Genome-wide association study identifies common and low-frequency variants at the AMHgene locus that strongly predict serum AMH levels in males

Anti-Müllerian hormone (AMH) is an essential messenger of sexual differentiation in the foetus and is an emerging biomarker of postnatal reproductive function in females. Due to a paucity of adequately sized studies, the genetic determinants of circulating AMH levels are poorly characterized. In samples from 2815 adolescents aged 15 from the ALSPAC study, we performed the first genome-wide association study of serum AMH levels across a set of ∼9 M ‘1000 Genomes Reference Panel’ imputed genetic variants. Genetic variants at the AMH protein-coding gene showed considerable allelic heterogeneity, with both common variants [rs4807216 (PMale = 2 × 10−49, Beta: ∼0.9 SDs per allele), rs8112524 (PMale = 3 × 10−8, Beta: ∼0.25)] and low-frequency variants [rs2385821 (PMale = 6 × 10−31, Beta: ∼1.2, frequency 3.6%)] independently associated with apparently large effect sizes in males, but not females. For all three SNPs, we highlight mechanistic links to AMH gene function and demonstrate highly significant sex interactions (PHet 0.0003–6.3 × 10−12), culminating in contrasting estimates of trait variance explained (24.5% in males versus 0.8% in females). Using these SNPs as a genetic proxy for AMH levels, we found no evidence in additional datasets to support a biological role for AMH in complex traits and diseases in men

Collecting saliva samples for DNA extraction from children and parents: findings from a pilot study using lay interviewers in the UK

In recent years there has been a substantial increase in the collection of biological data on social surveys. Biological data has hitherto been primarily collected by medically trained personnel in a clinic or laboratory setting or using specialist nurse interviewers in a home-visit setting. However, improvements in technology and the development of minimally or non- invasive data collection methods have made it increasingly feasible to collect bio-measures in a home setting using non-medically trained lay interviewers. In the field of genetic research, it has become increasingly common to collect DNA from saliva samples. This paper provides an account of a pilot study investigating the feasibility of collecting saliva samples for DNA extraction from mothers, fathers and children aged around 11 years old using lay interviewers on the UK Millennium Cohort Study. The pilot study was carried out in 2011 in five areas of the UK with one interviewer in each area. 45 families took part in the pilot and saliva samples were obtained from 73 per cent of mothers, 76 per cent of fathers and 74 per cent of children. We demonstrate that it is indeed viable to collect saliva samples for DNA extraction from children and parents using lay interviewers in a home setting, and provide practical suggestions about how the data collection process could be improved in order to achieve higher response rates and improved specimen quality. Our findings are relevant to other surveys planning to incorporate saliva sample collection for DNA extraction, particularly for those involving lay interviewers in a home setting

Vitamin D Status Is Not Associated with Outcomes of Experimentally-Induced Muscle Weakness and Pain in Young, Healthy Volunteers

Vitamin D receptors have been identified in skeletal muscle; and symptoms of vitamin D deficiency include muscle weakness and pain. Moreover, increased serum 25-hydroxyvitamin D (25(OH)D) concentrations have been associated with improved muscle function. To further clarify the importance of vitamin D to muscle, we examined the association between vitamin D status and exercise-induced muscle pain and weakness in healthy people. Muscle damage to the elbow flexors was induced with eccentric exercise (EE) in 48 individuals (22.5 ± 3.2 yrs). Muscle pain ratings following unloaded movement and peak isometric force (IF) were collected before EE and for 4 days post-EE. Linear regression was used to determine if serum 25(OH)D was a predictor of any outcome. In males, R2-values from 0.48 to 1.00. R2 for IF ranged from 0 to 0.02 and P-values from 0.48 to 1.00. In females, R2 for pain ratings ranged from 0.01 to 0.11 and P-values from 0.14 to 0.59. R2 for IF ranged from 0 to 0.04 and P-values from 0.41 to 0.90. In conclusion, vitamin D status did not predict muscle pain or strength after EE-induced muscle damage in young healthy men and women

Assessment of rates of recanting and hair testing as a biological measure of drug use in a general population sample of young people

AIMS: We investigate the extent of and factors associated with denial of previously reported cannabis and other illicit drug use, and assess the potential of hair testing for measuring substance use in general population samples. DESIGN: Birth cohort study. SETTING: United Kingdom, 1991–present. PARTICIPANTS: A total of 3643 participants who provided hair and self‐report measures of cannabis and other illicit drug use in the Avon Longitudinal Study of Parents and Children (ALSPAC) at age 18 years. MEASUREMENTS: Denial of ever use of cannabis and other illicit drugs at age 18 following previously reported use. Positive hair drug tests for cannabis and other illicit drugs, and expected numbers of false positives and false negatives based on expected sensitivity and specificity. FINDINGS: Cannabis and other illicit drug use was reported by 1223 and 393 individuals, respectively, before age 18 years. Of these 176 (14.4%) and 99 (25.2%), respectively, denied use at age 18. Denial of cannabis use decreased with the reporting of other substances and antisocial behaviour. Cannabis and other illicit drug use at age 18 was reported by 547 (22.5%) and 203 (8.4%) individuals, respectively. Of these, 111 (20.3%) and 13 (6.4%) were hair‐positive for cannabis and other illicit drugs, respectively. Based on hair testing for cannabis use we expect 0 [95% confidence interval (CI) = 0–169] false positives and 394 (95% CI = 323–449) false negatives compared to observed 362 potential false positives and 436 potential false negatives based on self‐report. In hair‐positive individuals, reporting the use of other substances and antisocial behaviour decreased the odds of a negative self‐report. CONCLUSIONS: Hair analysis provides an unreliable marker of substance use in general population samples. People who report more frequent substance use before age 18 are less likely to later deny previous substance use at age 18 than people who report occasional use

