Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls

Abstract

Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to play 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 ~19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated ~50% of all common CNVs larger than 500bp. 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, though in each case the locus had previously been identified in SNP-based studies, reflecting our observation that the majority of common CNVs which 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 which can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.

The evolutionary adaptation of the C282Y mutation to culture and climate during the European Neolithic

“…Models need to take into account the role of culture, human life history, niche construction and climates associated with migration routes and local habitation. A massive effort is underway in health and genetics to identify potentially deleterious alleles for a myriad of contemporary human diseases (Craddock et al, 2010), but we may miss the mark by only assuming contemporary cause and effect. Understanding the origins, history and possible ancestral adaptive value of alleles will shed more light on the relationship between genes, culture and the environment thereby advancing genetic research and in the process contributing to our understanding of the genetic basis of human health.…”

Insulin gene VNTR polymorphisms −2221MspI and −23HphI are associated with type 1 diabetes and latent autoimmune diabetes in adults: a meta-analysis

“…The cited works lacked the statistical power required to truly explore the effect of INS VNTRs on the risks of T1D and LADA. In addition, previously GWAS [38][39][40][41] reported the association between INS VNTR and T1D. However, owing to technical limitations, the results of Barrett et al [10] cannot clarify whether the INS VNTR itself, or another nearby genetic variant (i.e., rs711134), is actually causal.…”

A description of large-scale metabolomics studies: increasing value by combining metabolomics with genome-wide SNP genotyping and transcriptional profiling

“…This is most probably due to two reasons: first, the precise detection of CNVs represents a methodically more challenging undertaking compared to the differentiation of SNP alleles. Secondly, a key publication in 2010 described a GWAS of CNVs in 16 000 cases of eight common human diseases and 3000 shared controls (Wellcome Trust Case Control Consortium et al 2010). The authors typed these 19 000 individuals into distinct copy-number classes at 3432 polymorphic CNVs, thereby including an estimated w50% of all common CNVs with a size of larger than 500 bps.…”