Reassessment of the type I diabetes association of the OAS1 locus

Abstract

To reassess the type I diabetes (T1D) association of the OAS1 locus, the Type I Diabetes Genetics Consortium (T1DGC) genotyped 11 tag single-nucleotide polymorphisms spanning B41 kb from the 5 0 to 3 0 flanking region. For each sample obtained from over 2000 affected sib-pair families from nine cohorts, the genotyping was performed on both the Illumina Golden Gate and Sequenom iPlex platforms. The data suggest that there may be a weak association with T1D for two OAS1 polymorphisms, rs3741981 and rs10774671, in populations of European descent. The OAS1 locus is close to a recently identified T1D-associated linkage disequilibrium (LD) block in human chromosome 12q24. Extended LD in populations earlier examined may account for the prior observation of an association of T1D with OAS1 variants. This possibility needs to be addressed further by fine mapping of the T1D association represented in 12q24.

Overview of the Type I Diabetes Genetics Consortium

“…These data6,7 appear in this Supplement to Genes and Immunity . The genes that were evaluated and presented here are IL4R ,8 SUMO4 ,9 CTLA4 ,10 IL2RA ,11 PTPN22 ,12 IRS1 and PAX4 ,13 TCF7 ,14 VDR ,15 IL12B ,16 and OAS1 ,17 either by complete tagging of the gene or by characterizing the most associated SNP 7. A standard analysis of all 19 genes that were available has also been conducted and presented in this Supplement 18…”

Alternative splicing in multiple sclerosis and other autoimmune diseases

“…Caution, however, needs to be taken when assessing the contribution of individual OAS1 SNPs to the development of MS and other autoimmune diseases, due to the longrange linkage disequilibrium between OAS1 polymorphisms, 68,71 as well as recently reported inconsistencies in association of OAS1 with type 1 diabetes. 72,73 KLC1. One report suggests a possible involvement of a particular variant of the kinesin light-chain 1 (KLC1) gene in protection against MS. 74 Kinesin is involved in trafficking of the myelin synthesis apparatus 74,75 (hence a direct connection to MS), and a protective SNP within intron 13 of the KLC1 gene has been hypothesized to affect splicing.…”

The Type I Diabetes Genetics Consortium ‘Rapid Response’ family-based candidate gene study: strategy, genes selection, and main outcome

“…Some analyses, however, identified suggestive associations in stratified data (based on age at onset of T1D, HLA status, or population subgroups) (for example Morahan et al . ;39 Qu et al .,40 this volume). These results may represent interesting features related to disease mechanisms or genetic interactions.…”

“…The test of this hypothesis of population-specific effects will require comparable large-scale studies in well-characterized T1D cohorts. Population-specific effects are generally thought as genetically determined or resulting from gene–environment interactions; in the case of OAS1 , the reported association was restricted to the Canadian population (Qu et al .,40 this volume). It was proposed that this may result from extended LD blocks in Canadian population compared with other Caucasian populations, extending to a known region of T1D association on chromosome 12q24, also detected in GWAS replication performed in this study.…”