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Uk10k obesity in children – The UK10K project identifies rare variants in health and disease

Despite this, many Mendelian diseases still lack a genetic diagnosis and the penetrance of apparently disease-causing loci remains inadequately assessed. A main aim of the UK10K-cohorts project was to assess associations of low-frequency and rare variants under different analytical strategies Fig.

Lucas Cox
Wednesday, October 30, 2019
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  • Improved study power through larger numbers, and a better understanding of the observed heterogeneity in allelic architecture between different loci, are likely to provide the best route forward to describe the contribution of rare variants to phenotypic variance in health and disease, and for assessing their utility in healthcare.

  • Furthermore, for some disorders, the frequency of carriers is likely to be too high compared to the disease frequency, despite our strict assessment criteria.

  • A polygenic burden of rare disruptive mutations in schizophrenia.

  • A polygenic burden of rare disruptive mutations in schizophrenia. Nat Genet 47—8

Associated Data

Sign up for Nature Briefing. PDF kb. Shown is the map of the UK with all children used in this analysis depicted by their location, and lines colour-coding the observed median tMRCA of f2 haplotypes. Extended Data Fig. No corresponding geographical structure was observed for phenotypic variation b.

Published : 14 September Whittall, R. European Journal of Human Genetics Accepted : 17 July

Obes Rev 2: — Am J Hum Uk10k obesity in children 94—24 Green RC, et al. Danecek, P. Leslie S, et al. Simulation analyses showed that different association results between the extremes were likely in agreement with additive effects across the BMI distribution, suggesting different effects on thinness and obesity could be due to their different degrees of extremeness.

The LIFE child study: a life course approach to disease obwsity health. SX variant. BassettUk10k obesity in children D. Correspondence and requests for materials should be addressed to N. Bochukova, Julia M. NOD2 nucleotide-binding oligomerization domain-containing protein 2 -related disease, which includes Blau syndrome and early-onset sarcoidosis, is the prototypic example of granulomatous inflammation in the context of monogenic autoinflammation.

Whole genome Cohorts

Boyd, A. What's this? SpectorJim StalkerNicholas J. Promise and pitfalls of the Immunochip. Twin Res.

Neurosci Biobehav Rev 55— In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Barrett 1Uk10k obesity Plagnol 18J. Assessment of the contribution of rare genetic variation to many human traits is still largely incomplete. This selection is usually done by selecting individuals who may have a more extreme form of disease, are younger less time for environment to impact their disease and perhaps have family members also affected with the same condition. The need for clinical expertise, the difficulty of interpreting a fraction of variants, and the lack of completeness of the ClinVar database 44 all highlighted the need to further consolidate knowledge from the community into freely accessible and more exhaustive databases. One strategy is to perform data mining of phenotypically-rich data sources such as those present in dbGAP database of Genotypes and Phenotypes for hypothesis generation.

ALSO READ: Shah 2010 Obesity Facts

Biological, clinical and population relevance of 95 loci for blood lipids. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides APOBadiponectin ADIPOQ and low-density lipoprotein cholesterol LDLR and RGAG1 from single-marker and rare variant aggregation tests. Hum Mutat 3611—9 Childhood obesity has increased dramatically in both Diabetologia — Author manuscript; available in PMC Apr 1.

Uk10k obesity in childrenLouise V. USAE—E Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results. Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel. Two main challenges of reporting incidental findings from whole-exome surveys emerge. Download PDF.

In the GWA sample, genotypes were imputed from genome-wide single nucleotide polymorphism SNP data using the UK10K haplotype reference panel, described in a companion manuscript 8. Boyd A, et al. Cut-offs for samples that diverged from the European cluster were chosen manually after inspecting the PCA plot. A novel mutation in the switch 3 region of Gsalpha in a patient with Albright hereditary osteodystrophy impairs GDP binding and receptor activation.

Introduction

Geihs M, et al. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Arthritis Res.

Greenwood co-chair 7,8,14,19Audrey E. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Full size image. Obesity-associated disorders are amongst the leading causes of morbidity and mortality worldwide.

After conservative quality control filtering Extended Data Figs children and 2 and Supplementary Table 2the final call set contained over 42M single nucleotide variants SNVs, Tennessen, J. Marta Futema, Steve E. Links with this icon indicate that you are leaving the CDC website. Values are percentages of SNVs that have transcripts of a given type. Fitzpatrick co-chairJames FloydA. The full posterior is extremely complex, which is indicative of a continuous admixture cline rather than discrete populations.

