A human type 1 diabetes susceptibility locus maps to chromosome 21q22.3.
OBJECTIVE
The Type 1 Diabetes Genetics Consortium (T1DGC) has assembled and genotyped a large collection of multiplex families for the purpose of mapping genomic regions linked to type 1 diabetes. In the current study, we tested for evidence of loci associated with type 1 diabetes utilizing genome-wide linkage scan data and family-based association methods.


METHODS
A total of 2,496 multiplex families with type 1 diabetes were genotyped with a panel of 6,090 single nucleotide polymorphisms (SNPs). Evidence of association to disease was evaluated by the pedigree disequilibrium test. Significant results were followed up by genotyping and analyses in two independent sets of samples: 2,214 parent-affected child trio families and a panel of 7,721 case and 9,679 control subjects. RESULTS- Three of the SNPs most strongly associated with type 1 diabetes localized to previously identified type 1 diabetes risk loci: INS, IFIH1, and KIAA0350. A fourth strongly associated SNP, rs876498 (P = 1.0 x 10(-4)), occurred in the sixth intron of the UBASH3A locus at chromosome 21q22.3. Support for this disease association was obtained in two additional independent sample sets: families with type 1 diabetes (odds ratio [OR] 1.06 [95% CI 1.00-1.11]; P = 0.023) and case and control subjects (1.14 [1.09-1.19]; P = 7.5 x 10(-8)).


CONCLUSIONS
The T1DGC 6K SNP scan and follow-up studies reported here confirm previously reported type 1 diabetes associations at INS, IFIH1, and KIAA0350 and identify an additional disease association on chromosome 21q22.3 in the UBASH3A locus (OR 1.10 [95% CI 1.07-1.13]; P = 4.4 x 10(-12)). This gene and its flanking regions are now validated targets for further resequencing, genotyping, and functional studies in type 1 diabetes.
Concannon
Patrick
P
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA. pjc6n@virginia.edu
Onengut-Gumuscu
Suna
S
Todd
John A
JA
Smyth
Deborah J
DJ
Pociot
Flemming
F
Bergholdt
Regine
R
Akolkar
Beena
B
Erlich
Henry A
HA
Hilner
Joan E
JE
Julier
Cécile
C
Morahan
Grant
G
Nerup
Jørn
J
Nierras
Concepcion R
CR
Chen
Wei-Min
WM
Rich
Stephen S
SS
D002874:Chromosome Mapping / Q000379:methods; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide