Seven Regions of the Genome Show Evidence of Linkage to Type 1 Diabetes in a Consensus Analysis of 767 Multiplex Families

Abstract

Type 1 diabetes (T1D) is a genetically complex disorder of glucose homeostasis that results from the autoimmune destruction of the insulin-secreting cells of the pancreas. Two previous whole-genome scans for linkage to T1D in 187 and 356 families containing affected sib pairs (ASPs) yielded apparently conflicting results, despite partial overlap in the families analyzed. However, each of these studies individually lacked power to detect loci with locus-specific disease prevalence/sib-risk ratios (lambda(s)) <1.4. In the present study, a third genome scan was performed using a new collection of 225 multiplex families with T1D, and the data from all three of these genome scans were merged and analyzed jointly. The combined sample of 831 ASPs, all with both parents genotyped, provided 90% power to detect linkage for loci with lambda(s) = 1.3 at P=7.4x10(-4). Three chromosome regions were identified that showed significant evidence of linkage (P<2.2x10(-5); LOD scores >4), 6p21 (IDDM1), 11p15 (IDDM2), 16q22-q24, and four more that showed suggestive evidence (P<7.4x10(-4), LOD scores > or =2.2), 10p11 (IDDM10), 2q31 (IDDM7, IDDM12, and IDDM13), 6q21 (IDDM15), and 1q42. Exploratory analyses, taking into account the presence of specific high-risk HLA genotypes or affected sibs' ages at disease onset, provided evidence of linkage at several additional sites, including the putative IDDM8 locus on chromosome 6q27. Our results indicate that much of the difficulty in mapping T1D susceptibility genes results from inadequate sample sizes, and the results point to the value of future international collaborations to assemble and analyze much larger data sets for linkage in complex diseases.

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

“…The DNA samples from families used for the current analysis have previously been studied by genome-wide scan with microsatellite markers, 7,8 as well as by HLA typing, allowing exploratory analyses for possible interaction between PTPN22 and other loci in the genome. A comparison of the transmission of HLA haplotypes between affected offspring homozygous for the 1858C allele and those either heterozygous or homozygous for the 1858T allele revealed no significant differences in transmission ratio.…”

“…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.…”

Dense genome‐wide linkage analysis of rheumatoid arthritis, including covariates

“…It may be that the power of replication with the samples presently available is low and replication with samples of similar size would not be a practical way to confirm true RA gene regions. Both chromosome 2 regions and the chromosome 12 distal region have also been detected in other autoimmune diseases associated with RA, such as type 1 diabetes (34,35) and autoimmune thyroiditis (36), respectively. This suggests that these regions might harbor genes involved in common "autoimmune pathways.…”

The effect of HLA class II, insulin and CTLA4 gene regions on the development of humoral beta cell autoimmunity

“…Although the HLA gene region accounts for approximately half of the genetic disease susceptibility, a number of other 'minor' loci also contribute [9][10][11]. The insulin gene (INS; IDDM2) and the cytotoxic T-lymphocyteassociated protein 4 (CTLA4) gene regions (IDDM12) are considered as confirmed non-HLA disease susceptibility loci [12][13][14][15][16].…”