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Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10−11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10−10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10−122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.

Objectives This study characterized the determinants of carotid intima-media thickness (cIMT) in a large (n > 4,000) longitudinal cohort of healthy young people age 9 to 21 years. Background Greater cIMT is commonly used in the young as a marker of subclinical atherosclerosis, but its evolution at this age is still poorly understood. Methods Associations between cardiovascular risk factors and cIMT were investigated in both longitudinal (ages 9 to 17 years) and cross-sectional (ages 17 and 21 years) analyses, with the latter also related to other measures of carotid structure and stress. Additional use of ultra-high frequency ultrasound in the radial artery at age 21 years allowed investigation of the distinct layers (i.e., intima or media) that may underlie observed differences. Results Fat-free mass (FFM) and systolic blood pressure were the only modifiable risk factors positively associated with cIMT (e.g., mean difference in cIMT per 1-SD increase in FFM at age 17: 0.007 mm: 95% confidence interval [CI]: 0.004 to 0.010; p Conclusions Subtle changes in cIMT in the young may predominantly involve the media and represent physiological adaptations as opposed to subclinical atherosclerosis. Other vascular measures might be more appropriate for the identification of arterial disease before adulthood.

The stress hormone cortisol modulates fuel metabolism, cardiovascular homoeostasis, mood, inflammation and cognition. The CORtisol NETwork (CORNET) consortium previously identified a single locus associated with morning plasma cortisol. Identifying additional genetic variants that explain more of the variance in cortisol could provide new insights into cortisol biology and provide statistical power to test the causative role of cortisol in common diseases. The CORNET consortium extended its genome-wide association meta-analysis for morning plasma cortisol from 12,597 to 25,314 subjects and from ~2.2 M to ~7 M SNPs, in 17 population-based cohorts of European ancestries. We confirmed the genetic association with SERPINA6/SERPINA1. This locus contains genes encoding corticosteroid binding globulin (CBG) and α1-antitrypsin. Expression quantitative trait loci (eQTL) analyses undertaken in the STARNET cohort of 600 individuals showed that specific genetic variants within the SERPINA6/SERPINA1 locus influence expression of SERPINA6 rather than SERPINA1 in the liver. Moreover, trans-eQTL analysis demonstrated effects on adipose tissue gene expression, suggesting that variations in CBG levels have an effect on delivery of cortisol to peripheral tissues. Two-sample Mendelian randomisation analyses provided evidence that each genetically-determined standard deviation (SD) increase in morning plasma cortisol was associated with increased odds of chronic ischaemic heart disease (0.32, 95% CI 0.06–0.59) and myocardial infarction (0.21, 95% CI 0.00–0.43) in UK Biobank and similarly in CARDIoGRAMplusC4D. These findings reveal a causative pathway for CBG in determining cortisol action in peripheral tissues and thereby contributing to the aetiology of cardiovascular disease.

Failure of dermal protection or repair mechanisms might lead to visibly aged skin. The study aimed to identify genetic associations with perceived age. A genome-wide association study was undertaken in 423,992 adult participants of UK Biobank, using questionnaire data on perceived age and genetic data imputed to the Haplotype Reference Consortium imputation panel. Seventy-four to our knowledge previously unreported and independent associated genetic loci were identified (P

Background\ud \ud Adolescence marks a period where depression will commonly onset. Twin studies show that genetic influences play a role in how depression develops and changes across adolescence. Recent genome‐wide association studies highlight that common genetic variants – which can be combined into polygenic risk scores (PRS) – are also implicated in depression. However, the role of PRS in adolescent depression and changes in adolescent depression is not yet understood. We aimed to examine associations between PRS for five psychiatric traits and depressive symptoms measured across adolescence using cross‐sectional and growth‐curve models. The five PRS were as follows: depression (DEP), major depressive disorder (MDD), anxiety (ANX), neuroticism (NEU) and schizophrenia (SCZ).\ud Methods\ud \ud We used data from over 6,000 participants of the Avon Longitudinal Study of Parents and Children (ALSPAC) to examine associations between the five PRS and self‐reported depressive symptoms (Short Mood and Feelings Questionnaire) over 9 occasions from 10 to 24 years. The PRS were created from well‐powered genome‐wide association studies conducted in adult populations. We examined cross‐sectional associations between the PRS at each age and then again with longitudinal trajectories of depressive symptoms in a repeated measures framework using multilevel growth‐curve analysis to examine the severity and the rate of change.\ud Results\ud \ud There was strong evidence that higher PRS for DEP, MDD and NEU were associated with worse depressive symptoms throughout adolescence and into young adulthood in our cross‐sectional analysis, with consistent associations observed across all nine occasions. Growth‐curve analyses provided stronger associations (as measured by effect sizes) and additional insights, demonstrating that individuals with higher PRS for DEP, MDD and NEU had steeper trajectories of depressive symptoms across development, all with a greater increasing rate of change during adolescence. Evidence was less consistent for the ANX and SCZ PRS in the cross‐sectional analysis, yet there was some evidence for an increasing rate of change in adolescence in the growth‐curve analyses with the ANX PRS.\ud Conclusions\ud \ud These results show that common genetic variants as indexed by varying psychiatric PRS show patterns of specificity that influence both the severity and rate of change in depressive symptoms throughout adolescence and then into young adulthood. Longitudinal data that make use of repeated measures designs have the potential to provide greater insights how genetic factors influence the onset and persistence of adolescent depression.

Background: Longitudinal studies are crucial for identifying potential risk factors for infection with, and consequences of, COVID-19, but relationships can be biased if they are associated with invitation and response to data collection. We describe factors relating to questionnaire invitation and response in COVID-19 questionnaire data collection in a multigenerational birth cohort (the Avon Longitudinal Study of Parents and Children, ALSPAC). Methods: We analysed online questionnaires completed between the beginning of the pandemic and easing of the first UK lockdown by participants with valid email addresses who had not actively disengaged from the study. We assessed associations of pre-pandemic sociodemographic, behavioural, anthropometric and health-related factors with: i) being sent a questionnaire; ii) returning a questionnaire; and iii) item response (for specific questions). Analyses were conducted in three cohorts: the index children born in the early 1990s (now young adults; 41 variables assessed), their mothers (35 variables) and the mothers’ partners (27 variables). Results: Of 14,849 young adults, 41% were sent a questionnaire, of whom 57% returned one. Item response was >95%. In this cohort, 78% of factors were associated with being sent a questionnaire, 56% with returning one, and, as an example of item response, 20% with keyworker status response. For instance, children from mothers educated to degree-level had greater odds of being sent a questionnaire (OR=5.59; 95% CI=4.87-6.41), returning one (OR=1.60; 95% CI=1.31-1.95), and responding to items (e.g., keyworker status OR=1.65; 95% CI=0.88-3.04), relative to children from mothers with fewer qualifications. Invitation and response rates and associations were similar in all cohorts. Conclusions: These results highlight the importance of considering potential biases due to non-response when using longitudinal studies in COVID-19 research and interpreting results. We recommend researchers report response rates and factors associated with invitation and response in all COVID-19 observational research studies, which can inform sensitivity analyses.

Mutations in the melanocortin 4 receptor gene (MC4R) are associated with obesity but little is known about the prevalence and impact of such mutations throughout human growth and development. We examined the MC4R coding sequence in 5,724 participants from the Avon Longitudinal Study of Parents and Children, functionally characterized all nonsynonymous MC4R variants and examined their association with anthropometric phenotypes from childhood to early adulthood. The frequency of heterozygous loss-of-function (LoF) mutations in MC4R was ~1 in 337 (0.30%), considerably higher than previous estimates. At age 18 years, mean differences in body weight, body mass index and fat mass between carriers and noncarriers of LoF mutations were 17.76 kg (95% CI 9.41, 26.10), 4.84 kg m−2 (95% CI 2.19, 7.49) and 14.78 kg (95% CI 8.56, 20.99), respectively. MC4R LoF mutations may be more common than previously reported and carriers of such variants may enter adult life with a substantial burden of excess adiposity. Analysis of mutations in MC4R and associated anthropometric phenotypes in the ALSPAC birth cohort reveals a prevalence of heterozygous loss of function of 0.30% and provides evidence that these mutations are associated with substantial excess adiposity in early life.

