 and 0.70, respectively. Out of 315 parents, 84 responses were returned for test-retest reliability. All ICCs were good to excellent, ranging from 0.81 to 0.99. The PACV-Viet was confirmed to have construct validity. Using the PACV-Viet, 8.9% of the parents were found hesitant to childhood vaccination. Being unemployed and having seen the news about adverse events following immunisation were associated with parental vaccine hesitancy, with AOR = 3.2 (95% CI 1.3-8.0) and AOR = 4.5 (95% CI 1.2-16.7), respectively. CONCLUSIONS: The PACV-Viet is a valid and reliable tool. Community outreach is necessary to alleviate parents' concerns about childhood vaccination.

Associations between breast milk intake volume, macronutrient intake and infant growth in a longitudinal birth cohort: the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF).

Growth patterns of breastfed infants show substantial inter-individual differences, partly influenced by breast milk (BM) nutritional composition. However, BM nutritional composition does not accurately indicate BM nutrient intakes. This study aimed to examine the associations between both BM intake volumes and macronutrient intakes with infant growth. Mother-infant dyads (n 94) were recruited into the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) from a single maternity hospital at birth; all infants received exclusive breast-feeding (EBF) for at least 6 weeks. Infant weight, length and skinfolds thicknesses (adiposity) were repeatedly measured from birth to 12 months. Post-feed BM samples were collected at 6 weeks to measure TAG (fat), lactose (carbohydrate) (both by 1H-NMR) and protein concentrations (Dumas method). BM intake volume was estimated from seventy infants between 4 and 6 weeks using dose-to-the-mother deuterium oxide (2H2O) turnover. In the full cohort and among sixty infants who received EBF for 3+ months, higher BM intake at 6 weeks was associated with initial faster growth between 0 and 6 weeks (ß + se 3·58 + 0·47 for weight and 4·53 + 0·6 for adiposity gains, both P < 0·0001) but subsequent slower growth between 3 and 12 months (ß + se - 2·27 + 0·7 for weight and -2·65 + 0·69 for adiposity gains, both P < 0·005). BM carbohydrate and protein intakes at 4-6 weeks were positively associated with early (0-6 weeks) but tended to be negatively related with later (3-12 months) adiposity gains, while BM fat intake showed no association, suggesting that carbohydrate and protein intakes may have more functional relevance to later infant growth and adiposity.

Association between the person-centered maternity care experience and mental health after delivery in urban and rural Dhading, Nepal: a cross-sectional study.

BACKGROUND: Person-centered maternity care is a component of quality care, which includes effective communication, respect, and dignity. Supportive care has a positive effect on mothers' perinatal experience. In contrast, negative childbirth experiences can cause psychological problems. However, the impact of person-centered maternity care experience on mothers' mental health after delivery remains unknown. Therefore, in this study, we examined the association between person-centered maternity care experience at healthcare facilities and maternal mental health after delivery among Nepali women. METHODS: We conducted a cross-sectional study in urban and rural areas in Dhading District, Nepal. Participants were women who gave birth at public healthcare facilities, and their baby's age was between 1 and 12 months. After purposively selecting the target areas, we recruited the women from July to August 2019 and interviewed them using questionnaires. We conducted multiple regression analyses to analyze the association between delivery care experience and depressive symptoms and the association between delivery care experience and mental well-being. RESULTS: In total, 595 women were included in the data analysis. The experience of better person-centered maternity care was associated with lower depressive symptom scores in urban (unstandardized coefficient [B]= - 0.09, p < 0.001) and rural areas (B= - 0.10, p < 0.001). Moreover, the experience of better person-centered maternity care was associated with higher mental well-being scores in both urban (B= 0.30, p < 0.001) and rural areas (B= 0.15, p = 0.017). CONCLUSIONS: Person-centered maternity care was associated with lower depressive symptom scores and higher mental well-being, regardless of the setting in Nepal. Person-centered maternity care during childbirth can potentially improve mental health after delivery. Maternity care should be improved with more attention to person-centered maternity care aspects.

Accommodation and disability-specific differences in nutritional status of children with disabilities in Kathmandu, Nepal: A cross-sectional study.

