Showing papers in "Nature Genetics in 2010"
TL;DR: Evidence is provided that the remaining heritability is due to incomplete linkage disequilibrium between causal variants and genotyped SNPs, exacerbated by causal variants having lower minor allele frequency than the SNPs explored to date.
Abstract: SNPs discovered by genome-wide association studies (GWASs) account for only a small fraction of the genetic variation of complex traits in human populations. Where is the remaining heritability? We estimated the proportion of variance for human height explained by 294,831 SNPs genotyped on 3,925 unrelated individuals using a linear model analysis, and validated the estimation method with simulations based on the observed genotype data. We show that 45% of variance can be explained by considering all SNPs simultaneously. Thus, most of the heritability is not missing but has not previously been detected because the individual effects are too small to pass stringent significance tests. We provide evidence that the remaining heritability is due to incomplete linkage disequilibrium between causal variants and genotyped SNPs, exacerbated by causal variants having lower minor allele frequency than the SNPs explored to date.
3,759 citations
Elizabeth K. Speliotes1, Elizabeth K. Speliotes2, Cristen J. Willer3, Sonja I. Berndt +410 more•Institutions (86)
TL;DR: Genetic loci associated with body mass index map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor, which may provide new insights into human body weight regulation.
Abstract: Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and similar to 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 x 10(-8)), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
2,632 citations
University of Kiel1, Cedars-Sinai Medical Center2, Wellcome Trust Sanger Institute3, University of Pennsylvania4, QIMR Berghofer Medical Research Institute5, Peninsula College of Medicine and Dentistry6, University of Edinburgh7, University of Cambridge8, University of Otago9, University of Washington10, University of Groningen11, University of Liège12, Harvard University13, Casa Sollievo della Sofferenza14, King's College London15, University of Chicago16, Yale University17, Johns Hopkins University18, Ludwig Maximilian University of Munich19, Charité20, McGill University21, Lille University of Science and Technology22, Cincinnati Children's Hospital Medical Center23, Ghent University24, Torbay Hospital25, Mater Health Services26, Université libre de Bruxelles27, RWTH Aachen University28, University of Utah29, Örebro University30, Leiden University31, University of Paris32, Technion – Israel Institute of Technology33, University of Western Australia34, Tel Aviv University35, University of Dundee36, University of Manchester37, University of Pittsburgh38, Royal Hospital for Sick Children39, Katholieke Universiteit Leuven40, Guy's and St Thomas' NHS Foundation Trust41, University of Bern42, University of Toronto43, University of Amsterdam44, Karolinska Institutet45, University of Zurich46, Université de Montréal47, Emory University48, Newcastle University49
TL;DR: A meta-analysis of six Crohn's disease genome-wide association studies and a series of in silico analyses highlighted particular genes within these loci implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP.
Abstract: We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.
2,482 citations
TL;DR: A variance component approach implemented in publicly available software, EMMA eXpedited (EMMAX), that reduces the computational time for analyzing large GWAS data sets from years to hours is reported.
Abstract: Although genome-wide association studies (GWASs) have identified numerous loci associated with complex traits, imprecise modeling of the genetic relatedness within study samples may cause substantial inflation of test statistics and possibly spurious associations. Variance component approaches, such as efficient mixed-model association (EMMA), can correct for a wide range of sample structures by explicitly accounting for pairwise relatedness between individuals, using high-density markers to model the phenotype distribution; but such approaches are computationally impractical. We report here a variance component approach implemented in publicly available software, EMMA eXpedited (EMMAX), that reduces the computational time for analyzing large GWAS data sets from years to hours. We apply this method to two human GWAS data sets, performing association analysis for ten quantitative traits from the Northern Finland Birth Cohort and seven common diseases from the Wellcome Trust Case Control Consortium. We find that EMMAX outperforms both principal component analysis and genomic control in correcting for sample structure.
2,316 citations
TL;DR: It is demonstrated that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
Abstract: Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.
2,022 citations
TL;DR: Exome sequencing of a small number of unrelated affected individuals is a powerful, efficient strategy for identifying the genes underlying rare mendelian disorders and will likely transform the genetic analysis of monogenic traits.