Homozygosity for the SERPINA1 Z allele causes α1-antitrypsin deficiency, a rare condition that can cause lung and liver disease. However, the effects of Z allele heterozygosity on nonrespiratory phenotypes, and on lung function in the general population, remain unclear. We conducted a large, population-based study to determine Z allele effects on >2400 phenotypes in the UK Biobank (N=303 353). Z allele heterozygosity was strongly associated with increased height (β=1.02 cm, p=3.91×10−68), and with other nonrespiratory phenotypes including increased risk of gall bladder disease, reduced risk of heart disease and lower blood pressure, reduced risk of osteoarthritis and reduced bone mineral density, increased risk of headache and enlarged prostate, as well as with blood biomarkers of liver function. Heterozygosity was associated with higher height-adjusted forced expiratory volume in 1 s (FEV1) (β=19.36 mL, p=9.21×10−4) and FEV1/forced vital capacity (β=0.0031, p=1.22×10−5) in nonsmokers, whereas in smokers, this protective effect was abolished. Furthermore, we show for the first time that sex modifies the association of the Z allele on lung function. We conclude that Z allele heterozygosity and homozygosity exhibit opposing effects on lung function in the UK population, and that these associations are modified by smoking and sex. In exploratory analyses, heterozygosity for the Z allele also showed pleiotropic associations with nonrespiratory health-related traits and disease risk. Tweetable abstract @ERSpublications click to tweet Heterozygosity for the SERPINA1 Z allele is associated with higher lung function in nonsmokers (but this advantage is abolished by smoking) as well as a variety of nonrespiratory diseases and traits, including liver-, heart- and bone-related conditions https://bit.ly/37XC0Yg Introduction Homozygosity for the SERPINA1 Z allele (rs28929474(T)) is the commonest cause of severe α1-antitrypsin deficiency (AATD) and is a well-established genetic risk factor for lung diseases such as chronic obstructive pulmonary disease (COPD). However, the health consequences of heterozygosity for the Z allele are not as well-understood [1]. Given that approximately one in 30 Europeans is heterozygous for the Z allele, the phenotypic consequences of carriage of this allele could have important public health implications. Some previous studies have sought to characterise the effect of Z allele heterozygosity on nonrespiratory traits, particularly liver diseases [2–6]. However, these have often been carried out in small sample sizes and/or clinical subgroups. The recent development of phenome-wide association studies (PheWASs) and the availability of the well-phenotyped UK Biobank population-based cohort provides a platform for systematic investigation of the effects of heterozygosity for the Z allele on nonrespiratory traits. PheWASs test the association between genetic variants and a large number of phenotypic traits, including diseases and their subtypes, and potential intermediate phenotypes [7]. This differs from genome-wide association studies, which test a large number of variants across the genome for association with only one trait. The effect of Z allele heterozygosity on lung function traits and lung disease has been the subject of many studies. Recent COPD case–control and family-based studies have shown reduced lung function and increased risk of COPD in heterozygous current and former smokers [8–11]. However, a population-based study demonstrated no significant reductions in lung function in heterozygous smokers, despite having greater numbers of heterozygous smokers compared to previous studies [12]. It also showed enhanced lung function in heterozygous individuals overall, partially explained by strong association of the Z allele with increased height. This discrepancy may be due, in part, to the fact that identifying and recruiting study participants based on their health status (as in case–control studies [8, 9]) or based on the health status of a family member [10, 11] can lead to causal estimates that are subject to ascertainment bias [13], whereas population-based studies [12, 14] overcome these biases. The effects of the Z allele on lung function in relation to smoking status therefore remain uncertain. Finally, despite evidence for sex-differential effects of Z allele homozygosity on lung function [15, 16], we are not aware of any studies that have compared the effect of Z allele heterozygosity on lung function in males versus females. We therefore systematically evaluated the effects of Z allele heterozygosity in the UK biobank population, which in total includes >18 000 Z allele heterozygotes. We aimed: 1) to undertake the most extensive PheWAS to date, including blood biomarkers, for Z allele heterozygosity and homozygosity to identify effects beyond the respiratory system; and 2) to fully define the effects of Z allele heterozygosity on lung function measures (forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC)) in smokers and nonsmokers and in males and females.

Context Adult height is highly heritable, yet no genetic predictor has demonstrated clinical utility compared to mid-parental height. Objective To develop a polygenic risk score for adult height and evaluate its clinical utility. Design A polygenic risk score was constructed based on meta-analysis of genomewide association studies and evaluated on the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Subjects Participants included 442 599 genotyped White British individuals in the UK Biobank and 941 genotyped child-parent trios of European ancestry in the ALSPAC cohort. Interventions None. Main Outcome Measures Standing height was measured using stadiometer; Standing height 2 SDs below the sex-specific population average was considered as short stature. Results Combined with sex, a polygenic risk score captured 71.1% of the total variance in adult height in the UK Biobank. In the ALSPAC cohort, the polygenic risk score was able to identify children who developed adulthood short stature with an area under the receiver operating characteristic curve (AUROC) of 0.84, which is close to that of mid-parental height. Combining this polygenic risk score with mid-parental height or only one of the child’s parent’s height could improve the AUROC to at most 0.90. The polygenic risk score could also substitute mid-parental height in age-specific Khamis-Roche height predictors and achieve an equally strong discriminative power in identifying children with a short stature in adulthood. Conclusions A polygenic risk score could be considered as an alternative or adjunct to mid-parental height to improve screening for children at risk of developing short stature in adulthood in European ancestry populations.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

Background Variation in adiposity is associated with cardiometabolic disease outcomes, but mechanisms leading from this exposure to disease are unclear. This study aimed to estimate effects of body mass index (BMI) on an extensive set of circulating proteins. Methods We used SomaLogic proteomic data from up to 2737 healthy participants from the INTERVAL study. Associations between self-reported BMI and 3622 unique plasma proteins were explored using linear regression. These were complemented by Mendelian randomisation (MR) analyses using a genetic risk score (GRS) comprised of 654 BMI-associated polymorphisms from a recent genome-wide association study (GWAS) of adult BMI. A disease enrichment analysis was performed using DAVID Bioinformatics 6.8 for proteins which were altered by BMI. Results Observationally, BMI was associated with 1576 proteins (P −5), with particularly strong evidence for a positive association with leptin and fatty acid-binding protein-4 (FABP4), and a negative association with sex hormone-binding globulin (SHBG). Observational estimates were likely confounded, but the GRS for BMI did not associate with measured confounders. MR analyses provided evidence for a causal relationship between BMI and eight proteins including leptin (0.63 standard deviation (SD) per SD BMI, 95% CI 0.48–0.79, P = 1.6 × 10−15), FABP4 (0.64 SD per SD BMI, 95% CI 0.46–0.83, P = 6.7 × 10−12) and SHBG (−0.45 SD per SD BMI, 95% CI −0.65 to −0.25, P = 1.4 × 10−5). There was agreement in the magnitude of observational and MR estimates (R2 = 0.33) and evidence that proteins most strongly altered by BMI were enriched for genes involved in cardiovascular disease. Conclusions This study provides evidence for a broad impact of adiposity on the human proteome. Proteins strongly altered by BMI include those involved in regulating appetite, sex hormones and inflammation; such proteins are also enriched for cardiovascular disease-related genes. Altogether, results help focus attention onto new proteomic signatures of obesity-related disease.

BackgroundObservational data have reported that being overweight or obese, compared to being normal weight, is associated with a lower risk for death - the “obesity paradox”. We used Mendelian randomization (MR) to estimate causal effects of body mass index (BMI) on mortality risks in people with coronary heart disease (CHD), type 2 diabetes mellitus (T2DM) or malignancy in whom this paradox has been often reported.MethodsWe studied 457,746 White British UK Biobank participants including three subgroups with T2DM (n=19,737), CHD (n=21,925) or cancer (n=42,612) at baseline and used multivariable-adjusted Cox models and MR approaches to describe relationships between BMI and mortality risk. ResultsObservational Cox models showed J-shaped relationships between BMI and mortality risk including within disease subgroups in which the BMI values associated with minimum mortality risk were within overweight/obese ranges (26.5-32.5 kg/m2). In all participants, MR analyses showed a positive linear causal effect of BMI on mortality risk (HR for mortality per unit higher BMI: 1.05; 95% CI: 1.03-1.08), also evident in people with CHD (HR: 1.08; 95% CI: 1.01-1.14). Point estimates for hazard ratios across all BMI values in participants with T2DM and cancer were consistent with overall positive linear effects but confidence intervals included the null. ConclusionThese data support the idea that population efforts to promote intentional weight loss towards the normal BMI range would reduce, not enhance, mortality risk in the general population including, importantly, individuals with CHD.

The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective population-based cohort study which recruited pregnant women in 1990-1992 and has followed these women, their partners (Generation 0; G0) and offspring (Generation 1; G1) ever since. The study reacted rapidly to the COVID-19 pandemic, deploying online questionnaires in March and May 2020. Home-based antibody tests and a further questionnaire were sent to 5220 participants during a two-week period of October 2020. 4.2% (n=201) of participants reported a positive antibody test (3.2% G0s [n=81]; 5.6% G1s [n=120]). 43 reported an invalid test, 7 did not complete and 3 did not report their result. Participants uploaded a photo of their test to enable validation: all positive tests, those where the participant could not interpret the result and a 5% random sample were manually checked against photos. We report 92% agreement (kappa=0.853). Positive tests were compared to additional COVID-19 status information: 58 (1.2%) participants reported a previous positive test, 73 (1.5%) reported that COVID-19 was suspected by a doctor, but not tested and 980 (20.4%) believed they had COVID-19 due to their own suspicions. Of those reporting a positive result on our antibody test, 55 reported that they did not think they had had COVID-19. Results from antibody testing and questionnaire data will be complemented by health record linkage and results of other biological testing– uniting Pillar testing data with home testing and self-report. Data have been released as an update to the original datasets released in July 2020. It comprises: 1) a standard dataset containing all participant responses to all three questionnaires with key sociodemographic factors and 2) as individual participant-specific release files enabling bespoke research across all areas supported by the study. This data note describes the antibody testing, associated questionnaire and the data obtained from it.

