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Evidence From a Large U.K. Family Collection That Genes Influencing Age of Onset of Type 2 Diabetes Map to Chromosome 12p and to the MODY3/NIDDM2 Locus on 12q24

¹ Wellcome Trust Centre for Human Genetics, Oxford, U.K
² Department of Diabetes and Vascular Medicine, Peninsula Medical School, Exeter, U.K
³ Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
⁴ Department of Diabetes and Metabolic Medicine, St. Bartholomew’s and the Royal London, Queen Mary’s School of Medicine and Dentistry, London, U.K
⁵ Elsie Bertram Diabetes Centre, Norfolk and Norwich University Hospital, Norwich, U.K
⁶ Department of Medicine, Medical School, University of Newcastle, Newcastle, U.K

Additional information on genetic susceptibility effects relevant to type 2 diabetes pathogenesis can be extracted from existing genome scans by extending examination to related phenotypes such as age at disease onset. In this study, we report the reanalysis of data from 573 U.K. sibships ascertained for multiplex type 2 diabetes, using age at onset (assessed by the proxy measure of age at diagnosis) as the phenotype of interest. Genome-wide evidence for linkage to age at diagnosis was evaluated using both variance components and Haseman-Elston (HECOM) regression approaches, with extensive simulations to derive empirical significance values. There was broad agreement across analyses with six regions of interest (logarithm of odds [LOD] 1.18) identified on chromosomes 1qter, 4p15–4q12, 5p15, 12p13–12q13, 12q24, and 14q12–14q21. The strongest empirically "suggestive" evidence for linkage comes from regions on chromosome 12. The first region (12p13–12q13), peaking at D12S310 (variance components LOD [LOD_VC] = 2.08, empirical pointwise P = 0.0007; HECOM LOD [LOD_HECOM] = 2.58, P = 0.0010) seems to be novel. The second (12q24) peaking between D12S324 and D12S1659 (LOD_VC = 1.87, P = 0.0016; LOD_HECOM = 1.93, P = 0.0027) overlaps a region showing substantial prior evidence for diabetes linkage. These data provide additional evidence that genes mapping to these chromosomal regions are involved in the susceptibility to, and/or development of, type 2 diabetes.

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