A genome-wide scan in families with maturity-onset diabetes of the young: evidence for further genetic heterogeneity

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Timothy M Frayling, Cecilia M Lindgren, Jean Claude Chevre, Stephan Menzel, Marie Wishart, Yamina Benmezroua, Alison Brown, Julie C Evans, Pamidghantam Subba Rao, Christian Dina, Cécile Lecoeur, Timo Kanninen, Peter Almgren, Michael P Bulman, Youxiang Wang, James Mills, Rosemarie Wright-Pascoe, Melanie M Mahtani, Francesco Prisco, Angels Costa & 9 others Ignacio Cognet, Torben Hansen, Oluf Pedersen, Sian Ellard, Tiinamaija Tuomi, Leif C Groop, Philippe Froguel, Andrew T Hattersley, Martine Vaxillaire

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.
Original languageEnglish
JournalDiabetes
Volume52
Issue number3
Pages (from-to)872-81
Number of pages10
ISSN0012-1797
Publication statusPublished - 2003

    Research areas

  • Adolescent, Adult, Child, Chromosomes, Human, Pair 10, Chromosomes, Human, Pair 3, Chromosomes, Human, Pair 5, Chromosomes, Human, Pair 6, DNA-Binding Proteins, Diabetes Mellitus, Type 2, Female, Genetic Heterogeneity, Genetic Linkage, Genotype, Glucokinase, Hepatocyte Nuclear Factor 1, Hepatocyte Nuclear Factor 1-alpha, Hepatocyte Nuclear Factor 1-beta, Humans, Lod Score, Male, Microsatellite Repeats, Mutation, Nuclear Proteins, Pedigree, Transcription Factors

ID: 38454575