Maternal thyroid function and child educational attainment: prospective cohort study

Objective: To determine if first trimester maternal thyroid dysfunction is a critical determinant of child scholastic performance and overall educational attainment. Design: Prospective cohort study. Setting: Avon Longitudinal Study of Parents and Children cohort in the UK. Participants: 4615 mother-child pairs with an available first trimester sample (median 10 weeks gestation, interquartile range 8-12). Exposures: Free thyroxine, thyroid stimulating hormone, and thyroid peroxidase antibodies assessed as continuous measures and the seven clinical categories of maternal thyroid function. Main outcome measures: Five age-specific national curriculum assessments in 3580 children at entry stage assessment at 54 months, increasing up to 4461 children at their final school assessment at age 15. Results: No strong evidence of clinically meaningful associations of first trimester free thyroxine and thyroid stimulating hormone levels with entry stage assessment score or Standard Assessment Test scores at any of the key stages was found. Associations of maternal free thyroxine or thyroid stimulating hormone with the total number of General Certificates of Secondary Education (GCSEs) passed (range 0-16) were all close to the null: free thyroxine, rate ratio per pmol/L 1.00 (95% confidence interval 1.00 to 1.01); and thyroid stimulating hormone, rate ratio 0.98 (0.94 to 1.02). No important relationship was observed when more detailed capped scores of GCSEs allowing for both the number and grade of pass or when language, mathematics, and science performance were examined individually or when all educational assessments undertaken by an individual from school entry to leaving were considered. 200 (4.3%) mothers were newly identified as having hypothyroidism or subclinical hypothyroidism and 97 (2.1%) subclinical hyperthyroidism or hyperthyroidism. Children of mothers with thyroid dysfunction attained an equivalent number of GCSEs and equivalent grades as children of mothers with euthyroidism. Conclusions: Maternal thyroid dysfunction in early pregnancy does not have a clinically important association with impaired child performance at school or educational achievement

Hormonal contraceptive use increases serum 25-hydroxyvitamin D concentrations in active, young women [abstract]

Abstract only availableMany studies have shown that the estrogen in oral hormonal contraceptives (HC) increases serum 25-hydroxyvitamin D 25(OH)D concentrations in women. As a hormone that regulates gene transcription estrogen is known to increase Vitamin-D binding protein concentrations, and therefore 25(OH)D concentrations in the blood. Furthermore, Vitamin D is a major regulator of bone metabolism and its status within the blood influences circulating levels of bone turnover markers. The objective of this study was to determine the effects of HC use on serum 25OHD concentrations and biochemical markers of bone turnover in active young females. Thirty-nine young (age 18-33 years), active (≥5 h of aerobic exercise per week) women participated (HC users, n=16; Non-users, n=23). Of the HC users, 9 were taking monophasic HC; 7 were taking triphasic HC. Fasting serum samples were taken during the early follicular phase (d2-5 of the menstrual cycle) and were analyzed for 25OHD and biochemical bone markers [bone alkaline phosphatase (BAP), N-telopeptide of collagen cross-links (NTx), parathyroid hormone (PTH) and osteocalcin (OC)] using radioimmuno assay and ELISA, respectively. Serum 25OHD was significantly greater (p=.007) and BAP significantly lower (p=.002) in HC users compared with nonusers. No differences were found between groups for NTx, PTH or osteocalcin. Serum concentrations of BAP and Vitamin D were negatively correlated (r= -.453; p=.004). We conclude that HC use is associated with increased serum 25OHD concentrations and lower circulating BAP in young active females

Effects of maternal, gestational, and perinatal variables on neonatal line width observed in a modern UK birth cohort

OBJECTIVES: The objective of this study was to explore potential relationships between neonatal line (NNL) width and early life history variables such as maternal health, gestation, the birth process, and perinatal health. MATERIALS AND METHODS: Histological thin sections of deciduous canines were studied from 71 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). The width of the NNL was measured in three locations on the tooth crown using spatial mapping techniques (ArcGIS) from digital images from an Olympus VS-120 microscope. Life history variables were collected prospectively through a combination of clinical observations and questionnaires. RESULTS: Infants born late term or post term had narrower neonatal lines than those born prematurely or at full term. Infants born in Autumn (September to November) had narrower NNLs than those born at other times of year. NNLs in infants born to mothers with hypertension were wider than those without. Infants resuscitated at birth or born to obese mothers had narrower NNLs than those that were not. There was no association between NNL width and either the type or duration of delivery. DISCUSSION: The NNL in enamel is an irregular accentuated line, but the factors underlying its formation and width remain unclear. In contrast to some previous studies, we found no association between wider NNLs and long or difficult births. Instead, we found that the width of the neonatal line NNL varied in relation to parameters that reflected the prenatal environment and length of gestation

The long-term impact of folic acid in pregnancy on offspring DNA methylation : follow-up of the Aberdeen folic acid supplementation trial (AFAST)

Funding This work was supported by the NIHR Bristol Biomedical Research Centre at the University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. R.C.R., G.C.S., N.K., T.G., G.D.S. and C.L.R. work in a unit that receives funds from the University of Bristol and the UK Medical Research Council (MC_UU_12013/1, MC_UU_12013/2 and MC_UU_12013/8). This work was also supported by CRUK (grant number C18281/A19169) and the ESRC (grant number ES/N000498/1). C.M.T. is supported by a Wellcome Trust Career Re-entry Fellowship (grant number 104077/Z/14/Z).Peer reviewedPublisher PD