A search for type 1 diabetes susceptibility genes in families from the United Kingdom

Abstract

Genetic analysis of a mouse model of major histocompatability complex (MHC)-associated autoimmune type 1 (insulin-dependent) diabetes mellitus (IDDM) has shown that the disease is caused by a combination of a major effect at the MHC and at least ten other susceptibility loci elsewhere in the genome. A genome-wide scan of 93 affected sibpair families (ASP) from the UK (UK93) indicated a similar genetic basis for human type 1 diabetes, with the major genetic component at the MHC locus (IDDM1) explaining 34% of the familial clustering of the disease (lambda(s)=2.5; refs 3,4). In the present report, we have analysed a further 263 multiplex families from the same population (UK263) to provide a total UK data set of 356 ASP families (UK356). Only four regions of the genome outside IDDM1/MHC, which was still the only major locus detected, were not excluded at lambda(s)=3 and lod=-2, of which two showed evidence of linkage: chromosome 10p13-p11 (maximum lod score (MLS)=4.7, P=3x10(-6), lambda(s)=1.56) and chromosome 16q22-16q24 (MLS=3.4, P=6.5x10(-5), lambda(s)=1.6). These and other novel regions, including chromosome 14q12-q21 and chromosome 19p13-19q13, could potentially harbour disease loci but confirmation and fine mapping cannot be pursued effectively using conventional linkage analysis. Instead, more powerful linkage disequilibrium-based and haplotype mapping approaches must be used; such data is already emerging for several type 1 diabetes loci detected initially by linkage.

A functional polymorphism (1858C/T) in the PTPN22 gene is linked and associated with type I diabetes in multiplex families

“…In the case of SLE, Figure 1 Evidence for linkage to T1D on chromosomes 3 and 21 conditional on PTPN22 SNP genotype. Multipoint linkage analysis was conducted using the S-pairs scoring function in Genehunter Plus and genotype data from Mein et al 6 Maximized LOD scores were calculated using an exponential model with d constrained between 0 and 2. 21 For stratified analysis, individual families were given weights of 1 or 0 and the LOD scores were recalculated using these assigned weights.…”

“…3,4 More than 1000 multiplex T1D families have been studied by genome scans for evidence of linkage to T1D. [5][6][7][8][9] Although these linkage approaches have detected loci with demonstrable effects on familial clustering of T1D, the modest sibling risk ratios (eg, lsr1.3) predicted for several of these loci suggest that prohibitively large numbers of families may be required to derive a complete description of genetic risk for T1D from linkage studies alone. An alternative to linkage studies is direct investigation of candidate genes or single-nucleotide polymorphisms (SNPs) for allelic association with T1D in either a case-control or family-based design.…”

Genetic linkage and association studies of Type I diabetes: challenges and rewards

“…Later studies showed that HLA class II loci, including HLA-DRB1, DQB1 and DQA1, were even more strongly associated with diabetes. As a result of several genome-wide linkage screens [61,62,73,83], it is now clear that the most potent diabetes-predisposing genes in the entire genome are located in the HLA region on chromosome 6p21.3 (these HLA region susceptibility genes are now collectively referred to as IDDM1). However, because of the extensive degree of linkage disequilibrium among the various HLA loci, it has been difficult to determine which precise locus produces diabetes susceptibility (for review, see [92]).…”

Evidence of at least two type 1 diabetes susceptibility genes in the HLA complex distinct from HLA-DQB1, -DQA1 and –DRB1

“…Many chromosomal regions have been suggested to harbour disease susceptibility genes. 1,2 The strongest genetic contribution in humans has been mapped to the HLA complex on the short arm of chromosome 6 (IDDM1). The HLA class II region genes DQB1, DQA1 and DRB1 are of primary importance for disease susceptibility and resistance.…”