Abstract: We demonstrate the first successful application of exome sequencing to discover the gene for a rare mendelian disorder of unknown cause, Miller syndrome (MIM%263750). For four affected individuals in three independent kindreds, we captured and sequenced coding regions to a mean coverage of 40x and sufficient depth to call variants at approximately 97% of each targeted exome. Filtering against public SNP databases and eight HapMap exomes for genes with two previously unknown variants in each of the four individuals identified a single candidate gene, DHODH, which encodes a key enzyme in the pyrimidine de novo biosynthesis pathway. Sanger sequencing confirmed the presence of DHODH mutations in three additional families with Miller syndrome. Exome sequencing of a small number of unrelated affected individuals is a powerful, efficient strategy for identifying the genes underlying rare mendelian disorders and will likely transform the genetic analysis of monogenic traits.
1,980 citations
Benjamin F. Voight1, Benjamin F. Voight2, Laura J. Scott3, Valgerdur Steinthorsdottir4 +180 more•Institutions (53)
TL;DR: By combining genome-wide association data from 8,130 individuals with type 2 diabetes and 38,987 controls of European descent and following up previously unidentified meta-analysis signals, 12 new T2D association signals are identified with combined P < 5 × 10−8.
Abstract: By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
1,785 citations
Journal Article•
1,766 citations
TL;DR: It is shown that a relatively recent (>50 million years ago) genome-wide duplication has resulted in the transition from nine ancestral chromosomes to 17 chromosomes in the Pyreae, which partly support the monophyly of the ancestral paleohexaploidy of eudicots.
Abstract: We report a high-quality draft genome sequence of the domesticated apple (Malus × domestica). We show that a relatively recent (>50 million years ago) genome-wide duplication (GWD) has resulted in the transition from nine ancestral chromosomes to 17 chromosomes in the Pyreae. Traces of older GWDs partly support the monophyly of the ancestral paleohexaploidy of eudicots. Phylogenetic reconstruction of Pyreae and the genus Malus, relative to major Rosaceae taxa, identified the progenitor of the cultivated apple as M. sieversii. Expansion of gene families reported to be involved in fruit development may explain formation of the pome, a Pyreae-specific false fruit that develops by proliferation of the basal part of the sepals, the receptacle. In apple, a subclade of MADS-box genes, normally involved in flower and fruit development, is expanded to include 15 members, as are other gene families involved in Rosaceae-specific metabolism, such as transport and assimilation of sorbitol.
1,718 citations
TL;DR: This study identifies ∼3.6 million SNPs by sequencing 517 rice landraces and constructed a high-density haplotype map of the rice genome using a novel data-imputation method, demonstrating that an approach integrating second-generation genome sequencing and GWAS can be used as a powerful complementary strategy to classical biparental cross-mapping for dissecting complex traits in rice.
Abstract: Uncovering the genetic basis of agronomic traits in crop landraces that have adapted to various agro-climatic conditions is important to world food security. Here we have identified ∼ 3.6 million SNPs by sequencing 517 rice landraces and constructed a high-density haplotype map of the rice genome using a novel data-imputation method. We performed genome-wide association studies (GWAS) for 14 agronomic traits in the population of Oryza sativa indica subspecies. The loci identified through GWAS explained ∼ 36% of the phenotypic variance, on average. The peak signals at six loci were tied closely to previously identified genes. This study provides a fundamental resource for rice genetics research and breeding, and demonstrates that an approach integrating second-generation genome sequencing and GWAS can be used as a powerful complementary strategy to classical biparental cross-mapping for dissecting complex traits in rice.
1,718 citations
TL;DR: A compression approach is reported, called 'compressed MLM', that decreases the effective sample size of such datasets by clustering individuals into groups and a complementary approach, 'population parameters previously determined' (P3D), that eliminates the need to re-compute variance components.
Abstract: Mixed linear model (MLM) methods have proven useful in controlling for population structure and relatedness within genome-wide association studies. However, MLM-based methods can be computationally challenging for large datasets. We report a compression approach, called ‘compressed MLM’, that decreases the effective sample size of such datasets by clustering individuals into groups. We also present a complementary approach, ‘population parameters previously determined’ (P3D), that eliminates the need to re-compute variance components. We applied these two methods both independently and combined in selected genetic association datasets from human, dog and maize. The joint implementation of these two methods markedly reduced computing time and either maintained or improved statistical power. We used simulations to demonstrate the usefulness in controlling for substructure in genetic association datasets for a range of species and genetic architectures. We have made these methods available within an implementation of the software program TASSEL.
