[Show abstract][Hide abstract] ABSTRACT: Increased circulating plasma urate concentration is associated with an increased risk of coronary heart disease, but the extent of any causative effect of urate on risk of coronary heart disease is still unclear. In this study, we aimed to clarify any causal role of urate on coronary heart disease risk using Mendelian randomisation analysis.
Full-text · Article · Jan 2016 · The Lancet Diabetes & Endocrinology
[Show abstract][Hide abstract] ABSTRACT: Fortification of margarine with vitamin D was mandatory in Denmark during 1961-1985. The aim of the study was to assess whether gestational and early infancy exposure to margarine fortification was associated with seasonality of birth in Danish type 1 diabetes (T1D) patients. The risks of T1D in Danes born during various exposure periods around margarine fortification termination in 1985 were analyzed. As expected, the T1D hazards in males unexposed to margarine fortification and born in spring were higher than in males born in autumn: relevant hazard ratios (95% confidence intervals) in various exposure groups ranged from 1.74 (1.112/2.708) to 37.43 (1.804/776.558). There were no indications of seasonality of birth in males exposed to fortification, nor in both exposed and unexposed females. The study suggests that early life exposure to low-dose vitamin D from fortified food eliminates seasonality of birth in T1D male patients. Further studies are required to investigate the identified gender differences.
[Show abstract][Hide abstract] ABSTRACT: Reference panels from the 1000 Genomes (1000G) Project Consortium provide near complete coverage of common and low-frequency genetic variation with minor allele frequency ≥0.5% across European ancestry populations. Within the European Network for Genetic and Genomic Epidemiology (ENGAGE) Consortium, we have undertaken the first large-scale meta-analysis of genome-wide association studies (GWAS), supplemented by 1000G imputation, for four quantitative glycaemic and obesity-related traits, in up to 87,048 individuals of European ancestry. We identified two loci for body mass index (BMI) at genome-wide significance, and two for fasting glucose (FG), none of which has been previously reported in larger meta-analysis efforts to combine GWAS of European ancestry. Through conditional analysis, we also detected multiple distinct signals of association mapping to established loci for waist-hip ratio adjusted for BMI (RSPO3) and FG (GCK and G6PC2). The index variant for one association signal at the G6PC2 locus is a low-frequency coding allele, H177Y, which has recently been demonstrated to have a functional role in glucose regulation. Fine-mapping analyses revealed that the non-coding variants most likely to drive association signals at established and novel loci were enriched for overlap with enhancer elements, which for FG mapped to promoter and transcription factor binding sites in pancreatic islets, in particular. Our study demonstrates that 1000G imputation and genetic fine-mapping of common and low-frequency variant association signals at GWAS loci, integrated with genomic annotation in relevant tissues, can provide insight into the functional and regulatory mechanisms through which their effects on glycaemic and obesity-related traits are mediated.
[Show abstract][Hide abstract] ABSTRACT: The objective of the study was to assess whether gestational and early infancy exposure to low dose vitamin D from a mandatory margarine fortification programme in Denmark influenced the risk of developing type 1 diabetes (T1D) before age of 15 years. The study population included all individuals born in Denmark from 1983 to 1988 and consisted of 331,623 individuals. The 1st of June 1985, which was the date of issue of the new ministerial order cancelling mandatory fortification of margarine with vitamin D in Denmark, served as a reference point separating the studied population into various exposure groups. We further modelled birth cohort effects in children developing T1D as a linear spline, and compared the slopes between the birth cohorts with various prenatal and infancy exposures to vitamin D fortification. In total, 886 (0.26%) individuals developed T1D before the age of 15 years. The beta coefficients (95% CI), or slopes, for linear birth cohort effect in log Hazard Ratio (HR) per one month of birth in individuals born during the periods of gestational exposure, wash-out, and non-exposure were: 0.010 (-0.002/0.021), -0.010 (-0.035/0.018), and 0.008 (- 0.017/0.032), respectively. The beta coefficients (95% CI) for individuals born during the periods of first postnatal year exposure, wash-out, and non-exposure were: 0.007 (-0.016/0.030), 0.006 (-0.004/0.016), and 0.007 (-0.002/0.016), respectively. In conclusion, we found no evidence to support that exposure to low dose vitamin D from the Danish mandatory margarine fortification regimen during gestational and first postnatal year of life changed the risk of developing T1D before the age of 15 years.