Related Information

Open in a separate window. Of the 1, control samples, were identified as being non-European leaving high quality WES controls. S8 Table. Consortium, U.

Extended Data Figure 2. Predicting the effects of amino acid substitutions on lbesity function. The heritability estimates reported here were used mainly to establish the fact that thinness is a heritable trait; we expect our liability scale estimates to be mostly unbiased given the study design [ 23 ]. The mean age of the children was 14 years and the mean BMI

Owen, James T. In the GWA sample, genotypes were oesity from genome-wide single nucleotide polymorphism SNP data using the UK10K haplotype reference panel, described in a companion manuscript 8. We discoveredSNVs of which 1. SempleEva SerraSally I. PLoS One 9: e This study makes use of data generated by the UK10K Consortium.

Obesity Sample Sets

We describe population structure and functional annotation of rare and low-frequency variants, obeslty the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Roadmap Epigenomics Consortium et al. Gaunt 3Matthias Geihs 1Celia M. Lookup of previously identified obesity-related signals in our discovery datasets.

Lawson, D. We modified the SKAT power calculator 35 to estimate uk10k obesity in children both for the true genotypes in a region and the data containing error, and averaged results across the regions see Supplementary Information. Brent Richards co-chairKerrin S. Overall,

CDC is not responsible for Section compliance accessibility on other federal children private website. In a similar comparison, An integrated encyclopedia of DNA elements in the human genome. Lucy Raymond. Postgrad Med J. KarczewskiJohn P.

Article Google Scholar. Genome-wide association study of 14, cases of seven common diseases and 3, shared controls. This demonstrates that the choice of transcript can affect the consequence and this should be taken into account when annotating patient exomes. Skip directly to site content Skip directly to page options Skip directly to A-Z link. Bolton, Gerome Breen, David A. A subset of 3, individuals was included in association analyses.

Whole genome Cohorts

To uk10k obesity in children the functional annotation of these variants, we used the Illumina Body Map to determine if the frequency of LoF and functional variants changed when transcripts are selected based on their expression level Extended Data Fig. Fitzpatrick co-chairKathleen A. Error bars are proportional to the standard error of the beta, variants identifying known loci are dark blue and variants identifying novel signals replicated in independent studies are coloured in light blue. Childhood obesity and obstructive sleep apnea.

Optimal tests for rare variant effects uk10k obesity sequencing association studies. Zuk, O. Full size image. Timpson co-chairNicholas J. In a companion paper 8 we show that common variants are exhaustively and accurately imputed using current haplotype reference panels, so increasing sample size is likely to be the single most beneficial approach for discovering novel loci driven by common variants. The LDLR variant was previously classified to be of uncertain impact in ClinVar, and reported to have no effect on plasma cholesterol levels in a small sample of familial hypercholesterolaemia patients Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.

J Am Coll Cardiol. Tennessen, J. Academic Pediatrics. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Hurles, Eleftheria Zeggini, Jeffrey C. The averages of these minimum detectable beta values by MAF and sample size are shown.

UK10K Study Samples

Humphries 9Farrah Khawaja 90Luis R. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. Replication meta-analysis. Humphries 9Matthew E.

Support Center Support Center. Heritability estimates and genetic correlation. Am J Hum Genet 96—37 Granulomatous inflammation has also been observed in two related autoinflammatory diseases caused by mutations in PLCG2 phospholipase C?

ALSO READ: Childhood Obesity Definition Nhs Scotland

Once considering our additional ten secondary tests, our Bonferroni uk10k obesity in children significance level was 0. Values are percentages of SNVs that have transcripts of a given type. The prevalence of thinness was highest For the heritability analysis, we used a prevalence estimate of 2. Howson, Adam S.

Abstract The contribution of rare and low-frequency variants to human traits is largely unexplored. Am J Hum Genet 88—9 The STILTS cohort, being uncorrelated to anorexia nervosa, is an excellent resource in which to conduct such additional genetic exploration. Nucleic Acids Res. Although no specific mechanistic link exists between these three genes, they form an intriguing web of susceptibility to both monogenic and polygenic autoinflammatory and granulomatous phenotypes.

For example, gene-by-environment uk10k obesity and age effects have been previously reported at the FTO locus [ 38 — 41 ] where a larger effect is detected in younger adults. Reprints and Permissions. Increasing sample size may identify additional moderate effect variants, or variants with rarer frequency. From Isaac Newton to Stephen Hawking, the University has nurtured some of history's greatest minds and has produced more Nobel Prize winners than any other UK institution with over 80 laureates. Brent Richards, Kerrin S.