TL;DR: Recurrent somatic mutations affecting the polycomb-group oncogene EZH2, which encodes a histone methyltransferase responsible for trimethylating Lys27 of histone H3 (H3K27), are reported, consistent with the notion that EZh2 proteins with mutant Tyr641 have reduced enzymatic activity in vitro.
Abstract: Marco Marra and colleagues identify somatic mutations in EZH2 in diffuse large B-cell lymphomas and follicular lymphomas. EZH2 is a histone methyltransferase that participates in trimethylation of H3 Lys27 (H3K27) as part of the PRC2 complex. The mutations alter a single tyrosine residue in the SET domain of EZH2 and reduce the ability of PRC2 to trimethylate H3K27 in vitro.
Brigham and Women's Hospital1, Massachusetts Institute of Technology2, Harvard University3, National Institutes of Health4, University of Toronto5, University of Manchester6, Celera Corporation7, Leiden University8, Karolinska Institutet9, University of Texas at Austin10, Radboud University Nijmegen Medical Centre11, University of California, San Francisco12, VU University Amsterdam13, University of Leeds14, University of Oxford15, University of Aberdeen16, The Feinstein Institute for Medical Research17, Karolinska University Hospital18, University of Groningen19, University of California, Davis20, King's College21, University of Amsterdam22, University of Sheffield23, Hoffmann-La Roche24, University Health Network25, North Shore-LIJ Health System26, Broad Institute27
TL;DR: Seven new rheumatoid arthritis risk alleles were identified at genome-wide significance (P < 5 × 10−8) in an analysis of all 41,282 samples, and an additional 11 SNPs replicated at P < 0.05, suggesting that most represent genuine rhearatoid arthritisrisk alleles.
Abstract: To identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768 rheumatoid arthritis cases and 8,806 controls. Of 34 SNPs selected for replication, 7 new rheumatoid arthritis risk alleles were identified at genome-wide significance (P < 5 x 10(-8)) in an analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5 and PXK. We also refined associations at two established rheumatoid arthritis risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed rheumatoid arthritis risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P < 0.05, many of which are validated autoimmune risk alleles, suggesting that most represent genuine rheumatoid arthritis risk alleles.
TL;DR: The results strongly suggest that mutations in MLL2, which encodes a Trithorax-group histone methyltransferase, are a major cause of Kabuki syndrome.
Abstract: We demonstrate the successful application of exome sequencing to discover a gene for an autosomal dominant disorder, Kabuki syndrome (OMIM%147920). We subjected the exomes of ten unrelated probands to massively parallel sequencing. After filtering against existing SNP databases, there was no compelling candidate gene containing previously unknown variants in all affected individuals. Less stringent filtering criteria allowed for the presence of modest genetic heterogeneity or missing data but also identified multiple candidate genes. However, genotypic and phenotypic stratification highlighted MLL2, which encodes a Trithorax-group histone methyltransferase: seven probands had newly identified nonsense or frameshift mutations in this gene. Follow-up Sanger sequencing detected MLL2 mutations in two of the three remaining individuals with Kabuki syndrome (cases) and in 26 of 43 additional cases. In families where parental DNA was available, the mutation was confirmed to be de novo (n = 12) or transmitted (n = 2) in concordance with phenotype. Our results strongly suggest that mutations in MLL2 are a major cause of Kabuki syndrome.
University of North Carolina at Chapel Hill1, University of Texas Health Science Center at Houston2, University of Cambridge3, University of Pavia4, University of Milan5, Stanford University6, Kaiser Permanente7, National Institutes of Health8, University of Washington9, Wake Forest University10, Cedars-Sinai Medical Center11, Group Health Cooperative12, Lund University13, University of Michigan14, National Institute for Health and Welfare15, University of Helsinki16, Boston University17, University of Chicago18, International Agency for Research on Cancer19, Charles University in Prague20, Institut Gustave Roussy21, French Institute of Health and Medical Research22, University of Padua23, University of Glasgow24, Palacký University, Olomouc25, Trinity College, Dublin26, National and Kapodistrian University of Athens27, Newcastle University28, University of Aberdeen29, University of Turin30, Nofer Institute of Occupational Medicine31, Russian Academy32, University of Exeter33, Massachusetts Institute of Technology34, Harvard University35, Broad Institute36, VU University Amsterdam37, Erasmus University Rotterdam38, University of Virginia39, Virginia Commonwealth University40, University of Pennsylvania41, Duke University42, Tufts University43, University of Ioannina44
TL;DR: A meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium found the strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3, and three loci associated with number of cigarettes smoked per day were identified.
