Showing papers by "Armand Valsesia published in 2010"
••
TL;DR: It is concluded that the heritability void left by genome-wide association studies will not be accounted for by common CNVs, and 30 loci with CNVs that are candidates for influencing disease susceptibility are identified.
Abstract: Structural variations of DNA greater than 1 kilobase in size account for most bases that vary among human genomes, but are still relatively under-ascertained. Here we use tiling oligonucleotide microarrays, comprising 42 million probes, to generate a comprehensive map of 11,700 copy number variations (CNVs) greater than 443 base pairs, of which most (8,599) have been validated independently. For 4,978 of these CNVs, we generated reference genotypes from 450 individuals of European, African or East Asian ancestry. The predominant mutational mechanisms differ among CNV size classes. Retrotransposition has duplicated and inserted some coding and non-coding DNA segments randomly around the genome. Furthermore, by correlation with known trait-associated single nucleotide polymorphisms (SNPs), we identified 30 loci with CNVs that are candidates for influencing disease susceptibility. Despite this, having assessed the completeness of our map and the patterns of linkage disequilibrium between CNVs and SNPs, we conclude that, for complex traits, the heritability void left by genome-wide association studies will not be accounted for by common CNVs.
1,892 citations
••
Nicholas John Craddock1, Matthew E. Hurles2, Niall Cardin3, Richard D. Pearson3 +232 more•Institutions (34)
TL;DR: A large, direct genome-wide study of association between CNVs and eight common human diseases concludes that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis ofcommon human diseases.
Abstract: Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed approximately 19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated approximately 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
765 citations
••
Imperial College London1, University Hospital of Lausanne2, University of Lausanne3, Ludwig Institute for Cancer Research4, Swiss Institute of Bioinformatics5, École Polytechnique Fédérale de Lausanne6, Pasteur Institute7, Harvard University8, French Institute of Health and Medical Research9, Nancy-Université10, Boston Children's Hospital11, University of Cambridge12, University Medical Center Utrecht13, Necker-Enfants Malades Hospital14, University of Antwerp15, university of lille16, McGill University17, GlaxoSmithKline18, University of Tartu19, Estonian Biocentre20, University of Oulu21, Wellcome Trust Centre for Human Genetics22, University of Oxford23, Massachusetts Institute of Technology24, Wellcome Trust Sanger Institute25
TL;DR: A highly penetrant form of obesity is reported, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits, which highlights a promising strategy for identifying missing heritability in obesity and other complex traits.
Abstract: Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.
468 citations
••
French Institute of Health and Medical Research1, University of Lausanne2, Swiss Institute of Bioinformatics3, Ludwig Institute for Cancer Research4, Leiden University5, Gulf Coast Regional Blood Center6, Radboud University Nijmegen Medical Centre7, University of Copenhagen8, University of Zurich9, University Hospital Regensburg10, University Hospital of Lausanne11, GlaxoSmithKline12
TL;DR: An unexpected protective HLA haplotype is found near HLA-DQA2, which suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.
Abstract: Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10(-8)). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 x 10(-43)) and DRB1*1301-DQB1*0603 (P < 3 x 10(-7)). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10(-14)). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.
180 citations