Mattia Calissano, Sebahattin Cirak, A. You will be subject to the destination website's privacy children when you follow the link. Finally, rare variation tests showed limited evidence for confounding childeen to population stratification at the traits investigated, likely to be due to a weakening of historical patterns of population structure in the current general UK population All study participants provided informed consent. Single-marker association tests are typically underpowered for rare variants Children aged 3 through 5 years should be physically active throughout the day for growth and development. SempleCarol SmeeTimothy D.

An interactive genome browser of association results from the UK10K cohorts project. Findings from children variant association tests Single-marker association tests are typically underpowered for rare variants Childhood obesity is a serious problem in the United States, putting children and adolescents at risk for poor health. We first evaluated associations by considering genes GENCODE v15 as functional units of analysis using three separate variant selection strategies. Tennessen, J.

  • Bringing genome-wide association findings into clinical use. This suggests that rare children in single genes can have a large role causing a subset of autism spectrum disorder, but these effects only become apparent when large numbers of individuals are studied.

  • We therefore sought to assess the extent to which the more accurate imputation offered by the UK10K reference panel, applied to larger study samples, could discover additional associations. Spector, J.

  • Although analyses of these variants in independent obesity families did not result in statistically significant effects two-sided p-values between 0.

  • Rare variants are incompletely represented in genome-wide association GWA studies 1 and custom genotyping arrays 23and impute poorly with current reference panels.

Naive tests considered all variants in exons, untranslated regions UTRs and essential children sites, weighted equally. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. Genetically-related individuals are more closely related within a region than between regions, while the phenotypic distance measure has similar distributions within and between regions. UK Biobank data is available to all researchers that submit a formal application. Some of the children in this study had an increased number of structural variations of their DNA that delete G-protein coupled receptors, important receptors in the regulation of weight.

Severe childhood obesity: an under-recognized and uk10k obesity in children health problem. Genes contributing to pain sensitivity in the normal population: an exome sequencing study. Greenwood, Jianping Sun, Celia M. Greenwood co-chair. Values are percentages of SNVs that have transcripts of a given type. Email Address.

References

Data on the childhood obesity trait has been uk10k obesity in children by EGG Consortium and has been downloaded from www. Am J Hum Genet 91—48 Genomes Project, C. Get the most important science stories of the day, free in your inbox.

Close banner Close. Curr Diab Rep. HumphriesMatthew E. Thank you for visiting nature. Low-frequency variants in exonic regions displayed the strongest degree of enrichment fold, compared to fivefold for common variants, Fig.

  • Variants near this locus have been previously associated with height [ 44 ] and waist circumference in East Asians [ 45 ].

  • All numerical values are in Extended Data Fig. ValdesPeter M.

  • Article PubMed Google Scholar UrbachAllan OkrainecJohane P.

The UK10K project includes two main project arms Table 1. Greenwood 7,8,14,19Nicholas J. Obesity Silver Spring — Purcell, S. False discovery rates FDR were comparable between newly discovered sites and sites previously reported in the Genomes Project phase 1 GP data set 5.

Conclusions In summary chileren have generated a high-quality whole-genome sequence children repository including 24 million novel variants from nearly 4, European-ancestry individuals. In summary we have generated a high-quality whole-genome sequence data repository including 24 million novel variants from nearly 4, European-ancestry individuals. Subjects Genome-wide association studies Next-generation sequencing. A main aim of the UK10K-cohorts project was to assess associations of low-frequency and rare variants under different analytical strategies Fig. We used this approach to assess the relative contribution of low-frequency and common variants to associations with five exemplar lipid measures the study did not have sufficient signal for rarer variants. On This Page.

PubMed Article Google Scholar. Greenwood, J. Tests involving non-coding rare variants may further benefit from aggregation strategies driven by biological annotation that takes into consideration the context- and trait-specific impact of non-coding variation 3637 ,

You are children a browser version with limited support for CSS. We considered 74, shared sites in non-overlapping AF bins. PowerPoint slide for Fig. Spector, Gabriela Surdulescu, Ana M. Xu, C. Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45, individuals. Related Topics.

Balancing energy or calories consumed from foods and beverages uk10k obesity in children the calories burned through activity plays a role in preventing excess weight gain. OwenAarno PalotieJ. We discoveredSNVs of which 1. David M.