Contains fulltext : 231681.pdf (Publisher’s version ) (Closed access) To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P

Handedness, a consistent asymmetry in skill or use of the hands, has been studied extensively because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and 32 studies from the International Handedness Consortium, we conducted the world’s largest genome-wide association study of handedness (1,534,836 right-handed, 194,198 (11.0%) left-handed and 37,637 (2.1%) ambidextrous individuals). We found 41 genetic loci associated with left-handedness and seven associated with ambidexterity at genome-wide levels of significance (P < 5×10−8). Tissue enrichment analysis implicated the central nervous system and brain tissues including the hippocampus and cerebrum in the etiology of left-handedness. Pathways including regulation of microtubules, neurogenesis, axonogenesis and hippocampus morphology were also highlighted. We found suggestive positive genetic correlations between being left-handed and some neuropsychiatric traits including schizophrenia and bipolar disorder. SNP heritability analyses indicated that additive genetic effects of genotyped variants explained 5.9% (95% CI = 5.8% – 6.0%) of the underlying liability of being left-handed, while the narrow sense heritability was estimated at 12% (95% CI = 7.2% – 17.7%). Further, we show that genetic correlation between left-handedness and ambidexterity is low (rg = 0.26; 95% CI = 0.08 – 0.43) implying that these traits are largely influenced by different genetic mechanisms. In conclusion, our findings suggest that handedness, like many other complex traits is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders that has been observed in multiple observational studies.

Background: Prior observational studies have reported that higher levels of vitamin D are associated with decreased caries risk in children. However, these studies are prone to bias and confounding so do not provide causal inference. Genetic variants associated with a risk factor of interest can be used as proxies, in a Mendelian randomization (MR) analysis, to test for causal association with an outcome. The objective was to estimate the causal association between serum 25-hydroxyvitamin D (25(OH)D) (the commonly measured vitamin D metabolite in blood) and dental caries using a two-sample MR approach which estimates the causal effect of an exposure on an outcome. Methods: A total of 79 genetic variants reliably associated with 25(OH)D were identified from genome-wide association studies and used as a proxy measure of 25(OH)D. The association of this proxy measure with three outcome measures was tested; specifically: caries in primary teeth (n=17,035, aged 3-12 years), caries in permanent teeth in childhood and adolescence (n=13,386, aged 6-18 years), and caries severity in adulthood proxied by decayed, missing and filled tooth surfaces (DMFS) counts (n=26,792, aged 18-93 years). Results: The estimated causal effect of a one standard deviation increase in natural log-transformed 25(OH)D could be summarized as an odds ratio of 1.06 (95%CI: 0.81, 1.31; P=0.66) for caries in primary teeth and 1.00 (95%CI: 0.76, 1.23; P=0.97) for caries in permanent teeth in childhood and adolescence. In adults, the estimated casual effect of a one standard deviation increase in natural log-transformed 25(OH)D was 0.31 fewer affected tooth surfaces (95%CI: from 1.81 fewer DMFS to 1.19 more DMFS; P=0.68) Conclusions: The MR-derived effect estimates for these three measures are small in magnitude with wide confidence intervals and do not provide evidence for a causal relationship between 25(OH)D and dental caries. Version 1 of this article: Dodhia SA, West NX, Thomas SJ et al. "Is vitamin D a modifiable risk factor for dental caries? [version 1; peer review: 1 approved, 1 approved with reservations]". Wellcome Open Res 2020, 5:281, DOI: 10.12688/wellcomeopenres.16369.1

ObjectiveThis study aimed to investigate the role of cytokines as intermediates in the pathway from increased adiposity to disease.MethodsBMI and circulating levels of up to 41 cytokines were measured in individuals from three Finnish cohort studies (n = 8,293). Mendelian randomization (MR) was used to assess the impact of BMI on circulating cytokines and the impact of BMI‐driven cytokines on risk of obesity‐related diseases.ResultsObservationally, BMI was associated with 19 cytokines. For every SD increase in BMI, causal effect estimates were strongest for hepatocyte growth factor, monocyte chemotactic protein‐1 (MCP‐1), and tumor necrosis factor–related apoptosis‐inducing ligand (TRAIL) and were as ratios of geometric means 1.13 (95% CI: 1.08‐1.19), 1.08 (95% CI: 1.04‐1.14), and 1.13 (95% CI: 1.04‐1.21), respectively. TRAIL was associated with a small increase in the odds of coronary artery disease (odds ratio: 1.03; 95% CI: 1.00‐1.06). There was inconsistent evidence for a protective role of MCP‐1 against inflammatory bowel diseases.ConclusionsObservational and MR estimates of the effect of BMI on cytokine levels were generally concordant. There was little evidence for an effect of raised levels of BMI‐driven cytokines on disease. These findings illustrate the challenges of MR when applied in the context of molecular mediation.

Diarrhea is a major cause of infant mortality. Being a "nonsecretor" (having an inactive fucosyltransferase-2 gene) protects against diarrhea by inhibiting enteric infections. Breastfeeding also protects against diarrhea; however, the impact of maternal secretor status is unknown. In the ALSPAC cohort (N = 4971), we found that breastfeeding by nonsecretor mothers was especially protective against diarrhea, which could inform new prevention strategies.

Babies born clinically Small- or Large-for-Gestational-Age (SGA or LGA; sex- and gestational age-adjusted birth weight (BW) 90th percentile, respectively), are at higher risks of complications. SGA and LGA include babies who have experienced environment-related growth-restriction or overgrowth, respectively, and babies who are heritably small or large. However, the relative proportions within each group are unclear. We assessed the extent to which common genetic variants underlying variation in birth weight influence the probability of being SGA or LGA. We calculated independent fetal and maternal genetic scores (GS) for BW in 11,951 babies and 5,182 mothers. These scores capture the direct fetal and indirect maternal (via intrauterine environment) genetic contributions to BW, respectively. We also calculated maternal fasting glucose (FG) and systolic blood pressure (SBP) GS. We tested associations between each GS and probability of SGA or LGA. For the BW GS, we used simulations to assess evidence of deviation from an expected polygenic model. Higher BW GS were strongly associated with lower odds of SGA and higher odds of LGA (ORfetal = 0.75 (0.71,0.80) and 1.32 (1.26,1.39); ORmaternal = 0.81 (0.75,0.88) and 1.17 (1.09,1.25), respectively per 1 decile higher GS). We found evidence that the smallest 3% of babies had a higher BW GS, on average, than expected from their observed birth weight (assuming an additive polygenic model: Pfetal = 0.014, Pmaternal = 0.062). Higher maternal SBP GS was associated with higher odds of SGA P = 0.005. We conclude that common genetic variants contribute to risk of SGA and LGA, but that additional factors become more important for risk of SGA in the smallest 3% of babies., Author summary Babies in the lowest or highest 10% of the population distribution of birth weight (BW) for a given gestational age are referred to as Small- or Large-for-Gestational-Age (SGA or LGA) respectively. These babies have higher risks of complications compared with babies with BW closer to the average. SGA and LGA babies may have experienced growth restriction or overgrowth, respectively, but may alternatively just be at the tail ends of the normal growth distribution. The relative proportions of normal vs. sub-optimal growth within these groups is unclear. To examine the role of common genetic variation in SGA and LGA, we tested their associations with a fetal genetic score (GS) for BW in 11,951 European-ancestry individuals. We also tested associations with maternal GS (5,182 mothers) for offspring BW, fasting glucose and systolic blood pressure, each of which influences fetal growth via the in utero environment. We found fetal and maternal GS were associated with SGA and LGA, supporting strong maternal and fetal genetic contributions to birth weight in both tails of the distribution. However, within the smallest 3% of babies, the maternal and fetal GS for BW were higher than expected, suggesting factors additional to common genetic variation are more important in determining birth weight in these very small babies.

