The imprinted DLK1-MEG3 gene region on chromosome 14q32.2 alters susceptibility to type 1 diabetes

Abstract

Genome-wide association (GWA) studies to map common disease susceptibility loci have been hugely successful, with over 300 reproducibly associated loci reported to date. However, these studies have not yet provided convincing evidence for any susceptibility locus subject to parent-of-origin effects. Using imputation to extend existing GWA datasets, we have obtained robust evidence at rs941576 for paternally inherited risk of type 1 diabetes (T1D; ratio of allelic effects for paternal versus maternal transmissions = 0.75; 95% confidence interval (CI) = 0.71-0.79). This marker is in the imprinted region of chromosome 14q32.2, which contains the functional candidate gene DLK1. Our meta-analysis also provided support at genome-wide significance for a T1D locus at chromosome 19p13.2. The highest association was at marker rs2304256 (odds ratio (OR) = 0.86; 95%CI = 0.82-0.90) in the TYK2 gene, which has previously been associated with systemic lupus erythematosus and multiple sclerosis.

Figure 1

The imprinted region on chromosome 14q32.2. The region shown is delimited by the most distant genes known to be imprinted 8 with positions according to Hs_NCBI36. The top panel shows -log 10(p) from 1 degree of freedom tests of association with SNPs across the region. SNPs which were directly genotyped are in black, SNPs imputed from HapMap in blue. The second panel shows the location and orientation of genes in the region. Paternally expressed genes are shown in blue, maternally expressed genes in black. The third panel shows recombination rates (cm/Mb) from HapMap. A solid green line shows the location of rs941576 in all panels for reference.