[Show abstract][Hide abstract] ABSTRACT: Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 x 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
[Show abstract][Hide abstract] ABSTRACT: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated approximately 2,000, approximately 3,700 and approximately 9,500 SNPs explained approximately 21%, approximately 24% and approximately 29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
[Show abstract][Hide abstract] ABSTRACT: Little is known about genes regulating male puberty. Further, while many identified pubertal timing variants associate with age at menarche, a late manifestation of puberty, and body mass, little is known about these variants' relationship to pubertal initiation or tempo. To address these questions, we performed genome-wide association meta-analysis in over 11,000 European samples with data on early pubertal traits, male genital and female breast development, measured by the Tanner scale. We report the first genome-wide significant locus for male sexual development upstream of MKL2 (P=8.9 x 10(-9)), a menarche locus tagging a developmental pathway linking earlier puberty with reduced pubertal growth (P=4.6 x 10(-5)) and short adult stature (P=1.1 x 10(-11)) in both males and females. Furthermore, our results indicate that a proportion of menarche loci are important for pubertal initiation in both sexes.Consistent with epidemiological correlations between increased prepubertal body mass and earlier pubertal timing in girls, BMI-increasing alleles correlated with earlier breast development. In boys, some BMI-increasing alleles associated with earlier, and others with delayed, sexual development; these genetic results mimic the controversy in epidemiological studies, some of which show opposing correlations between prepubertal BMI and male puberty. Our results contribute to our understanding of the pubertal initiation program in both sexes, and indicate that although mechanisms regulating pubertal onset in males and females may largely be shared, the relationship between body mass and pubertal timing in boys may be complex and requires further genetic studies.
Full-text · Article · Apr 2014 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: There is a widening perception that many factors (lifestyle and others e.g., acute/chronic inflammation) may causally lower vitamin D levels. Observationally, smoking tends to be associated with lower vitamin D levels. Smokers also have increased fracture risk and decreased bone mass suggesting a potential causal effect of smoking on vitamin D. It has also been suggested that tobacco smoke chemicals may influence vitamin D metabolism and function. However, determining a causal link between smoking and lower vitamin D is problematic in conventional epidemiological studies due to confounding by other lifestyle factors. We performed a Mendelian randomisation analysis, using data on 32,823 individuals from the Consortium for Causal Analysis Research in Tobacco and Alcohol to investigate the causal nature of the associations of smoking with vitamin D levels. Associations between a smoking related variant (rs1051730/rs16969968) and serum vitamin D (25(OH)D) were assessed by linear regression stratified by smoking status (categorised as never, former, current, ever (former and current), and non (never and former)) and adjusted for age, sex, and geographic region, and additionally for body mass index (BMI). Observational associations between smoking status and vitamin D were assessed by linear regression, adjusted for age, sex, and month of data collection and additionally for geographic region, socio-economic status and BMI. Results from individual studies were meta-analysed. Interactions between smoking status and genotype were assessed using the Cochran Q statistic. We discuss the implications of these results for furthering understanding of the causal effect of smoking on vitamin D. This will inform the development of relevant public health messages and campaigns, and also potentially aid the development of novel treatments for disease outcomes. This is a work in progress and we anticipate that results will be available within a month.
[Show abstract][Hide abstract] ABSTRACT: Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated similar to 2,000, similar to 3,700 and similar to 9,500 SNPs explained similar to 21%, similar to 24% and similar to 29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/beta-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
[Show abstract][Hide abstract] ABSTRACT: Substantial advances have been made in identifying common genetic variants influencing cardiometabolic traits and disease outcomes through genome wide association studies. Nevertheless, gaps in knowledge remain and new questions have arisen regarding the population relevance, mechanisms, and applications for healthcare. Using a new high-resolution custom single nucleotide polymorphism (SNP) array (Metabochip) incorporating dense coverage of genomic regions linked to cardiometabolic disease, the University College-London School-Edinburgh-Bristol (UCLEB) consortium of highly-phenotyped population-based prospective studies, aims to: (1) fine map functionally relevant SNPs; (2) precisely estimate individual absolute and population attributable risks based on individual SNPs and their combination; (3) investigate mechanisms leading to altered risk factor profiles and CVD events; and (4) use Mendelian randomisation to undertake studies of the causal role in CVD of a range of cardiovascular biomarkers to inform public health policy and help develop new preventative therapies.
[Show abstract][Hide abstract] ABSTRACT: During aging, intracranial volume remains unchanged and represents maximally attained brain size, while various interacting biological phenomena lead to brain volume loss. Consequently, intracranial volume and brain volume in late life reflect different genetic influences. Our genome-wide association study (GWAS) in 8,175 community-dwelling elderly persons did not reveal any associations at genome-wide significance (P < 5 x 10(-8)) for brain volume. In contrast, intracranial volume was significantly associated with two loci: rs4273712 (P = 3.4 x 10(-11)), a known height-associated locus on chromosome 6q22, and rs9915547 (P = 1.5 x 10(-12)), localized to the inversion on chromosome 17q21. We replicated the associations of these loci with intracranial volume in a separate sample of 1,752 elderly persons (P = 1.1 x 10(-3) for 6q22 and 1.2 x 10(-3) for 17q21). Furthermore, we also found suggestive associations of the 17q21 locus with head circumference in 10,768 children (mean age of 14.5 months). Our data identify two loci associated with head size, with the inversion at 17q21 also likely to be involved in attaining maximal brain size.