Background: Prior observational studies have reported that higher levels of vitamin D are associated with decreased caries risk in children. However, these studies are prone to bias and confounding so do not provide causal inference. Genetic variants associated with a risk factor of interest can be used as proxies, in a Mendelian randomization (MR) analysis, to test for causal association with an outcome. The objective was to estimate the causal association between serum 25-hydroxyvitamin D (25(OH)D) (the commonly measured vitamin D metabolite in blood) and dental caries using a MR approach which estimates the causal effect of an exposure on an outcome. Methods: A total of 79 genetic variants reliably associated with 25(OH)D were identified from genome-wide association studies and used as a proxy measure of 25(OH)D. The association of this proxy measure with three outcome measures was tested; specifically: caries in primary teeth (n=17,035, aged 3-12 years), caries in permanent teeth in childhood and adolescence (n=13,386, aged 6-18 years), and caries severity in adulthood proxied by decayed, missing and filled tooth surfaces (DMFS) counts (n=26,792, aged 18-93 years). Results: The estimated causal effect of a one standard deviation increase in natural log-transformed 25(OH)D could be summarized as an odds ratio of 1.06 (95%CI: 0.81, 1.31; P=0.66) for caries in primary teeth and 1.00 (95%CI: 0.76, 1.23; P=0.97) for caries in permanent teeth in childhood and adolescence. In adults, the estimated casual effect of a one standard deviation increase in natural log-transformed 25(OH)D was 0.31 fewer affected tooth surfaces (95%CI: from 1.81 fewer DMFS to 1.19 more DMFS; P=0.68) Conclusions: The MR-derived effect estimates for these three measures are small in magnitude with wide confidence intervals and do not provide evidence against the null hypothesis of no effect.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located nearNEDD4LandSLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (R(g)ranging from 0.11 to 0.76, P-values, CP received funding from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London. MMcC is a Wellcome Senior Investigator and an NIHR Senior Investigator. MMcC received funding from Wellcome (090532, 106130, 098381, 203141, 212259), NIDDK (U01DK105535), and NIHR (NF-SI-0617-10090). TGMV was supported by ZonMW (TOP 40-00812-9811010). DLC was supported by the American Diabetes Association Grant 1-17-PDF-077. SFAG is supported by the Daniel B. Burke Chair for Diabetes Research and NIH Grant R01 HD058886. NVT is funded by a pre-doctoral grant from the Agencia de Gestio d'Ajuts Universitaris i de Recerca (2017 FI_B 00636), Generalitat de Catalunya -Fons Social Europeu. BK received personal funding from the European Research Council Advanced Grant META-GROWTH (ERC-2012-AdG -no. 322605). BF was supported by an Oak Foundation Fellowship. RMF and RNB are supported by Sir Henry Dale Fellowship (Wellcome Trust and Royal Society grant: WT104150). ATH is supported by a Wellcome Trust Senior Investigator award (grant number 098395/Z/12/Z). DM is supported by a Canada Research Chair. DLC was supported by the American Diabetes Association Grant 1-17-PDF077. JTL was supported by the Finnish Cultural Foundation. DIB received a KNAW Academy Professor Award (PAH/6635). MH received PhD scholarship funding from TARGET (http://target.ku.dk), The Danish Diabetes Academy (http://danishdiabetesacademy.dk) and the Copenhagen Graduate School of Health and Medical Sciences. VWVJ received funding from the Netherlands Organization for Health Research and Development (VIDI 016.136.361) and the European Research Council (ERC-2014-CoG-648916). ISF was supported by the European Research Council, Wellcome Trust (098497/Z/12/Z), Medical Research Council (MRC_MC_UU_12012/5), the NIHR Cambridge Biomedical Research Centre, the Botnar Foundation, the Bernard Wolfe Health Neuroscience Endowment and the European Community's Seventh Framework Programme (FP7/2007-2013) project Beta-JUDO n degrees 279153. IB acknowledges funding from Wellcome (WT206194). ES works in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3). GDS works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1). KC received funds from the French National Agency of Research, F-CRIN/FORCE. All funding for the studies that provided the underlying data for this manuscript can be found in S1 Text. The funders had no role in study design, data collection and analysis, data interpretation, decision to publish, or preparation of the manuscript.

The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective population-based cohort study which recruited pregnant women in 1990-1992 and has followed these women, their partners and their offspring ever since. The study reacted rapidly to the coronavirus disease 2019 (COVID-19) pandemic, deploying an online questionnaire early on during lockdown (from 9th April to 15th May). In late May 2020, a second questionnaire was developed asking about physical and mental health, lifestyle and behaviours, employment and finances. The online questionnaire was deployed across the parent and offspring generations between the 26th May and 5th July 2020. 6482 participants completed the questionnaire (2639 original mothers, 1039 original fathers/partners, 2711 offspring (mean age ~28 years) and 93 partners of offspring). 1039 new participants who did not respond to the first questionnaire deployed in April completed the second questionnaire. A positive COVID-19 was reported by 36 (0.6%) participants (12 G0 and 24 G1), 91 (1.4%; 35 G0 and 56 G1) reported that they had been told by a doctor they likely had COVID-19 and 838 (13%; 422 G0 and 416 G1) suspected that they have had COVID-19. Using algorithmically estimated cases based on symptoms, we estimate that the predicted prevalence of COVID-19 from mid-April to time of questionnaire completion was 3.1%. Data from both COVID questionnaires will be complemented with linkage to health records and results of biological testing as they become available. Data has been released as an update to the original dataset released in May 2020. It comprises: 1) a standard dataset containing all participant responses to both questionnaires with key sociodemographic factors and 2) as a composite release coordinating data from the existing resource, thus enabling bespoke research across all areas supported by the study. This data note describes the second questionnaire and the data obtained from it.

Glycaemic traits are used to diagnose and monitor type 2 diabetes, and cardiometabolic health. To date, most genetic studies of glycaemic traits have focused on individuals of European ancestry. Here, we aggregated genome-wide association studies in up to 281,416 individuals without diabetes (30% non-European ancestry) with fasting glucose, 2h-glucose post-challenge, glycated haemoglobin, and fasting insulin data. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P-8), 80% with no significant evidence of between-ancestry heterogeneity. Analyses restricted to European ancestry individuals with equivalent sample size would have led to 24 fewer new loci. Compared to single-ancestry, equivalent sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase understanding of diabetes pathophysiology by use of trans-ancestry studies for improved power and resolution.

Highlights • Alcohol PRS derived in the general population associated with consumption during pregnancy. • Maternal alcohol PRS associated with perinatal depression at 32 weeks gestation. • Maternal alcohol PRS associated with decreased offspring intellectual ability at age 13. • Offspring alcohol PRS did not predict offspring alcohol consumption in adolescence., Background Heavy alcohol consumption often co-occurs with mental health problems; this could be due to confounding, shared biological mechanisms, or causal effects. Polygenic risk scores (PRS) for alcohol use can be used to explore this association at critical life stages. Design We characterized a PRS reliably associated with patterns of adult alcohol consumption by 1) validating whether it predicts own alcohol use at different life-stages (pregnancy, adolescence) of interest for mental health impact. Additionally, we explored associations of alcohol PRS on mental health phenotypes 2) within-individuals (using own alcohol PRS on own phenotypes) and 3) intergenerationally (using maternal alcohol PRS on offspring phenotypes). We used data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (n = 960–7841). Additional substance abuse behaviors and mental health/behavioral outcomes were investigated (alcohol phenotypes n = 22; health phenotypes n = 91). Findings Maternal alcohol PRS was associated with consumption during pregnancy (strongest signal: alcohol frequency at 18 weeks’ gestation: β = 0.041, 95%CI = 0.0.02–0.06), p = 1.01 × 10−5, adjusted R2 = 1.6 %), offspring alcohol PRS did not predict offspring alcohol consumption. We found evidence for an association of maternal alcohol PRS with own perinatal depression (OR = 1.10, 95% CI = 1.02 to 1.18, p = 0.022) and decreased offspring intellectual ability (β=-0.209, 95% CI -0.38 to -0.04, p= 0.016). Conclusions These alcohol PRS are a valid proxy for maternal alcohol use in pregnancy. Offspring alcohol PRS was not associated with drinking in adolescence. Consistently with results from different study designs, we found evidence that maternal alcohol PRS are associated with both prenatal depression and decreased offspring intellectual ability.

Introduction High plasma triacylglyceride levels are known to be associated with increased risk of atherosclerotic cardiovascular disease. Apolipoprotein C-III (apoC-III) is a key regulator of plasma triacylglyceride levels and is associated with hypertriglyceridemia via a number of pathways. There is consistent evidence for an association of cardiovascular events with blood apoC-III level, with support from human genetic studies of APOC3 variants. As such, apoC-III has been recognised as a potential therapeutic target for patients with severe hypertriglyceridaemia with one of the most promising apoC-III-targeting drugs, volanesorsen, having recently progressed through Phase III trials. Objectives To exploit a rare loss of function variant in APOC3 (rs138326449) to characterise the potential long-term treatment effects of apoC-III targeting interventions on the metabolome. Methods In a recall-by-genotype study, 115 plasma samples were analysed by UHPLC-MS to acquire non-targeted metabolomics data. The study included samples from 57 adolescents and 33 adults. Overall, 12 985 metabolic features were tested for an association with APOC3 genotype. Results 144 uniquely annotated metabolites were found to be associated with rs138326449(APOC3). The highest proportion of associated metabolites belonged to the acyl-acyl glycerophospholipid and triacylglyceride metabolite classes. In addition to the anticipated (on-target) reduction of metabolites in the triacylglyceride and related classes, carriers of the rare variant exhibited previously unreported increases in levels of a number of metabolites from the acyl-alkyl glycerophospholipid and ceramide classes. Conclusion Overall, our results suggest that therapies targeting apoC-III may potentially achieve a broad shift in lipid profile that favours better metabolic health.

BackgroundThe rs1344706 polymorphism in ZNF804A is robustly associated with schizophrenia (SZ), yet brain and behavioral phenotypes related to this variant have not been extensively characterized. In turn, SZ is associated with abnormal non-rapid eye movement (NREM) sleep neurophysiology. To examine whether rs1344706 is associated with intermediate neurophysiological traits in the absence of disease, we assessed the relationship between genotype, sleep neurophysiology, and sleep-dependent memory consolidation in healthy participants.MethodsWe recruited healthy adult males, with no history of psychiatric disorder, from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Participants were homozygous for either the SZ-associated ‘A’ allele (N=25) or the alternative ‘C’ allele (N=22) at rs1344706. Actigraphy, polysomnography (PSG) and a motor sequencing task (MST) were used to characterize daily activity patterns, sleep neurophysiology and sleep-dependent memory consolidation.ResultsAverage MST learning and sleep-dependent performance improvements were similar across genotype groups, but with increased variability in the AA group. CC participants showed increased slow-wave and spindle amplitudes, plus augmented coupling of slow-wave activity across recording electrodes after learning. Slow-waves and spindles in those with the AA genotype were insensitive to learning, whilst slow-wave coherence decreased following MST training.ConclusionWe describe evidence that rs1344706 polymorphism in ZNF804A is associated with changes in experience- and sleep-dependent, local and distributed neural network activity that supports offline information processing during sleep in a healthy population. These findings highlight the utility of sleep neurophysiology in mapping the impacts of SZ-associated variants on neural circuit oscillations and function.