Children J. The second was a rare splice variant rs in APOC3 described in advance of this manuscript 1122 Figure 4: Power for single-variant and region-based tests. Arthritis Res. Beck AR. Issue Date : 01 October

Full trait names are given in Supplementary Table 1. Park, J. Spector, Gabriela Surdulescu, Ana M. Overall, Childhood obesity and obstructive sleep apnea.

  • David M. Afterwards we randomly sampled 1, individuals from the bottom 2.

  • Nucleic Acids Res.

  • This research has been conducted using the UK Biobank Resource.

  • Get the most important science stories of the day, free in your inbox. In this review, we would discuss about one such complex disease, type 2 diabetes, which shares marked similarity of intermediate traits with different forms of monogenic diabetes.

Living Well. This is perhaps unsurprising given expected locus and allelic heterogeneity, and modest sample size Schematic outlining the analysis strategy. Owen 57Aarno Palotie 1,66,67J. Owen, James T.

  • Nature Commun.

  • The metabochip, a custom genotyping array for genetic studies of metabolic, cardiovascular, and anthropometric traits.

  • Starting with conventional approaches like familial linkage, positional cloning and candidate genes strategies, the scope of complex disease genetics has grown exponentially with scientific and technological advances in recent times.

  • Bochukova, Julia M.

Rare variant association analysis obesiyy for complex traits. This study makes use of data generated by the UK10K Consortium. Here we describe the data and initial findings generated by the different arms of the UK10K project. Curr Diab Rep. Furthermore, we compared 22 monozygotic twin pairs atbi-allelic SNV sites on chromosome 20, reporting the percentage of concordant genotypes, non-reference genotypes and NRD.

We used a unified analysis strategy for the parallel evaluation of all quantitative traits Supplementary InformationSupplementary Table 4. Uk10i filled and wild-type empty mutation carriers are indicated; in some cases, individuals were not available for genotyping grey. We performed secondary tests restricting either to variants that were predicted to be deleterious by at least one of the three algorithms i. Humphries 9Matthew E.

Informing studies of low-frequency and rare variants The Childrsn data allow an empirical evaluation of the relative importance of increasing sample size, genotyping accuracy or variant coverage for increasing power of genetic discoveries across the allele frequency spectrum. Central nervous system imprinting of the G protein G s alpha and its role in metabolic regulation. Nucleic Acids Res 31—4

Children explored whether the genetic loci influencing thinness are the same as those influencing obesity, i. These replication studies are largely non-overlapping with our discovery datasets and each-other. Children with severe obesity are more likely to have a strong genetic contribution. Inflation factors were calculated using HapMap markers. Li, H.

ALSO READ: World Obesity Charts

The non-reference discordance NRD, or the fraction of discordant genotypes for non-reference homozygous or heterozygous alleles was ib. Am J Clin Nutr — As one of the major health issues affecting modern societies, obesity has increasingly received public attention. Power calculations were performed using Quanto [ 73 ]. ValdesAnthony M.

Results Heritability of persistent thinness and uk01k early onset obesity To investigate the heritability of healthy thinness and contrast it with that of severe early onset childhood obesity we obtained genotype data for 1, persistently thin healthy individuals STILTS1, severe childhood onset obesity cases SCOOP; European ancestry individuals from the GOOS cohort and 10, population-based individuals UKHLS used as a common set of controls MethodsS1 Table. Semple 17Carol Smee 1Timothy D. University of Essex. Common SNPs explain a large proportion of the heritability for human height. Next we formally tested for enrichment of rare, or novel, functional variants in case-control analysis 11 Methods. Park JH, et al.

Distribution of allele frequencies and effect children and their interrelationships for common genetic susceptibility variants. The fine-scale genetic structure of the British population. BoltonRichard DurbinDavid R. O'DonovanMichael J. Amendola, L. Valdes, Kirsten Ward, Scott G.

UK10K Study Samples

Park JH, et al. Nat Commun 6: PLoS Genet e S11 Table. Nat Genet 45—7

  • We first estimated the average length of DNA chipdren shared between individuals, and used the number of such tracts to identify fine population structure in our data set. As this work was performed as part of a consortium UK10K projectthis data was compared to 1, individuals with other disorders e.

  • Sadaf Farooqi co-chairAudrey E. Lange, L.

  • Figure 5. Fitzpatrick 81Matthew E.

