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Diabetologia. 2012 Apr;55(4):996-1000. doi: 10.1007/s00125-012-2450-3. Epub 2012 Jan 26.

Confirmation of novel type 1 diabetes risk loci in families.

Author information

  • 1Department of Medical Genetics, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. jason.cooper@cimr.cam.ac.uk

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.

PMID:
22278338
[PubMed - indexed for MEDLINE]
PMCID:
PMC3296014
Free PMC Article
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