Background: Previous research has suggested that intrauterine alcohol exposure is associated with a variety of adverse outcomes in offspring. However, few studies have investigated its association with offspring internalising disorders in late adolescence. Methods: Using data from the Avon Longitudinal Study of Parents and Children (ALSPAC), we investigated the associations of maternal drinking in pregnancy with offspring depression at age 18 and 24 (n = 13480). We also examined partner drinking as a negative control for intrauterine exposure for comparison.Results: Offspring of mothers that consumed any alcohol at 18 weeks gestation were at increased risk of having a diagnosis of depression (fully adjusted model: OR 1.17, 95% CI 1.02 to 1.34), but there was no clear evidence of association between partners alcohol consumption at 18 weeks gestation during pregnancy and increased risk of offspring depression (fully adjusted model: OR 0.87, 95% CI 0.74 to 1.01). Post-estimation tests found a positive difference between the association of maternal and partner alcohol use on offspring depression, showing a stronger association for maternal compared to partner alcohol use (OR 1.41, CI 1.07 to 1.84).Conclusions: Maternal drinking in pregnancy was associated with increased risk of offspring depression at age 18. Residual confounding may explain this association, but the negative control comparison of paternal drinking provides some evidence that it may be causal, and this warrants further investigation.

Babies born clinically Small- or Large-for-Gestational-Age (SGA or LGA; sex- and gestational age-adjusted birth weight (BW) th or >90th percentile, respectively), are at higher risks of complications. SGA and LGA include babies who have experienced growth-restriction or overgrowth, respectively, and babies who are naturally small or large. However, the relative proportions within each group are unclear. We aimed to assess the extent to which the genetics of normal variation in birth weight influence the probability of SGA/LGA. We calculated independent fetal and maternal genetic scores (GS) for BW in 12,125 babies and 5,187 mothers. These scores capture the direct fetal and indirect maternal (via intrauterine environment) genetic contributions to BW, respectively. We also calculated maternal fasting glucose (FG) and systolic blood pressure (SBP) GS. We tested associations between each GS and probability of SGA or LGA. For the BW GS, we used simulations to assess evidence of deviation from an expected polygenic model.Higher BW GS were strongly associated with lower odds of SGA and higher odds of LGA (ORfetal=0.65 (0.60,0.71) and 1.47 (1.36,1.59); ORmaternal=0.80 (0.76,0.87) and 1.23 (1.15,1.31), respectively per 1 decile higher GS). Associations were in accordance with a polygenic model except in the smallest 3% of babies (Pfetal=0.0034, Pmaternal=0.023). Higher maternal GS for FG and SBP were associated with higher odds of LGA and SGA respectively (both PWe conclude that common genetic variants contribute to risk of SGA and LGA, but that additional factors become more important for risk of SGA in the smallest 3% of babies. Naturally low maternal glucose and blood pressure levels may additionally contribute to risk of SGA and LGA, respectively.Author SummaryBabies in the lowest or highest 10% of the population distribution of birth weight (BW) for a given gestational age are referred to as Small- or Large-for-Gestational-Age (SGA or LGA) respectively. These babies have higher risks of complications compared to babies with BW closer to the mean. SGA and LGA babies may have experienced growth restriction or overgrowth, respectively, but may alternatively just be at the tail ends of the normal growth distribution. The relative proportions of normal vs. sub-optimal growth within these groups is unclear. To examine the role of common genetic variation in SGA and LGA, we tested their associations with a fetal genetic score (GS) for BW in 12,125 European-ancestry individuals. We also tested associations with maternal GS (5,187 mothers) for offspring BW, fasting glucose and systolic blood pressure, each of which influences fetal growth via the in utero environment. We found all fetal and maternal GS were associated with SGA and LGA, supporting strong maternal and fetal genetic contributions to birth weight in both tails of the distribution. However, within the smallest 3% of babies, the maternal and fetal GS for BW were higher than expected, suggesting factors additional to common genetic variation are more important in determining birth weight in these very small babies.

We aimed to increase our understanding of the genetic determinants of vitamin D levels by undertaking a large-scale genome-wide as- sociation study (GWAS) of serum 25 hydroxyvitamin D (25OHD). To do so, we used imputed genotypes from 401,460 white British UK Biobank participants with available 25OHD levels, retaining single-nucleotide polymorphisms (SNPs) with minor allele frequency (MAF) > 0.1% and imputation quality score > 0.3. We performed a linear mixed model GWAS on standardized log-transformed 25OHD, adjusting for age, sex, season of measurement, and vitamin D supplementation. These results were combined with those from a previous GWAS including 42,274 Europeans. In silico functional follow-up of the GWAS results was undertaken to identify enrich- ment in gene sets, pathways, and expression in tissues, and to investigate the partitioned heritability of 25OHD and its shared herita- bility with other traits. Using this approach, the SNP heritability of 25OHD was estimated to 16.1%. 138 conditionally independent SNPs were detected (p value < 6.6 3 109) among which 53 had MAF < 5%. Single variant association signals mapped to 69 distinct loci, among which 63 were previously unreported. We identified enrichment in hepatic and lipid metabolism gene pathways and enriched expression of the 25OHD genes in liver, skin, and gastrointestinal tissues. We observed partially shared heritability between 25OHD and socio-economic traits, a feature which may be mediated through time spent outdoors. Therefore, through a large 25OHD GWAS, we identified 63 loci that underline the contribution of genes outside the vitamin D canonical metabolic pathway to the genetic architec- ture of 25OHD.

Background: Adolescence marks a period where depression will commonly onset and previous research using twin studies has suggested that genetic influences play a role in how depression develops and changes across adolescence. Recent genome-wide association studies have also shown that common genetic variants — which can be brought together as polygenic risk scores (PRS) — are also implicated in depression. However, the role of PRS in adolescent depression and changes in adolescent depression is not yet understood. The aim of this study was to examine the association between a PRS for depressive symptoms and depressive symptoms across adolescence and young adulthood, and how polygenic risk is associated with changes in depressive symptoms using two methods: cross-sectional analysis and multilevel growth curve modelling to examine the rate of change over time. Methods: Using data from over 6000 participants of the Avon Longitudinal Study of Parents and Children (ALSPAC) we examined associations between genetic liability to depressive symptoms (polygenic risk score (PRS) for depressive symptoms) and self-reported depressive symptoms (short mood and feelings questionnaire over 9 occasions from 10-24 years). We examined cross-sectional associations at each age and trajectories of depressive symptoms in a repeated measures framework using growth curve analysis. Results: The PRS was associated with depressive symptoms throughout adolescence and young adulthood in both cross-sectional and growth curve analyses, though associations were stronger in the latter analyses. Growth curve analyses also provided additional insights, demonstrating that individuals with a higher PRS had steeper trajectories of depressive symptoms across adolescence with a greater increasing rate of change. Conclusions: In a longitudinal study spanning adolescence to early adult life, these results show that common genetics variants as indexed by a PRS for depressive symptoms influence both the severity of rate of change in adolescent depressive symptoms. Longitudinal data that make use of repeated measures designs have the potential to provide insights into the factors that influence the onset and persistence of adolescent depression.

Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2 kg/m2) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m2) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P ≤ 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.

Previous studies report that dental caries is partially heritable, but there is uncertainty in the magnitude of genetic effects and little understanding of how genetic factors might influence caries progression or caries subtypes. This study aimed to estimate the relative importance of genetic and environmental factors in the etiology of different caries outcomes using a twin-based design. Analysis included up to 41,678 twins in the Swedish Twin Register aged 7 to 97 y, and dental data were obtained from preexisting dental records. The outcome measures were 1) summary indices of caries experience, 2) parameters representing trajectory in caries progression derived from longitudinal modeling, and 3) caries scores in groups of biologically similar tooth surfaces derived from hierarchical clustering of tooth surfaces (termed caries clusters). Additive genetic factors explained between 49.1% and 62.7% of variation in caries scores and between 50.0% and 60.5% of variation in caries trajectories. Seven caries clusters were identified, which had estimates of heritability lying between 41.9% and 54.3%. Shared environmental factors were important for only some of these clusters and explained 16% of variation in fissure caries in molar teeth but little variation in other clusters of caries presentation. The genetic factors influencing these clusters were only partially overlapping, suggesting that different biological processes are important in different groups of tooth surfaces and that innate liability to some patterns of caries presentation may partially explain why groups of tooth surfaces form clusters within the mouth. These results provide 1) improved quantification of genetic factors in the etiology of caries and 2) new data about the role of genetics in terms of longitudinal changes in caries status and specific patterns of disease presentation, and they may help lay the foundations for personalized interventions in the future.

Smoking usually begins in adolescence, and early onset of smoking has been linked to increased risk of later life disease. There is a need to better understand the biological impact of cigarette smoking behaviours in adolescence. DNA methylation profiles related to smoking behaviours and cessation in adulthood have been previously identified, but alterations arising from smoking initiation have not been thoroughly investigated. We aimed to investigate DNA methylation in the Avon Longitudinal Study of Parents and Children in relation to (1) different smoking measures, (2) time since smoking initiation and frequency of smoke exposure and (3) latent classes of smoking behaviour. Using 2620 CpG sites previously associated with cigarette smoking, we investigated DNA methylation change in relation to own smoking measures, smoke exposure duration and frequency, and using longitudinal latent class analysis of different smoking behaviour patterns in 968 adolescents. Eleven CpG sites located in seven gene regions were differentially methylated in relation to smoking in adolescence. While only AHRR (cg05575921) showed a robust pattern of methylation in relation to weekly smoking, several CpGs showed differences in methylation among individuals who had tried smoking compared with non-smokers. In relation to smoke exposure duration and frequency, cg05575921 showed a strong dose–response relationship, while there was evidence for more immediate methylation change at other sites. Our findings illustrate the impact of cigarette smoking behaviours on DNA methylation at some smoking-responsive CpG sites, even among individuals with a short smoking history.