Abstract: Consistent but indirect evidence has implicated genetic factors in smoking behavior1,2. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], b = 1.03, standard error (s.e.) = 0.053, beta = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], b = 0.367, s. e. = 0.059, beta = 5.7 x 10(-10); and rs1028936[A], b = 0.446, s. e. = 0.074, beta = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], b = 0.333, s. e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.
TL;DR: It is demonstrated that a point mutation in OsSPL14 perturbs OsmiR156-directed regulation of OsSPl14, generating an 'ideal' rice plant with a reduced tiller number, increased lodging resistance and enhanced grain yield.
Abstract: Increasing crop yield is a major challenge for modern agriculture. The development of new plant types, which is known as ideal plant architecture (IPA), has been proposed as a means to enhance rice yield potential over that of existing high-yield varieties. Here, we report the cloning and characterization of a semidominant quantitative trait locus, IPA1 (Ideal Plant Architecture 1), which profoundly changes rice plant architecture and substantially enhances rice grain yield. The IPA1 quantitative trait locus encodes OsSPL14 (SOUAMOSA PROMOTER BINDING PROTEIN-LIKE 14) and is regulated by microRNA (miRNA) OsmiR156 in vivo. We demonstrate that a point mutation in OsSPL14 perturbs OsmiR156-directed regulation of OsSPL14, generating an 'ideal' rice plant with a reduced tiller number, increased lodging resistance and enhanced grain yield. Our study suggests that OsSPL14 may help improve rice grain yield by facilitating the breeding of new elite rice varieties.
TL;DR: In this article, the finding of homozygous EZH2 mutations in 9 of 12 individuals with 7q acquired uniparental disomy was described, and the mutations resulted in premature chain termination or direct abrogation of histone methyltransferase activity.
Abstract: Abnormalities of chromosome 7q are common in myeloid malignancies, but no specific target genes have yet been identified. Here, we describe the finding of homozygous EZH2 mutations in 9 of 12 individuals with 7q acquired uniparental disomy. Screening of a total of 614 individuals with myeloid disorders revealed 49 monoallelic or biallelic EZH2 mutations in 42 individuals; the mutations were found most commonly in those with myelodysplastic/myeloproliferative neoplasms (27 out of 219 individuals, or 12%) and in those with myelofibrosis (4 out of 30 individuals, or 13%). EZH2 encodes the catalytic subunit of the polycomb repressive complex 2 (PRC2), a highly conserved histone H3 lysine 27 (H3K27) methyltransferase that influences stem cell renewal by epigenetic repression of genes involved in cell fate decisions. EZH2 has oncogenic activity, and its overexpression has previously been causally linked to differentiation blocks in epithelial tumors. Notably, the mutations we identified resulted in premature chain termination or direct abrogation of histone methyltransferase activity, suggesting that EZH2 acts as a tumor suppressor for myeloid malignancies.
TL;DR: A high level of linkage disequilibrium in the soybean genome is identified, suggesting that marker-assisted breeding of soybean will be less challenging than map-based cloning and to facilitate future breeding and quantitative trait analysis.
Abstract: We report a large-scale analysis of the patterns of genome-wide genetic variation in soybeans. We re-sequenced a total of 17 wild and 14 cultivated soybean genomes to an average of approximately ×5 depth and >90% coverage using the Illumina Genome Analyzer II platform. We compared the patterns of genetic variation between wild and cultivated soybeans and identified higher allelic diversity in wild soybeans. We identified a high level of linkage disequilibrium in the soybean genome, suggesting that marker-assisted breeding of soybean will be less challenging than map-based cloning. We report linkage disequilibrium block location and distribution, and we identified a set of 205,614 tag SNPs that may be useful for QTL mapping and association studies. The data here provide a valuable resource for the analysis of wild soybeans and to facilitate future breeding and quantitative trait analysis.
University of Oxford1, King's College London2, University of Manchester3, Radboud University Nijmegen4, Wellcome Trust Sanger Institute5, University of London6, University of Sheffield7, Trinity College, Dublin8, Wellcome Trust9, Medical University of Graz10, University of Erlangen-Nuremberg11, Queen Mary University of London12, Western Infirmary13, Karolinska Institutet14, St George's, University of London15, University of Dundee16, University of Göttingen17, University of Gothenburg18, Sapienza University of Rome19, University of Cambridge20, University of Münster21, Moorfields Eye Hospital22, University College London23, University of Bristol24
TL;DR: These findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis and report compelling evidence for an interaction between the HLA-C and ERAP1 loci.
