A genome-wide scan in families with maturity-onset diabetes of the young: evidence for further genetic heterogeneity.
Frayling TM., Lindgren CM., Chevre JC., Menzel S., Wishart M., Benmezroua Y., Brown A., Evans JC., Rao PS., Dina C., Lecoeur C., Kanninen T., Almgren P., Bulman MP., Wang Y., Mills J., Wright-Pascoe R., Mahtani MM., Prisco F., Costa A., Cognet I., Hansen T., Pedersen O., Ellard S., Tuomi T., Groop LC., Froguel P., Hattersley AT., Vaxillaire M.
Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene disorder characterized by non-insulin-dependent diabetes, an early onset and autosomal dominant inheritance. Mutations in six genes have been shown to cause MODY. Approximately 15-20% of families fitting MODY criteria do not have mutations in any of the known genes. These families provide a rich resource for the identification of new MODY genes. This will potentially enable further dissection of clinical heterogeneity and bring new insights into mechanisms of beta-cell dysfunction. To facilitate the identification of novel MODY loci, we combined the results from three genome-wide scans on a total of 23 families fitting MODY criteria. We used both a strict parametric model of inheritance with heterogeneity and a model-free analysis. We did not identify any single novel locus but provided putative evidence for linkage to chromosomes 6 (nonparametric linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169-175 cM), and to chromosomes 3 (heterogeneity LOD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score 1.22 at 175 cM) in 14 more strictly defined families. Our results provide evidence for further heterogeneity in MODY.