Circulating 25-hydroxyvitamin D (25OHD) is an appealing potential intervention for cancer risk and has been associated with oral and oropharyngeal cancer risk but evidence is inconsistent. The availability of genetic variants, uncorrelated with known confounders, but predictive of 25OHD and genetic data in a large oral and oropharyngeal cancer collaboration aids causal inference when assessing this association. A total of 5,133 oral and oropharyngeal cancer cases and 5,984 controls with genetic data were included in the study. Participants were based in Europe, North America and South America and were part of the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network. Five genetic variants reliably associated with circulating 25OHD were used to create a relative genetic measure of 25OHD. In the absence of measured 25OHD, two-sample Mendelian randomization using individual level outcome data were used to estimate causal odds ratios (OR) for cancer case status per standard deviation increase in log25OHD. Analyses were replicated in an independent population-based cohort (UK Biobank). In the GAME-ON study, there was little evidence of a causal association between circulating 25OHD and oral cancer (OR = 0.86 [0.68;1.09], p = 0.22), oropharyngeal cancer (OR = 1.28 [0.72;2.26], p = 0.40) or when sites were combined (OR = 1.01 [0.74;1.40], p = 0.93). Replication in UK Biobank and pooled estimates produced similar results. Our study suggests that a clinically relevant protective effect of 25OHD on oral and oropharyngeal cancer risk is unlikely and supplementation of the general population with 25OHD is unlikely to be beneficial in preventing these cancers.

Background Body mass index (BMI) is criticized for not distinguishing fat from lean mass and ignoring fat distribution, leaving its ability to detect health effects unclear. Objectives The aim of this study was to compare BMI with total and regional fat indexes from dual-energy x-ray absorptiometry in their associations with cardiometabolic traits. Duration of exposure to and change in each index across adolescence were examined in relation to detailed traits in young adulthood. Methods BMI was examined alongside total, trunk, arm, and leg fat indexes (each in kilograms per square meter) from dual-energy x-ray absorptiometry at ages 10 and 18 years in relation to 230 traits from targeted metabolomics at age 18 years in 2,840 offspring from the Avon Longitudinal Study of Parents and Children. Results Higher total fat mass index and BMI at age 10 years were similarly associated with cardiometabolic traits at age 18 years, including higher systolic and diastolic blood pressure, higher very low-density lipoprotein and low-density lipoprotein cholesterol, lower high-density lipoprotein cholesterol, higher triglycerides, and higher insulin and glycoprotein acetyls. Associations were stronger for both indexes measured at age 18 years and for gains in each index from age 10 to 18 years (e.g., 0.45 SDs [95% confidence interval: 0.38 to 0.53] in glycoprotein acetyls per SD unit gain in fat mass index vs. 0.38 SDs [95% confidence interval: 0.27 to 0.48] per SD unit gain in BMI). Associations resembled those for trunk fat index. Higher lean mass index was weakly associated with traits and was not protective against higher fat mass index. Conclusions The results of this study support abdominal fatness as a primary driver of cardiometabolic dysfunction and BMI as a useful tool for detecting its effects., Central Illustration

In the accompanying paper,1 Tan et al conclude that in people with heart failure (HF) there is a strikingly lower prevalence of atrial fibrillation (AF) among Asian people in Singapore compared with European people in New Zealand (NZ). When seeking an explanation for this, they found that Asian patients with HF with diabetes had less AF than Asian patients without diabetes. This lower rate of diabetes is unexpected and could be called a paradox since previous cohort studies had shown diabetes to be associated with a higher risk of AF.2 3 Both of these findings, if correct, are of importance. Ethnic differences might point to an underlying genetic cause of AF; if diabetes does not cause AF (in Asians) then lifestyle changes to prevent diabetes4 might not prevent AF, as has been suggested.5 Despite the potential interest of the findings in this work, it is important to consider that the design of the study has an important bearing on the results and their interpretation. The prevalence of AF may be lower in Asian people in Singapore, as the authors suggest, but this may be due to untestable differences in the make-up of the peoples in the study or because of a differential survivor bias, prerecruitment. Here we consider the problem of collider bias and how the structure of this study may have influenced the results and their interpretation. The paper1 is an observational study looking at data from a previous prospective multicentre longitudinal study6 based in NZ and Singapore. In this original study, patients with HF were assessed at baseline and followed over 2 years in two countries, NZ and Singapore. People were selected from 9598 presenting with HF to hospital or attending a hospital clinic for management of HF within 6 months of decompensated HF. …

Background The potential benefits of gaining body muscle for cardiovascular disease (CVD) susceptibility, and how these compare with the potential harms of gaining body fat, are unknown. We compared associations of early life changes in body lean mass and handgrip strength versus body fat mass with atherogenic traits measured in young adulthood. Methods and findings Data were from 3,227 offspring of the Avon Longitudinal Study of Parents and Children (39% male; recruited in 1991–1992). Limb lean and total fat mass indices (kg/m2) were measured using dual-energy X-ray absorptiometry scans performed at age 10, 13, 18, and 25 y (across clinics occurring from 2001–2003 to 2015–2017). Handgrip strength was measured at 12 and 25 y, expressed as maximum grip (kg or lb/in2) and relative grip (maximum grip/weight in kilograms). Linear regression models were used to examine associations of change in standardised measures of these exposures across different stages of body development with 228 cardiometabolic traits measured at age 25 y including blood pressure, fasting insulin, and metabolomics-derived apolipoprotein B lipids. SD-unit gain in limb lean mass index from 10 to 25 y was positively associated with atherogenic traits including very-low-density lipoprotein (VLDL) triglycerides. This pattern was limited to lean gain in legs, whereas lean gain in arms was inversely associated with traits including VLDL triglycerides, insulin, and glycoprotein acetyls, and was also positively associated with creatinine (a muscle product and positive control). Furthermore, this pattern for arm lean mass index was specific to SD-unit gains occurring between 13 and 18 y, e.g., −0.13 SD (95% CI −0.22, −0.04) for VLDL triglycerides. Changes in maximum and relative grip from 12 to 25 y were both positively associated with creatinine, but only change in relative grip was also inversely associated with atherogenic traits, e.g., −0.12 SD (95% CI −0.18, −0.06) for VLDL triglycerides per SD-unit gain. Change in fat mass index from 10 to 25 y was more strongly associated with atherogenic traits including VLDL triglycerides, at 0.45 SD (95% CI 0.39, 0.52); these estimates were directionally consistent across sub-periods, with larger effect sizes with more recent gains. Associations of lean, grip, and fat measures with traits were more pronounced among males. Study limitations include potential residual confounding of observational estimates, including by ectopic fat within muscle, and the absence of grip measures in adolescence for estimates of grip change over sub-periods. Conclusions In this study, we found that muscle strengthening, as indicated by grip strength gain, was weakly associated with lower atherogenic trait levels in young adulthood, at a smaller magnitude than unfavourable associations of fat mass gain. Associations of muscle mass gain with such traits appear to be smaller and limited to gains occurring in adolescence. These results suggest that body muscle is less robustly associated with markers of CVD susceptibility than body fat and may therefore be a lower-priority intervention target., Joshua Bell and co-workers study muscle strengthening in early adulthood and associations with atherogenic biomarkers., Author summary Why was this study done? Higher body fat likely causes heart disease, but fat loss remains difficult to maintain. Evidence is less robust on whether gaining body muscle mass or strength would reduce the risk of heart disease, and how the size of potential benefit from muscle or strength gain compares with the expected harm of fat gain. Examining naturally occurring changes in lean mass, grip strength, and fat mass across early stages of life, when ageing-related chronic diseases are rare, should naturally reduce the potential for confounding by subclinical disease and enable less biased estimates of the effect of each body compartment on markers of heart health. What did the researchers do and find? We used data on approximately 3,000 young people from a British birth cohort study to examine repeated measures of body fat and lean mass taken from body scanning performed during childhood, adolescence, and young adulthood, as well as repeated measures of handgrip strength from childhood and young adulthood. We examined associations between these exposures and detailed measures taken from blood samples in young adulthood including apolipoprotein-B-related cholesterol, which reflects susceptibility to heart disease. This enabled us to compare how strongly different body compartments relate to heart health and to pinpoint at what stage of early life (before adulthood) each may be most impactful. We found that gaining lean mass and grip strength were only weakly related to healthier levels of blood markers in young adulthood, and mainly among males, with only lean mass gains occurring in adolescence appearing potentially beneficial. Gaining fat mass was more strongly and consistently related to poorer health in young adulthood, again particularly among males. What do these findings mean? These findings suggest that greater benefits to heart health may be expected from reducing body fat than from gaining body muscle. They further suggest that the regular use of muscle matters more than the volume or intentional building up of muscle for avoiding heart disease. Body muscle is still likely to benefit other functional aspects of health including mobility, and these benefits should still be relayed to patients and the public.