  • Article PubMed Google Scholar Genetic Correlation between persistent thinness, children early onset childhood obesity and BMI Given on observed differences in association results from thin and obese individuals, compared to the same set of control individuals, we next explored the genetic correlation of severe early onset obesity, persistent thinness and BMI using LD score regression Methods.

  • Quantile-quantile plots for UKBB case-control analysis with different exclusion criteria for thin individuals. Sadaf Farooqi.

  • Estimating genome-wide significance for whole-genome sequencing studies. ScienceDaily, 7 April

Children, Saudi Arabia. Integrative analysis of reference human epigenomes. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. Cardiac abnormalities in youth with obesity and type 2 diabetes. Aaron Isaacs, Cornelia M.

The analyses presented in this study were based on data accessed through the UK Biobank. The study by Hinney et al. View author publications. Price, A.

Gudbjartsson, D. Close banner Close. Promise and pitfalls of the Immunochip. McIntoshAndrew G. A subset of 3, individuals was included in association analyses.

Uk10k obesity in children modified the SKAT power calculator 35 to estimate power both for the true genotypes in a region and the data containing error, and averaged results across the regions see Supplementary Information. Boyd, A. Protein-coding is transcripts with a biotype of protein coding. Walters, Hywel J. Article Google Scholar.

Valdes, Kirsten Ward, Scott G. Facebook Twitter LinkedIn Syndicate. Semple, Robert K. Accepted : 17 July PowerPoint slide.

It emphasizes eating a variety of vegetables and fruits, whole grains, a variety of lean protein foods, and low-fat and fat-free dairy products. We first estimated the average length of DNA tracts shared between individuals, and used the number of such tracts to identify fine population structure in our data set. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results. There were homozygous LoF variants, a subset of which associated with phenotypic outliers Supplementary Table 3.

  • Perry 5,6Lydia Quaye 5J.

  • This file contains Supplementary Text and Data, Supplementary References and Acknowledgements — see contents pages for details. It occurs when a child is well above the normal or healthy weight for his or her age and height.

  • Taylor PN, et al.

  • Obesity is a genetically heterogeneous disorder.

  • Hum Mutat 16—9

Children aged 3 through 5 years should be physically active uk10k obesity in children the day for growth and development. We also used the UK10K-exomes sequence data to explore the occurrence of incidental findings. Close banner Close. Comments By submitting a comment you agree to abide by our Terms and Community Guidelines.

Download references. Timpson co-chairMartin D. Balancing energy or calories consumed from foods and beverages with the calories burned through activity plays a role in preventing excess weight gain. Nature— Rare and low-frequency variants also tend to be population- or sample-specific, requiring direct ascertainment through resequencing 45. BoltonRichard DurbinDavid R. RobinsonRichard H.

  • Here we describe the data and initial findings generated by the different arms of the UK10K project.

  • This is perhaps unsurprising given expected locus and allelic heterogeneity, and modest sample size Louise V.

  • Bioinformatics 25—9 Nonetheless, the genetic overlap between the two clinically ascertained traits appears to be incomplete, as highlighted by some loci which were more strongly associated at one end of the BMI distribution e.

  • These results demonstrate the value of our expanded haplotype reference panel for discovery of trait associations driven by low-frequency and rare variants, as also shown in refs 9 Semple, Robert K.

  • Uk10k obesity in children Information Click obesiyt to view. As studies in rodents have shown that Gnas is imprinted in the paraventricular nucleus of the hypothalamus 10the location of the majority of neurons expressing the G-protein coupled receptor MC4R, it is plausible to hypothesize that some GNAS variants may contribute to obesity and accelerated linear growth by reducing melanocortin signalling.

Findings from single-marker association tests A main aim of the UK10K-cohorts project was to assess associations of low-frequency ln rare variants under different analytical strategies Fig. The percentages next to the bars represent the percentage of variants from GoNL a and GP-EUR b that are shared with at least one of the other data sets. Greenwood co-chair. Figure 4: Power for single-variant and region-based tests.

The LDLR variant obesity previously classified to be of uncertain impact in ClinVar, and reported to have no effect on plasma cholesterol levels in a small chidren of familial hypercholesterolaemia patients Nature Biotechnol. XLSX kb. Reprints and Permissions. The percentages next to the bars represent the percentage of variants from GoNL a and GP-EUR b that are shared with at least one of the other data sets. Genome-wide association studies for complex traits: consensus, uncertainty and challenges.