[Show abstract][Hide abstract] ABSTRACT: Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
[Show abstract][Hide abstract] ABSTRACT: On September 29, 2011, acknowledged experts in the field of vitamin D, mainly European, were brought together in order to discuss the recent scientific advances in relation to vitamin D: the current requirements and associations with various health outcomes. In this article, the discussions resulting from the meeting are summarized.
Several groups at risk for developing vitamin D insufficiency have been identified. Accordingly, reviews indicate that a significant percentage of the population worldwide have serum 25-hydroxyvitamin D levels below 50 nmol/l. In addition to the role of vitamin D in bone health, recent studies suggest that it may play a pivotal role in other systems, e.g., the cardiovascular system, pancreas, muscle, immune system and brain. Most evidence, however, is obtained from observational studies and yet inconclusive.
To exchange and broaden knowledge on the requirements for vitamin D and its effect on various health outcomes, a workshop entitled “Vitamin D Expert Meeting: Do we get enough?”, was organized.
Despite low vitamin D levels worldwide, consensus on the definition of deficiency is not yet reached. In order to define cut-off points for vitamin D whilst taking into account extraskeletal health effects, randomized controlled trials in these fields are warranted. The experts do emphasize that there is evidence to suggest an important role for vitamin D in the maintenance of optimal bone health at all ages and that vitamin D supplementation, in most studies co-administered with calcium, reduces fracture risk in the senior population.
To reach a serum 25-hydroxyvitamin D level of 50 nmol/l older adults aged ≥65 years are therefore recommended to meet a mean daily vitamin D intake of 20 μg (800 IU), which is best achieved with a supplement.
Full-text · Article · Dec 2012 · Osteoporosis International
[Show abstract][Hide abstract] ABSTRACT: Maternal smoking during pregnancy is associated with low birth weight. Common variation at rs1051730 is robustly associated with smoking quantity and was recently shown to influence smoking cessation during pregnancy, but its influence on birth weight is not clear. We aimed to investigate the association between this variant and birth weight of term, singleton offspring in a well-powered meta-analysis. We stratified 26 241 European origin study participants by smoking status (women who smoked during pregnancy versus women who did not smoke during pregnancy) and, in each stratum, analysed the association between maternal rs1051730 genotype and offspring birth weight. There was evidence of interaction between genotype and smoking (P = 0.007). In women who smoked during pregnancy, each additional smoking-related T-allele was associated with a 20 g [95% confidence interval (95% CI): 4-36 g] lower birth weight (P = 0.014). However, in women who did not smoke during pregnancy, the effect size estimate was 5 g per T-allele (95% CI: -4 to 14 g; P = 0.268). To conclude, smoking status during pregnancy modifies the association between maternal rs1051730 genotype and offspring birth weight. This strengthens the evidence that smoking during pregnancy is causally related to lower offspring birth weight and suggests that population interventions that effectively reduce smoking in pregnant women would result in a reduced prevalence of low birth weight.
Full-text · Article · Sep 2012 · Human Molecular Genetics
[Show abstract][Hide abstract] ABSTRACT: Background
A season of birth effect in immune-mediated diseases (ID) such as multiple sclerosis and type 1 diabetes has been consistently reported. We aimed to investigate whether season of birth influences the risk of rheumatoid arthritis, Crohn's disease, ulcerative colitis and systemic lupus erythematosus in addition to multiple sclerosis, and to explore the correlation between the risk of ID and predicted ultraviolet B (UVB) light exposure and vitamin D status during gestation.
The monthly distribution of births of patients with ID from the UK (n = 115,172) was compared to that of the general population using the Cosinor test. Predicted UVB radiation and vitamin D status in different time windows during pregnancy were calculated for each month of birth and correlated with risk of ID using the Spearman's correlation coefficient.
The distributions of ID births significantly differed from that of the general population (P = 5e-12) with a peak in April (odds ratio = 1.045, 95% confidence interval = 1.024, 1.067, P < 0.0001) and a trough in October (odds ratio = 0.945, 95% confidence interval = 0.925, 0.966, P < 0.0001). Stratification by disease subtype showed seasonality in all ID but Crohn's disease. The risk of ID was inversely correlated with predicted second trimester UVB exposure (Spearman's rho = -0.49, P = 0.00005) and third trimester vitamin D status (Spearman's rho = -0.44, P = 0.0003).
The risk of different ID in the UK is significantly influenced by the season of birth, suggesting the presence of a shared seasonal risk factor or factors predisposing to ID. Gestational UVB and vitamin D exposure may be implicated in the aetiology of ID.
[Show abstract][Hide abstract] ABSTRACT: To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 x 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 x 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height(1), their effects on infant head circumference were largely independent of height (P = 3.8 x 10(-7) for rs7980687 and P = 1.3 x 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 x 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume(2), Parkinson's disease and other neurodegenerative diseases(3-5), indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life.