Background: Effective measurement and adaption of eating behaviours (e.g., eating speed) may improve weight loss and weight over time. We assessed whether the Mandometer, a portable weighing scale connected to a computer that generates a graph of food removal rate from the plate to which it is connected, together with photo-imaging of food, might prove a less intensive and more economical approach to measuring eating behaviours at large scale. Methods: We deployed the Mandometer in the home environment to measure main meals over three days of 95 21-year-old participants of the Avon Longitudinal Study of Parents and Children. We used multi-level models to describe food weight and eating speed and, as exemplar analyses, examined the relationship of eating behaviours with body mass index (BMI), dietary composition (fat content) and genotypic variation (the FTO rs9939609 variant). Using this pilot data, we calculated the sample size required to detect differences in food weight and eating speed between groups of an exposure variable. Results: All participants were able to use the Mandometer effectively after brief training. In exemplar analyses, evidence suggested that obese participants consumed more food than those of "normal" weight (i.e., BMI 19 to 2) and that A/A FTO homozygotes (an indicator of higher weight) ate at a faster rate compared to T/T homozygotes. There was also some evidence that those with a high-fat diet consumed less food than those with a low-fat diet, but little evidence that individuals with medium- or high-fat diets ate faster. Conclusions: We demonstrated the potential for assessing eating weight and speed in a short-term home setting and combining this with information in a research setting. This study may offer the opportunity to design interventions tailored for at-risk eating behaviours, offering advantages over the “one size fits all” approach of current failing obesity interventions.

The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective population-based cohort study which recruited pregnant women in 1990-1992 and has followed these women, their partners (Generation 0; G0) and their offspring (Generation 1; G1) ever since. The study has reacted rapidly and repeatedly to the coronavirus disease 2019 (COVID-19) pandemic, deploying online questionnaires throughout the pandemic. In November/December 2020, a fourth questionnaire was deployed asking about physical and mental health, lifestyle and behaviours, employment and finances. G0 participants were offered an online questionnaire between 17th November 2020 and 7th February 2021, while G1 participants were offered both online and paper questionnaires between 1st December 2020 and 19th March 2021. Of 15,844 invitations, 8,643 (55%) participants returned the questionnaire (3,101 original mothers [mean age 58.6 years], 1,172 original fathers/partners [mean age 61.5 years] and 4,370 offspring [mean age 28.4 years]). Of these 8,643 participants, 2,012 (23%) had not returned a previous COVID-19 questionnaire, while 3,575 (41%) had returned all three previous questionnaires. In this questionnaire, 300 participants (3.5%) reported a previous positive COVID-19 test, 110 (1.3%) had been told by a doctor they likely had COVID-19, and 759 (8.8%) suspected that they had had COVID-19. Based on self-reported symptoms, between October 2020 and February 2021 359 participants (4.2%) were predicted COVID-19 cases. COVID data is being complemented with linkage to health records and Public Health England pillar testing results as they become available. Data has been released as an update to the previous COVID-19 datasets. It comprises: 1) a standard dataset containing all participant responses to both questionnaires with key sociodemographic factors; and 2) as a composite release coordinating data from the existing resource, thus enabling bespoke research across all areas supported by the study. This data note describes the fourth questionnaire and the data obtained from it.

Context: Serum thyroid hormone levels differ between children and adults, but have not been studied longitudinally through childhood. Objective: To assess changes in thyroid-stimulating hormone (TSH) and thyroid hormone levels over childhood and their interrelationships. Design: Cohort study. Setting: The Avon Longitudinal Study of Parents and Children, a population-based birth cohort. Participants: A total of 4442 children who had thyroid function measured at age 7, and 1263 children who had thyroid function measured at age 15. Eight hundred eighty-four children had measurements at both ages. Main Outcome Measures: Reference ranges for TSH, free tri-iodothyronine (FT3), free thyroxine (FT4), their longitudinal stability, and interrelationships. Results: Children at age 7 years had a higher FT3 [6.17 pmol/L, standard deviation (SD) 0.62] than children at age 15 (5.83 pmol/L, SD 0.74); P < 0.0001 with 23.2% of children at age 7 having FT3 above the adult reference range. Higher FT3 levels at age 7 in boys (P = 0.0001) and girls (P = 0.04) were associated with attainment of a more advanced pubertal stage at age 13. TSH was positively associated with FT3 at age 7 and age 15 even after adjusting for confounders. In contrast, TSH was negatively associated with FT4. Conclusions: There are substantial changes in TSH and thyroid hormone levels over childhood, in particular for FT3, which appear to relate to pubertal readiness. Our data provide increased insight into the evolution of the pituitary–thyroid axis over childhood and may have implications for determining optimal ranges for thyroid hormone replacement in children., We studied thyroid function in children at ages 7 and 15 years. We identified FT3 levels were substantially higher at age 7, and higher levels of FT3 were associated with more advanced puberty.

Handedness, a consistent asymmetry in skill or use of the hands, has been studied extensively because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and 32 studies from the International Handedness Consortium, we conducted the world’s largest genome-wide association study of handedness (1,534,836 right-handed, 194,198 (11.0%) left-handed and 37,637 (2.1%) ambidextrous individuals). We found 41 genetic loci associated with left-handedness and seven associated with ambidexterity at genome-wide levels of significance (P < 5×10−8). Tissue enrichment analysis implicated the central nervous system and brain tissues including the hippocampus and cerebrum in the etiology of left-handedness. Pathways including regulation of microtubules, neurogenesis, axonogenesis and hippocampus morphology were also highlighted. We found suggestive positive genetic correlations between being left-handed and some neuropsychiatric traits including schizophrenia and bipolar disorder. SNP heritability analyses indicated that additive genetic effects of genotyped variants explained 5.9% (95% CI = 5.8% – 6.0%) of the underlying liability of being left-handed, while the narrow sense heritability was estimated at 12% (95% CI = 7.2% – 17.7%). Further, we show that genetic correlation between left-handedness and ambidexterity is low (rg = 0.26; 95% CI = 0.08 – 0.43) implying that these traits are largely influenced by different genetic mechanisms. In conclusion, our findings suggest that handedness, like many other complex traits is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders that has been observed in multiple observational studies.

Objective The identification of new causal risk factors has the potential to improve cardiovascular disease (CVD) risk prediction and the development of new treatments to reduce CVD deaths. In the general population, we sought to determine whether cortisol is a causal risk factor for CVD and coronary heart disease (CHD). Design and methods Three approaches were adopted to investigate the association between cortisol and CVD/CHD. First, we used multivariable regression in two prospective nested case-control studies (total 798 participants, 313 incident CVD/CHD with complete data). Second, a random-effects meta-analysis of these data and previously published prospective associations was performed (total 6680 controls, 696 incident CVD/CHD). Finally, one- and two-sample Mendelian randomization analyses were performed (122,737 CHD cases, 547,261 controls for two-sample analyses). Results In the two prospective nested case–control studies, logistic regression adjusting for sex, age, BMI, smoking and time of sampling, demonstrated a positive association between morning plasma cortisol and incident CVD (OR: 1.28 per 1 SD higher cortisol, 95% CI: 1.06–1.54). In the meta-analysis of prospective studies, the equivalent result was OR: 1.18, 95% CI: 1.06–1.31. Results from the two-sample Mendelian randomization were consistent with these positive associations: OR: 1.06, 95% CI: 0.98–1.15. Conclusions All three approaches demonstrated a positive association between morning plasma cortisol and incident CVD. Together, these findings suggest that elevated morning cortisol is a causal risk factor for CVD. The current data suggest strategies targeted at lowering cortisol action should be evaluated for their effects on CVD.

