Tests for Genetic Interactions in Type 1 Diabetes

Linkage and Stratification Analyses of 4,422 Affected Sib-Pairs

  1. and the Type 1 Diabetes Genetics Consortium
  1. 1Centre for Diabetes Research, Western Australian Institute for Medical Research, University of Western Australia, Crawley, Australia
  2. 2Centre for Medical Research, University of Western Australia, Crawley, Australia
  3. 3Centre for Clinical Immunology and Biomedical Statistics, Murdoch University, Perth, Australia
  4. 4Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
  5. 5Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia
  6. 6Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
  7. 7Roche Molecular Systems, Pleasanton, California
  8. 8Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama
  9. 9Institut National de la Santé et de la Recherche Médicale, Cognitive Neuroimaging Unit, Institut de Genomique Centre National de Genotypage, Evry, France
  10. 10Steno Diabetes Center, Gentofte, Denmark
  11. 11Juvenile Diabetes Research Foundation, New York, New York
  12. 12Science Park, University Hospital Glostrup, Glostrup, Denmark
  13. 13Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K.
  14. 14Wake Forest University School of Medicine, Winston-Salem, North Carolina
  1. Corresponding author: Grant Morahan, gem{at}waimr.uwa.edu.au.

Abstract

OBJECTIVE Interactions between genetic and environmental factors lead to immune dysregulation causing type 1 diabetes and other autoimmune disorders. Recently, many common genetic variants have been associated with type 1 diabetes risk, but each has modest individual effects. Familial clustering of type 1 diabetes has not been explained fully and could arise from many factors, including undetected genetic variation and gene interactions.

RESEARCH DESIGN AND METHODS To address this issue, the Type 1 Diabetes Genetics Consortium recruited 3,892 families, including 4,422 affected sib-pairs. After genotyping 6,090 markers, linkage analyses of these families were performed, using a novel method and taking into account factors such as genotype at known susceptibility loci.

RESULTS Evidence for linkage was robust at the HLA and INS loci, with logarithm of odds (LOD) scores of 398.6 and 5.5, respectively. There was suggestive support for five other loci. Stratification by other risk factors (including HLA and age at diagnosis) identified one convincing region on chromosome 6q14 showing linkage in male subjects (corrected LOD = 4.49; replication P = 0.0002), a locus on chromosome 19q in HLA identical sibs (replication P = 0.006), and four other suggestive loci.

CONCLUSIONS This is the largest linkage study reported for any disease. Our data indicate there are no major type 1 diabetes subtypes definable by linkage analyses; susceptibility is caused by actions of HLA and an apparently random selection from a large number of modest-effect loci; and apart from HLA and INS, there is no important susceptibility factor discoverable by linkage methods.

  • Received August 23, 2010.
  • Accepted December 15, 2010.

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