BACKGROUND: Worldwide, more than 150 million children < 18 years live with disabilities. These children are more vulnerable to malnutrition regardless of institutional care that they receive, such as daycare or residential care. In Nepal, little is known about the status of malnutrition and factors associated with malnutrition among children with disabilities. This study was conducted to investigate the factors associated with malnutrition based on the types of disability and accommodation. METHODS: This institution-based, cross-sectional study was conducted in 22 institutions in the Kathmandu Valley, Nepal. From these institutions, parents/guardians of all children with disabilities were recruited who were present there on the day of data collection. They were interviewed using a structured questionnaire. The questionnaire included questions on demographic characteristics, disability type and severity, accommodation place, feeding practices, and dietary patterns. The outcome variables, stunting, underweight, and obesity were measured using height-for-age, weight-for-age, and body mass index-for-age, respectively. A generalized linear model was used to investigate the factors associated with stunting and underweight, and multinomial logistic regression was used to identify the factors associated with overweight and obesity. RESULTS: Among the 345 children with disabilities, 45% were stunted, 33% were underweight, 19% were thin, and 12% were overweight. Children with physical disabilities (relative risk ratio = 1.88, 95% confidence interval [CI] = 1.26-2.81) were more likely to be stunted than those with sensory disabilities. Children with autism (adjusted odds ratio [aOR] = 5.56, 95% CI: 1.23-25.23) and intellectual disabilities (aOR = 5.84, 95% CI: 1.59-21.51) were more likely to be overweight and obese than those with sensory disabilities. No evidence was found regarding an association between accommodation type and malnutrition. CONCLUSION: Children with disabilities are vulnerable to malnutrition in several ways. Different types of disabilities are associated with different forms of malnutrition. Considering the types of disabilities, tailor-made approaches should be adopted to improve malnutrition status.

Understanding competency of nursing students in the course of case-based learning in Cambodia: a convergent mixed method study.

BACKGROUND: In the last decade, nursing education has begun to reform to competency-based education worldwide, including in low-and middle-income countries. Case-Based Learning (CBL), an approach to delivering competency-based education, contributes to acquiring critical thinking competency, problem-solving, higher knowledge, professional value and attitude. However, it needs to be taught in a culturally appropriate manner. In Cambodia, CBL was initiated in a classroom and clinical practicum by faculty and preceptors who graduated from the upgrading course. This study examined the factors associated with the competency level of nursing students, explored the practice and perceptions of teaching-learning activities among students, faculty members and preceptors and assessed the coherence of qualitative and quantitative findings. METHODS: This was a convergent, mixed methods study. Data were collected from eight educational institutions for quantitative and qualitative studies and seven hospitals for qualitative studies. From June to September 2019, a cross-sectional survey of nursing students in the third year of the three-year programme (n = 719), eight focus group discussions (FGDs; n = 55) with 6-8 members and 15 FGDs with faculty (n = 38) and clinical preceptors (n = 37) with 4-7 members were conducted to elicit the teaching-learning experience and perceptions. Multiple linear regression was performed to investigate the factors associated with student competency. Moreover, the study conducted thematic content analysis on the qualitative data. The integrated analysis was presented as side-by-side joint displays. RESULTS: First, the quantitative and qualitative findings confirmed each other 's CBL learning experiences. Students had higher levels of nursing competencies if they had CBL experiences, both in the classroom and clinical practicum, both in a group manner. Next, the quantitative and qualitative findings complemented students' academic satisfaction with the teaching by faculty members and preceptors. Finally, the quantitative and qualitative findings were expanded to explain students' academic satisfaction with the programme. CONCLUSIONS: The finding of CBL experiences in a group and students' satisfaction with faculty members' and preceptors' teaching improved nursing students' competency development. Meanwhile, students' satisfaction with the design and delivery of the educational programme provides implications for policy level to narrow the theory and practice gaps in low- and middle-income countries.

Epigenome-wide association study of incident type 2 diabetes: a meta-analysis of five prospective European cohorts.

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 <1.1 × 10-7). Sixty-four out of 76 (84.2%) CpG sites were confirmed by directionally consistent effects and p values <0.05 in an independent cohort of Indian Asians. However, on adjustment for baseline BMI only four CpG sites remained genome-wide significant, and addition of the 76 CpG methylation risk score to a prediction model including established predictors of type 2 diabetes (age, sex, BMI and HbA1c) 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.

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.

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.

Distinct Body Mass Index Trajectories to Young-Adulthood Obesity and Their Different Cardiometabolic Consequences.

[Figure: see text].

Longitudinal associations between prepubertal childhood total energy and macronutrient intakes and subsequent puberty timing in UK boys and girls.