BackgroundType 2 diabetes develops for many years before diagnosis. We aimed to reveal early metabolic features characterising liability to adult disease by examining genetic liability to adult type 2 diabetes in relation to detailed metabolic traits across early life.Methods and FindingsData were from up to 4,761 offspring from the Avon Longitudinal Study of Parents and Children cohort. Linear models were used to examine effects of a genetic risk score (GRS, including 162 variants) for adult type 2 diabetes on 4 repeated measures of 229 traits from targeted nuclear magnetic resonance (NMR) metabolomics. These traits included lipoprotein subclass-specific cholesterol and triglyceride content, amino and fatty acids, inflammatory glycoprotein acetyls, and others, and were measured in childhood (age 8y), adolescence (age 16y), young-adulthood (age 18y), and adulthood (age 25y). For replication, two-sample Mendelian randomization (MR) was conducted using summary data from genome-wide association studies of metabolic traits from NMR in an independent sample of adults (N range 13,476 to 24,925; mean (SD) age range 23.9y (2.1y) to 61.3y (2.9y)). Among ALSPAC participants (49.7% male), the prevalence of type 2 diabetes was very low across time points (< 5 cases when first assessed at age 16y; 7 cases (0.4%) when assessed at age 25y). At age 8y, type 2 diabetes liability (per SD-higher GRS) was associated with lower lipids in high-density lipoprotein (HDL) particle subtypes – e.g. −0.03 SD (95% CI = −0.06, −0.003; P = 0.03) for total lipids in very-large HDL. At age 16y, associations remained strongest with lower lipids in HDL and became stronger with pre-glycemic traits including citrate (−0.06 SD, 95% CI = −0.09, −0.02; P = 1.41×10−03) and with glycoprotein acetyls (0.05 SD, 95% CI = 0.01, 0.08; P = 0.01). At age 18y, associations were stronger with branched chain amino acids including valine (0.06 SD; 95% CI = 0.02, 0.09; P = 1.24×10−03), while at age 25y, associations had strengthened with VLDL lipids and remained consistent with previously altered traits including HDL lipids. Results of two-sample MR in an independent sample of adults indicated persistent patterns of effect of type 2 diabetes liability, with higher type 2 diabetes liability positively associated with VLDL lipids and branched chain amino acid levels, and inversely associated with HDL lipids – again for large and very large HDL particularly (−0.004 SD (95% CI = −0.007, −0.002; P = 8.45×10−04) per 1 log odds of type 2 diabetes for total lipids in large HDL). Study limitations include modest sample sizes for ALSPAC analyses and limited coverage of protein and hormonal traits; insulin was absent as it is not quantified by NMR and not consistently available at each time point. Analyses were restricted to white-Europeans which reduced confounding by population structure but limited inference to other ethnic groups.ConclusionsOur results support perturbed HDL lipid metabolism as one of the earliest features of type 2 diabetes liability which precedes higher branched chain amino acid and inflammatory glycoprotein acetyl levels. This feature is apparent in childhood as early as age 8y, decades before the clinical onset of disease.Author summaryWhy was this study done?Type 2 diabetes develops for many years before diagnosis. Clinical disease is characterised by numerous metabolic perturbations that are detectable in circulation, but which of these reflect the developmental stages of type 2 diabetes – as opposed to independent causes of type 2 diabetes or markers of other disease processes – is unknown. Revealing traits specific to type 2 diabetes development could inform the targeting of key pathways to prevent the clinical onset of disease and its complications.Genetic liability to type 2 diabetes is less prone to confounding than measured type 2 diabetes or blood glucose and may help reveal early perturbations in the blood that arise in response to type 2 diabetes liability itself.What did the researchers do and find?We examined effects of genetic liability to adult type 2 diabetes, based on a genetic risk score including 162 variants, on detailed metabolic traits measured on the same individuals across four stages of early life – childhood (age 8y), adolescence (age 16y), young-adulthood (age 18y), and adulthood (age 25y).We found that higher type 2 diabetes liability was associated most consistently across ages with lower lipid content in certain subtypes of HDL particles. Effects were more gradual on higher lipid content in VLDL particles and on higher branched chain amino acid and inflammatory glycoprotein acetyl levels.What do these findings mean?Signs of type 2 diabetes liability are detectable in the blood in childhood, decades before the disease becomes noticeable. These signs, taken to reflect the early features of, or coincident with, disease, likely involve lower lipid content in HDL particles, followed by higher levels of branched chain amino acids and inflammation.Genetic risk scores for adult diseases can be integrated with metabolic measurements taken earlier in life to help to reveal the timing at which signs of disease liability become visible and the traits most central to its development.

Glycosuria is a condition where glucose is detected in urine at higher concentrations than normal (i.e. not detectable). Glycosuria at some point during pregnancy has an estimated prevalence of 50% and is associated with adverse outcomes in both mothers and offspring. Little is currently known about the genetic contribution to this trait or the extent to which it overlaps with other seemingly related traits, e.g. diabetes. We performed a genome-wide association study (GWAS) for self-reported glycosuria in pregnant mothers from the Avon Longitudinal Study of Parents and Children (cases/controls = 1249/5140). We identified two loci, one of which (lead SNP = rs13337037; chromosome 16; odds ratio of glycosuria per effect allele: 1.42; 95% CI: 1.30, 1.56; P = 1.97 × 10−13) was then validated using an obstetric measure of glycosuria measured in the same cohort (227/6639). We performed a secondary GWAS in the 1986 Northern Finland Birth Cohort (NFBC1986; 747/2991) using midwife-reported glycosuria and offspring genotype as a proxy for maternal genotype. The combined results revealed evidence for a consistent effect on glycosuria at the chromosome 16 locus. In follow-up analyses, we saw little evidence of shared genetic underpinnings with the exception of urinary albumin-to-creatinine ratio (Rg = 0.64; SE = 0.22; P = 0.0042), a biomarker of kidney disease. In conclusion, we identified a genetic association with self-reported glycosuria during pregnancy, with the lead SNP located 15kB upstream of SLC5A2, a target of antidiabetic drugs. The lack of strong genetic correlation with seemingly related traits such as type 2 diabetes suggests different genetic risk factors exist for glycosuria during pregnancy.

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

Severe obesity is a rapidly growing global health threat. Although often attributed to unhealthy lifestyle choices or environmental factors, obesity is known to be heritable and highly polygenic; the majority of inherited susceptibility is related to the cumulative effect of many common DNA variants. Here we derive and validate a new polygenic predictor comprised of 2.1 million common variants to quantify this susceptibility and test this predictor in more than 300,000 individuals ranging from middle age to birth. Among middle-aged adults, we observe a 13-kg gradient in weight and a 25-fold gradient in risk of severe obesity across polygenic score deciles. In a longitudinal birth cohort, we note minimal differences in birthweight across score deciles, but a significant gradient emerged in early childhood and reached 12 kg by 18 years of age. This new approach to quantify inherited susceptibility to obesity affords new opportunities for clinical prevention and mechanistic assessment. © 2019 Author(s), National Human Genome Research Institute (1K08HG0101), Wellcome Trust (202802/Z/16/Z), University of Bristol NIHR Biomedical Research Centre (S- BRC-1215-20011), National Human Genome Research Institute (HG008895), National Heart, Lung, and Blood Institute (NHLBI) HHSN268201300025C, National Heart, Lung, and Blood Institute (NHLBI) HHSN268201300026C, National Heart, Lung, and Blood Institute (NHLBI) HHSN268201300027C, National Heart, Lung, and Blood Institute (NHLBI) HHSN268201300028C, National Heart, Lung, and Blood Institute (NHLBI) HHSN268201300029C, National Heart, Lung, and Blood Institute (NHLBI) HHSN268200900041C, National Institute on Aging (AG0005), NHLBI (AG0005), National Human Genome Research Institute (U01-HG004729), National Human Genome Research Institute (U01-HG04424), National Human Genome Research Institute (U01-HG004446), Wellcome (102215/2/13/2)

[no abstract]

The Avon Longitudinal Study of Parents and Children (ALSPAC) is a prospective population-based study. Initial recruitment of pregnant women took place in 1990-1992 and the health and development of the index children from these pregnancies and their family members have been followed ever since. The eligible sampling frame was constructed retrospectively using linked recruitment and health service records. Additional offspring that were eligible to enrol in the study have been welcomed through major recruitment drives at the ages of 7 and 18 years; and through opportunistic contacts since the age of 7. This data note provides a status update on the recruitment of the index children since the age of 7 years with a focus on enrolment since the age of 18, which has not been previously described. A total of 913 additional G1 (the cohort of index children) participants have been enrolled in the study since the age of 7 years with 195 of these joining since the age of 18. This additional enrolment provides a baseline sample of 14,901 G1 participants who were alive at 1 year of age.

Loci discovered by genome-wide association studies predominantly map outside protein-coding genes. The interpretation of the functional consequences of non-coding variants can be greatly enhanced by catalogs of regulatory genomic regions in cell lines and primary tissues. However, robust and readily applicable methods are still lacking by which to systematically evaluate the contribution of these regions to genetic variation implicated in diseases or quantitative traits. Here we propose a novel approach that leverages genome-wide association studies’ findings with regulatory or functional annotations to classify features relevant to a phenotype of interest. Within our framework, we account for major sources of confounding not offered by current methods. We further assess enrichment of genome-wide association studies for 19 traits within Encyclopedia of DNA Elements- and Roadmap-derived regulatory regions. We characterize unique enrichment patterns for traits and annotations driving novel biological insights. The method is implemented in standalone software and an R package, to facilitate its application by the research community.

INTRODUCTION: It is crucial to understand the factors that introduce variability before applying metabolomics to clinical and biomarker research.OBJECTIVES: We quantified technical and biological variability of both fasting and postprandial metabolite concentrations measured using 1H NMR spectroscopy in plasma samples.METHODS: In the Netherlands Epidemiology of Obesity study (n = 6,671), 148 metabolite concentrations (101 metabolites belonging to lipoprotein subclasses) were measured under fasting and postprandial states (150 minutes after a mixed liquid meal). Technical variability was evaluated among 265 fasting and 851 postprandial samples, with the identical blood plasma sample being measured twice by the same laboratory protocol. Biological reproducibility was assessed by measuring 165 individuals twice across time for evaluation of short- (3 years) biological variability. Intra-class coefficients (ICCs) were used to assess variability. The ICCs of the fasting metabolites were compared with the postprandial metabolites using two-sided paired Wilcoxon test separately for short- and long-term measurements.RESULTS: Both fasting and postprandial metabolite concentrations showed high technical reproducibility using 1H NMR spectroscopy (median ICC = 0.99). Postprandial metabolite concentrations revealed slightly higher ICC scores than fasting ones in short-term repeat measures (median ICC in postprandial and fasting metabolite concentrations 0.72 versus 0.67, Wilcoxon p-value = 8.0×10-14). Variability did not increase further in a long-term repeat measure, with median ICC in postprandial of 0.64 and in fasting metabolite concentrations 0.66.CONCLUSION: Technical reproducibility is excellent. Biological reproducibility of postprandial metabolite concentrations showed a less or equal variability than fasting metabolite concentrations over time.