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Confirmation of novel type 1 diabetes risk loci in families.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Cooper, JD 
Howson, JMM 
Smyth, D 
Walker, NM 
Stevens, H 

Abstract

AIMS/HYPOTHESIS: Over 50 regions of the genome have been associated with type 1 diabetes risk, mainly using large case/control collections. In a recent genome-wide association (GWA) study, 18 novel susceptibility loci were identified and replicated, including replication evidence from 2,319 families. Here, we, the Type 1 Diabetes Genetics Consortium (T1DGC), aimed to exclude the possibility that any of the 18 loci were false-positives due to population stratification by significantly increasing the statistical power of our family study. METHODS: We genotyped the most disease-predicting single-nucleotide polymorphisms at the 18 susceptibility loci in 3,108 families and used existing genotype data for 2,319 families from the original study, providing 7,013 parent-child trios for analysis. We tested for association using the transmission disequilibrium test. RESULTS: Seventeen of the 18 susceptibility loci reached nominal levels of significance (p < 0.05) in the expanded family collection, with 14q24.1 just falling short (p = 0.055). When we allowed for multiple testing, ten of the 17 nominally significant loci reached the required level of significance (p < 2.8 × 10(-3)). All susceptibility loci had consistent direction of effects with the original study. CONCLUSIONS/INTERPRETATION: The results for the novel GWA study-identified loci are genuine and not due to population stratification. The next step, namely correlation of the most disease-associated genotypes with phenotypes, such as RNA and protein expression analyses for the candidate genes within or near each of the susceptibility regions, can now proceed.

Description

Keywords

Diabetes Mellitus, Type 1, Genetic Loci, Genetic Predisposition to Disease, Genotype, Humans, Polymorphism, Single Nucleotide, White People

Journal Title

Diabetologia

Conference Name

Journal ISSN

0012-186X
1432-0428

Volume Title

55

Publisher

Springer Science and Business Media LLC
Sponsorship
National Institute of Diabetes and Digestive and Kidney Diseases (U01DK062418)
Wellcome Trust (079895/Z/06/B)
Wellcome Trust (091157/Z/10/B)
British Heart Foundation (None)
Wellcome Trust (091157/Z/10/Z)