Abstract: To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10⁻⁸ and two loci with a combined P < 5 × 10⁻⁷). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10⁻⁶). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.
Queen Mary University of London1, University of Groningen2, Utrecht University3, University of Debrecen4, National Institutes of Health5, University of Milan6, University Medical Center Utrecht7, Hungarian Academy of Sciences8, Casa Sollievo della Sofferenza9, King's College London10, Wellcome Trust Sanger Institute11, University of Tampere12, Trinity College, Dublin13, Mater Misericordiae University Hospital14, Sapienza University of Rome15, Leiden University16, Mayo Clinic17, University of California, Los Angeles18, University of Helsinki19, University of Naples Federico II20, Beckman Research Institute21, University of Milano-Bicocca22
TL;DR: This article performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects, and genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls.
Abstract: We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression.
Iris M. Heid1, Anne U. Jackson2, Joshua C. Randall3, Tthomas W. Winkler1 +352 more•Institutions (90)
TL;DR: A meta-analysis of genome-wide association studies for WHR adjusted for body mass index provides evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
Abstract: Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
TL;DR: This work identified and validated unique non-synonymous de novo mutations in nine genes and identified six likely to be pathogenic based on gene function, evolutionary conservation and mutation impact that could explain the majority of all mental retardation cases in the population.
Abstract: The per-generation mutation rate in humans is high. De novo mutations may compensate for allele loss due to severely reduced fecundity in common neurodevelopmental and psychiatric diseases, explaining a major paradox in evolutionary genetic theory. Here we used a family based exome sequencing approach to test this de novo mutation hypothesis in ten individuals with unexplained mental retardation. We identified and validated unique non-synonymous de novo mutations in nine genes. Six of these, identified in six different individuals, are likely to be pathogenic based on gene function, evolutionary conservation and mutation impact. Our findings provide strong experimental support for a de novo paradigm for mental retardation. Together with de novo copy number variation, de novo point mutations of large effect could explain the majority of all mental retardation cases in the population.
TL;DR: In this paper, the authors characterized the transcriptional reorganization of large intergenic non-coding RNAs (lincRNAs) that occurs upon derivation of human iPSCs and identified numerous lincRNA whose expression is linked to pluripotency.
Abstract: The conversion of lineage-committed cells to induced pluripotent stem cells (iPSCs) by reprogramming is accompanied by a global remodeling of the epigenome, resulting in altered patterns of gene expression. Here we characterize the transcriptional reorganization of large intergenic non-coding RNAs (lincRNAs) that occurs upon derivation of human iPSCs and identify numerous lincRNAs whose expression is linked to pluripotency. Among these, we defined ten lincRNAs whose expression was elevated in iPSCs compared with embryonic stem cells, suggesting that their activation may promote the emergence of iPSCs. Supporting this, our results indicate that these lincRNAs are direct targets of key pluripotency transcription factors. Using loss-of-function and gain-of-function approaches, we found that one such lincRNA (lincRNA-RoR) modulates reprogramming, thus providing a first demonstration for critical functions of lincRNAs in the derivation of pluripotent stem cells.
TL;DR: In this article, the quantitative trait locus WFP (WEALTHY FARMER PANICLE) encodes OsSPL�4 (SQUAMOSA PROMOTER BINDING PROTEIN-LIKE 4, also known as IPA�).
Abstract: �Identification of alleles that improve crop production and lead to higher-yielding varieties are needed for food security. Here we show that the quantitative trait locus WFP (WEALTHY FARMER’S PANICLE) encodes OsSPL�4 (SQUAMOSA PROMOTER BINDING PROTEIN-LIKE � 4, also known as IPA�). Higher expression of OsSPL14 in the reproductive stage promotes panicle branching and higher grain yield in rice. OsSPL14 controls shoot branching in the vegetative stage and is affected by microRNA excision. We also demonstrate the feasibility of using the OsSLP14 WFP allele to increase rice crop yield. Introduction of the highyielding OsSPL14 WFP allele into the standard rice variety
Johns Hopkins University1, University of Freiburg2, University of Lübeck3, University of Regensburg4, University of Washington5, University of Maryland, Baltimore6, Washington University in St. Louis7, Boston University8, University of Iceland9, Memorial Hospital of South Bend10, National Institutes of Health11, Erasmus University Rotterdam12, University of Greifswald13, McMaster University14, Mayo Clinic15, University of Mainz16, Wake Forest University17, Harvard University18, Swiss Tropical and Public Health Institute19, University of Basel20, Innsbruck Medical University21, Leipzig University22, Western General Hospital23, University of Texas Health Science Center at Houston24, Cedars-Sinai Medical Center25, University of Pittsburgh26, Ludwig Maximilian University of Munich27, University of Ulm28, University of Edinburgh29, University of Split30, University of Zagreb31, Uppsala University32, University of Kiel33, University of London34, University of Oxford35, Amgen36, University of Michigan37, University of Geneva38, Capital Medical University39, University of California, San Francisco40, Heidelberg University41
TL;DR: The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry to identify new susceptibility loci for reduced renal function as estimated by serum creatinine, serum cystatin c and CKD.
Abstract: Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
TL;DR: The genome-wide association study of 2,000 individuals with Parkinson's disease and unaffected controls confirmed associations with SNCA and MAPT and detected a new association with the HLA region, which was uniform across all genetic and environmental risk strata and was strong in sporadic and late-onset disease.
Abstract: Haydeh Payami and colleagues report results of a genome-wide association study for Parkinson's disease. They identify common variants in the HLA region associated with the late-onset sporadic form of the disease and replicate published associations with SNCA, MAPT and GAK.
TL;DR: It is shown that species-specific transposable elements have substantially altered the transcriptional circuitry of pluripotent stem cells and have wired new genes into the core regulatory network of embryonic stem cells.
Abstract: Detection of new genomic control elements is critical in understanding transcriptional regulatory networks in their entirety. We studied the genome-wide binding locations of three key regulatory proteins (POU5F1, also known as OCT4; NANOG; and CTCF) in human and mouse embryonic stem cells. In contrast to CTCF, we found that the binding profiles of OCT4 and NANOG are markedly different, with only approximately 5% of the regions being homologously occupied. We show that transposable elements contributed up to 25% of the bound sites in humans and mice and have wired new genes into the core regulatory network of embryonic stem cells. These data indicate that species-specific transposable elements have substantially altered the transcriptional circuitry of pluripotent stem cells.
TL;DR: Analysis of EZH2 deletions, missense and frameshift mutations strongly suggests that EZh2 is a tumor suppressor in myelodysplastic syndromes.
Abstract: In myelodysplastic syndromes (MDS), deletions of chromosome 7 or 7q are common and correlate with a poor prognosis. The relevant genes on chromosome 7 are unknown. We report here that EZH2, located at 7q36.1, is frequently targeted in MDS. Analysis of EZH2 deletions, missense and frameshift mutations strongly suggests that EZH2 is a tumor suppressor. As EZH2 functions as a histone methyltransferase, abnormal histone modification may contribute to epigenetic deregulation in MDS.
TL;DR: The first genome-wide analysis of transcriptional interactions using the mouse globin genes in erythroid tissues reveals extensive and preferential intra- and interchromosomal transcription interactomes, establishing a new gene expression paradigm.
Abstract: Peter Fraser and colleagues report a genome-wide analysis of transcription interactions involving the globin genes in mouse erythroid cells. They demonstrate that the transcription factor Klf1 mediates preferential co-associations between genes it regulates.
TL;DR: Previously identified breast cancer susceptibility loci were found to show larger effect sizes in this study of familial breast cancer cases than in previous population-based studies, consistent with polygenic susceptibility to the disease.
Abstract: Breast cancer is the most common cancer in women in developed countries. To identify common breast cancer susceptibility alleles, we conducted a genome-wide association study in which 582,886 SNPs were genotyped in 3,659 cases with a family history of the disease and 4,897 controls. Promising associations were evaluated in a second stage, comprising 12,576 cases and 12,223 controls. We identified five new susceptibility loci, on chromosomes 9, 10 and 11 (P = 4.6 x 10(-7) to P = 3.2 x 10(-15)). We also identified SNPs in the 6q25.1 (rs3757318, P = 2.9 x 10(-6)), 8q24 (rs1562430, P = 5.8 x 10(-7)) and LSP1 (rs909116, P = 7.3 x 10(-7)) regions that showed more significant association with risk than those reported previously. Previously identified breast cancer susceptibility loci were also found to show larger effect sizes in this study of familial breast cancer cases than in previous population-based studies, consistent with polygenic susceptibility to the disease.