PURPOSE: Early puberty is associated with adverse health outcomes. To identify potential modifiable factors for puberty timing, we examined the associations of prepubertal childhood macronutrient intakes with puberty timing in boys and girls. METHODS: In the Avon Longitudinal Study of Parents and Children, macronutrient intakes at age 6 years were predicted using random intercepts linear regression models of dietary data at 3, 4, 7 (assessed by food frequency questionnaires) and 7.5 years (by 3-day food diaries). Timings of puberty onset (Tanner stage 2 genital or breast (B2) development) and puberty completion (voice breaking (VB) or menarche) were calculated from annual parental and child reports at 8-17 years. Age at peak height velocity (PHV) was derived from repeated height measurements at 5-20 years. Linear regression models were fit to estimate the associations of total energy (TEI) and macronutrient intakes (carbohydrate, fat, protein) with puberty timing traits, adjusting for maternal and infant characteristics. RESULTS: Among 3811 boys, higher TEI, but no macronutrient, was associated with earlier VB. Among 3919 girls, higher TEI was associated with earlier ages at B2, PHV, and menarche. Higher protein intake but not carbohydrate or fat intake (in energy partition models) and substitution of dietary protein for carbohydrate (in nutrient density and residual models) was associated with earlier B2, PHV, and menarche in girls. Findings were not attenuated on additional adjustment for body fat percentage during adolescence. CONCLUSIONS: These findings suggest habitual total energy intakes in children, and protein intakes in girls, as potential modifiable determinants of puberty timing.

Associations between abdominal adiposity, body size and objectively measured physical activity in infants from Soweto, South Africa.

OBJECTIVES: Considering the importance of the early life period, in conjunction with the increasing prevalence of adiposity and insufficient physical activity already evident in early childhood, this study aimed to determine associations between abdominal adiposity, body size, and objectively measured physical activity in infancy. METHODS: Infants (n = 138, aged 3-24 months) from Soweto, South Africa were recruited to this cross-sectional study. Visceral (VAT) and subcutaneous abdominal fat (SAT) were measured using ultrasound. Physical activity was assessed using accelerometry and analysed at the hourly level. Multilevel linear regression analyses were run with body composition exposures adjusted for age, sex, and length; models with VAT and SAT were also adjusted for total abdominal fat. RESULTS: Mean (SD) age was 11.8 (7.6) months; 86% were normal weight, 7% were underweight and 7% overweight. In linear models, no body composition variable was significantly associated with physical activity. Physical activity was higher with each increasing length tertile (ANOVA p < 0.01); with a mean(95%CI) 29(60-60)mg in the lowest tertile, 39(71-71)mg in the middle tertile, and 50(81-82)mg in the highest tertile. Infants with normal weight had higher mean(95%CI) physical activity (40(70-80)mg) than underweight (34(73-85)mg, p = 0.01) or overweight infants (31(63-78)mg, ANOVA p < 0.01). When also adjusting for total abdominal fat, infants in the lowest SAT tertile had higher physical activity than those in the middle or highest SAT tertiles (p < 0.01). CONCLUSIONS: These findings lend support for higher physical activity as a marker of healthy growth in the first two years of life.

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

[This corrects the article DOI: 10.1371/journal.pgen.1007813.].

A one-year study of human milk oligosaccharide profiles in the milk of healthy UK mothers and their relationship to maternal FUT2 genotype.

Human milk oligosaccharides (HMOs) are indigestible carbohydrates with prebiotic, pathogen decoy and immunomodulatory activities that are theorized to substantially impact infant health. The objective of this study was to monitor HMO concentrations over 1 year to develop a long-term longitudinal dataset. HMO concentrations in the breast milk of healthy lactating mothers of the Cambridge Baby Growth and Breastfeeding Study (CBGS-BF) were measured at birth, 2 weeks, 6 weeks, 3 months, 6 months and 12 months postpartum. HMO quantification was conducted by high-performance anion-exchange chromatography with pulsed amperometric detection using a newly validated "dilute-and-shoot" method. This technique minimizes sample losses and expedites throughput, making it particularly suitable for the analysis of large sample sets. Varying patterns of individual HMO concentrations were observed with changes in lactation timepoint and maternal secretor status, with the most prominent temporal changes occurring during the first 3 months. These data provide valuable information for the development of human milk banks in view of targeted distribution of donor milk based on infant age. Maternal FUT2 genotype was determined based on identification at single-nucleotide polymorphism rs516246 and compared with the genotype expected based on phenotypic markers in the HMO profile. Surprisingly, two mothers genotyped as secretors produced milk that displayed very low levels of 2'-fucosylated moieties. This unexpected discrepancy between genotype and phenotype suggests that differential enzyme expression may cause substantial variation in HMO profiles between genotypically similar mothers, and current genotypic methods of secretor status determination may require validation with HMO markers from milk analysis.

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.