Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease

Abstract

We densely genotyped, using 1000 Genomes Project pilot CEU and additional re-sequencing study variants, 183 reported immune-mediated disease non-HLA risk loci in 12,041 celiac disease cases and 12,228 controls. We identified 13 new celiac disease risk loci at genome wide significance, bringing the total number of known loci (including HLA) to 40. Multiple independent association signals are found at over a third of these loci, attributable to a combination of common, low frequency, and rare genetic variants. In comparison with previously available data such as HapMap3, our dense genotyping in a large sample size provided increased resolution of the pattern of linkage disequilibrium, and suggested localization of many signals to finer scale regions. In particular, 29 of 54 fine-mapped signals appeared localized to specific single genes - and in some instances to gene regulatory elements. We define a complex genetic architecture of risk regions, and refine risk signals, providing a next step towards elucidating causal disease mechanisms.

THEMIS and PTPRK in celiac intestinal mucosa: coexpression in disease and after in vitro gliadin challenge

“…More recently, the immunochip genotyping array has fine-mapped these regions and reported additional 13 susceptibility loci. 4 Many of the 39 non-HLA regions associated with the genetic risk to CD development are also shared with other autoimmune diseases; in particular, type 1 diabetes and rheumatoid arthritis.…”

“…The finemapping immunochip study revealed a major association peak spanning 2 kb (chr6: 128 332-128 335 kb) marked by rs55743914 (in the 3 0 -UTR of PTPRK) and a broader secondary signal (chr6: 128 307-128 339 kb) marked by rs72975916, tipping the scale in favor of PTPRK. 4 However, no functional confirmation of these candidate genes has been performed.…”

Age-dependent variation of genotypes in MHC II transactivator gene (CIITA) in controls and association to type 1 diabetes

“…3,12,13 Genome-wide significant association to celiac disease has recently been reported for markers in the CIITA gene. 14 In addition, increased susceptibility to myocardial infarction (MI), rheumatoid arthritis (RA) and multiple sclerosis (MS) has been demonstrated for a polymorphism (rs3087456) in the 5 0 region of type III CIITA. 15 However, this association has not always been replicated in later studies, and the outcome of the analysis is varying depending on which control group that has been used.…”

Local Joint Testing Improves Power and Identifies Hidden Heritability in Association Studies

“…In this work we investigate a local joint-testing approach to analysis of genetic data sets in which pairs of variants from the same locus are examined simultaneously for association with a phenotype. The motivation for our approach comes from the mounting evidence that complex traits are highly polygenic (Visscher et al 2012), that causal variants are not evenly distributed across the genome (Gusev et al 2013), that known associated loci often harbor multiple causal variants (Udler et al 2009;Fellay et al 2010;Trynka et al 2011;Wood et al 2011;Liu et al 2012;Patsopoulos et al 2013;Pickrell 2014), and that the underlying causal variants can be in linkage disequilibrium (LD) with each other (Corradin et al 2014).…”