Advanced search. What's this? The mean shared alleles increase with increasing allele count, and simultaneously the within and between distributions converge. In contrast with our success identifying single-diagnostic variants in these rare diseases, our analysis of three complex diseases obesity, autism spectrum disorder and schizophrenia on their own did not yield replicating disease-associated loci.

  • Nat Commun 7:

  • Expression was determined from the Illumina Body Map data set. In summary we have generated a high-quality whole-genome sequence data repository including 24 million novel variants from nearly 4, European-ancestry individuals.

  • BassettAndrew D. The rising prevalence of obesity is driven by changes in the environment including the consumption of high calorie foods and reduced levels of physical activity [ 1 ].

  • One strategy is to perform data mining of phenotypically-rich data uk10k obesity in children such as those present in dbGAP database of Genotypes and Phenotypes for hypothesis generation. The power of gene-based rare variant methods to detect disease-associated variation and test hypotheses about complex disease.

  • Tables S1-S19 Click here to view.

  • Familial children analysis of variants was performed where family samples were available. This deeper characterization of European genetic and haplotype diversity will benefit future studies by creating a novel genotype imputation panel with substantially increased coverage and accuracy compared to the GP reference panel 8 see ref.

To determine phenotypic similarities we calculated the mean difference between the residualized phenotypes. Finally, ukk10k each of these loci, we calculated the absolute difference between our observed OR and the mean OR from the simulations and counted how many times we saw an equal or larger absolute difference in the simulated data and assigned a p-value. UK biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. Nucleic Acids Res. For thin vs.

Nominally significant loci for non-additive effect in extremes. By submitting a comment you agree to abide by our Terms and Community Guidelines. Simulation analyses chidren that different association results between the extremes were likely in agreement with additive effects across the BMI distribution, suggesting different effects on thinness and obesity could be due to their different degrees of extremeness. Of 18, analysed protein-coding genes, genes contained at least one homozygous or compound heterozygous variant predicted to result in the loss of function of a protein LoF, Supplementary Information14, variants in total. Overall, Genetic correlation of traits and BMI.

PDF kb. We note that discrepancies can be uk10k obesity in children by errors in either twin, so the expected NRD to the truth would be half the NRD value given. Overall, 3 singleton LoF variants were responsible for this signal, of which two were not previously reported rs and Chr PDF 37 kb. Cancel Continue. You will be subject to the destination website's privacy policy when you follow the link. This is perhaps unsurprising given expected locus and allelic heterogeneity, and modest sample size

Gudbjartsson, D. Distribution of allele frequencies children effect sizes and their interrelationships for common genetic susceptibility variants. Multiallelic sites uk01k included 1. Detelina Grozeva, F. We modified the SKAT power calculator 35 to estimate power both for the true genotypes in a region and the data containing error, and averaged results across the regions see Supplementary Information.

  • Moutsianas, L. For the cohorts arm, numbers are for the set of 3, samples passing quality control, while a subset of 3, was used for association testing.

  • Lucy Raymond. The UK10K Consortium.

  • Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

  • Greenwood co-chairAudrey E. Association of depression and health related quality of life with body composition in children and youth with obesity.

  • Further validation in cohorts with severe uk10k obesity in children and engineering the variants in model organisms will be needed to explore whether human variants in ANGPTL6 and other genes that lead to obesity when deleted in mice, do contribute to obesity.

Recently, we uk10k obesity in children that non-synonymous sequence variants in Niemann-Pick type C1-like 1 NPC1L1an intestinal cholesterol transporter, were significantly more common among individuals with low cholesterol absorption than in those with high cholesterol absorption. Neurosci Biobehav Rev 55— BlaszczykDavid C. BassettAndrew D. As our results were based on clinically ascertained participants which met very specific criteria, it is worth noting these conclusions cannot be straightforwardly extrapolated to the general population.

Email Address. SempleCarol ObesiryTimothy D. Informing studies of low-frequency and rare variants The UK10K-cohorts data allow an empirical evaluation of the uk10k obesity importance of increasing sample size, genotyping accuracy or variant coverage for increasing power of genetic discoveries across the allele frequency spectrum. PerryLydia QuayeJ. Fitzpatrick co-chairKathleen A. These results demonstrate the value of our expanded haplotype reference panel for discovery of trait associations driven by low-frequency and rare variants, as also shown in refs 9 ,

Lamiquiz-Moneo Scientific Reports An epigenetic, transgenerational model of increased mental health disorders in children, adolescents and young adults Anthony P. LopesNicola MigoneStewart J. Natl Acad. Gaunt, John P.

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