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.

Figure 1

Multipoint linkage analysis, using GeneHunter-Plus, in merged T1D data set. LOD scores were calculated using ASM under an exponential model, with δ constrained between 0 and 2. LOD scores are plotted against chromosomal position (in cM).

Figure 2

Multipoint analysis of linkage to T1D on chromosome 10, conditioning on HLA. LOD scores are plotted against chromosomal position in centimorgans. Solid line indicates the baseline LOD score in all families for which HLA-typing data were available (N=453). Dotted line indicates LOD score in families in which all ASPs were HLA-DR3/DR4 heterozygotes (N=159). Dashed line indicates LOD score in families for which HLA-typing data were available, excluding families in which all ASPs were HLA-DR3/DR4 heterozygotes (N=294).

Figure 3

Multipoint analysis of linkage to T1D on chromosome 6, conditioning on age at onset. LOD scores are plotted against chromosomal position in centimorgans. Solid line indicates the baseline LOD score in all families for which age-at-onset data were available (N=682). Dashed line indicates LOD score in families in which all affected siblings had onset of disease at age ⩽11 years (N=287).