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Multicenter Study
. 2009 Apr;58(4):1018-22.
doi: 10.2337/db08-1551. Epub 2009 Jan 9.

Genome-wide scan for linkage to type 1 diabetes in 2,496 multiplex families from the Type 1 Diabetes Genetics Consortium

Patrick Concannon  1 , Wei-Min Chen, Cécile Julier, Grant Morahan, Beena Akolkar, Henry A Erlich, Joan E Hilner, Jørn Nerup, Concepcion Nierras, Flemming Pociot, John A Todd, Stephen S Rich; Type 1 Diabetes Genetics Consortium
Affiliations
Multicenter Study

Genome-wide scan for linkage to type 1 diabetes in 2,496 multiplex families from the Type 1 Diabetes Genetics Consortium

Patrick Concannon et al. Diabetes. 2009 Apr.

Abstract

Objective: Type 1 diabetes arises from the actions of multiple genetic and environmental risk factors. Considerable success at identifying common genetic variants that contribute to type 1 diabetes risk has come from genetic association (primarily case-control) studies. However, such studies have limited power to detect genes containing multiple rare variants that contribute significantly to disease risk.

Research design and methods: The Type 1 Diabetes Genetics Consortium (T1DGC) has assembled a collection of 2,496 multiplex type 1 diabetic families from nine geographical regions containing 2,658 affected sib-pairs (ASPs). We describe the results of a genome-wide scan for linkage to type 1 diabetes in the T1DGC family collection.

Results: Significant evidence of linkage to type 1 diabetes was confirmed at the HLA region on chromosome 6p21.3 (logarithm of odds [LOD] = 213.2). There was further evidence of linkage to type 1 diabetes on 6q that could not be accounted for by the major linkage signal at the HLA class II loci on chromosome 6p21. Suggestive evidence of linkage (LOD > or =2.2) was observed near CTLA4 on chromosome 2q32.3 (LOD = 3.28) and near INS (LOD = 3.16) on chromosome 11p15.5. Some evidence for linkage was also detected at two regions on chromosome 19 (LOD = 2.84 and 2.54).

Conclusions: Five non-HLA chromosome regions showed some evidence of linkage to type 1 diabetes. A number of previously proposed type 1 diabetes susceptibility loci, based on smaller ASP numbers, showed limited or no evidence of linkage to disease. Low-frequency susceptibility variants or clusters of loci with common alleles could contribute to the linkage signals observed.

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Figures

FIG. 1.
FIG. 1.
Genome-wide evidence for linkage to type 1 diabetes. Evidence for linkage was evaluated using Merlin, and LOD scores were calculated using the Kong and Cox linear NPL model (10,11). LOD scores are plotted on the vertical axis versus chromosomal position on the horizontal axis. LOD scores at region 15.5–110.5 cM on chromosome 6 are larger than four and not shown. The dotted horizontal line indicates a LOD of 2.2. The dashed line indicates a LOD of 3.6.
See this image and copyright information in PMC

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