A Genome-Wide Scan in Families With Maturity-Onset Diabetes of the Young
Evidence for Further Genetic Heterogeneity
- Timothy M. Frayling1,
- Cecilia M. Lindgren2,
- Jean Claude Chevre3,
- Stephan Menzel4,
- Marie Wishart4,
- Yamina Benmezroua3,
- Alison Brown4,
- Julie C. Evans1,
- Pamidghantam Subba Rao4,
- Christian Dina3,
- Cécile Lecoeur5,
- Timo Kanninen26,
- Peter Almgren2,
- Michael P. Bulman1,
- Youxiang Wang4,
- James Mills7,
- Rosemarie Wright-Pascoe7,
- Melanie M. Mahtani8,
- Francesco Prisco9,
- Angels Costa10,
- Ignacio Cognet10,
- Torben Hansen11,
- Oluf Pedersen11,
- Sian Ellard1,
- Tiinamaija Tuomi12,
- Leif C. Groop2,
- Philippe Froguel35,
- Andrew T. Hattersley1 and
- Martine Vaxillaire3
- 1Department of Diabetes and Vascular Medicine, Postgraduate School of Medicine and Health, Science, University of Exeter, Exeter, U.K
- 2Department of Endocrinology, Wallenberg Laboratory, Lund University, Malmö, Sweden
- 3CNRS UPRESA 8090, Institute of Biology & Pasteur Institute of Lille, Lille, France
- 4The Wellcome Trust Centre for Human Genetics, Oxford, U.K
- 5Queen Mary and Westfield College, University of London, and Barts & the London Genome Centre, London, U.K
- 6BioComputing, Helsinki, Finland
- 7Department of Basic Medical Sciences, Faculty of Medical Sciences, University of the West Indies, Mona, Kingston, West Indies, Jamaica
- 8Whitehead Institute of Biomedical Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts
- 9Department of Pediatrics, Second University of Naples, Naples Italy
- 10Endocrinology and Diabetes Unit, IDIBAPS, Hospital Clinic Universitari, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain
- 11Steno Diabetes Center, Gentofte, Denmark
- 12Department of Internal Medicine, Division of Endocrinology, Helsinki University Central Hospital, Helsinki, Finland
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 β-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.
Address correspondence and reprint requests to Dr. M. Vaxillaire, CNRS UMR 8090, Institut de Biologie and Institut Pasteur de Lille, 1 rue du Pr Calmette, B.P. 447, 59021 Lille Cedex, France. E-mail:.
Received for publication 2 June 2002 and accepted in revised form 18 December 2002.
T.M.F., C.M.L., and J.C.C. contributed equally to this work.
J.C.C. is currently affiliated with the Department of Pediatrics and Medicine, Naomi Berrie Diabetes Center, Columbia University College of Physicians and Surgeons, New York, New York, T.M.F. is a career scientist of the South and West National Health Service Research Directorate; and S.M. is an R.D. Lawrence Research Fellow of the British Diabetic Association.
GCK, glycolytic enzyme glucokinase; GH, GeneHunter; GIFT, Genomic Integrated Force for Type 2 Diabetes; HLOD, heterogeneity LOD; HNF, hepatocyte nuclear factor; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; IPF, insulin promoter factor; LOD, logarithm of the odds; MODY, maturity-onset diabetes of the young; NPL, nonparametric linkage.