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


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.
Concannon
Patrick
P
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA. patcon@virginia.edu
Chen
Wei-Min
WM
Julier
Cécile
C
Morahan
Grant
G
Akolkar
Beena
B
Erlich
Henry A
HA
Hilner
Joan E
JE
Nerup
Jørn
J
Nierras
Concepcion
C
Pociot
Flemming
F
Todd
John A
JA
Rich
Stephen S
SS
D002874:Chromosome Mapping; D002877:Chromosomes, Human; D002886:Chromosomes, Human, Pair 17; D041321:Chromosomes, Human, X; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D015894:Genome, Human; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D008126:Lod Score; D018570:Risk Assessment
D005819:Genetic Markers; D006680:HLA Antigens