Identification of a Locus for Maturity-Onset Diabetes of the Young on Chromosome 8p23

Identification of a Locus for Maturity-Onset Diabetes of the Young on Chromosome 8p23 Sung-Hoon Kim 1 3 , Xiaowei Ma 1 3 , Stanislawa Weremowicz 2 4 , Tonino Ercolino 1 3 , Christine Powers 1 , Wojciech Mlynarski 1 3 , K. Aviva Bashan 1 , James H. Warram 1 , Josyf Mychaleckyj 5 , Stephen S. Rich 5 , Andrzej S. Krolewski 1 3 and Alessandro Doria 1 3 1 Research Division, Joslin Diabetes Center, Boston, Massachusetts 2 Cytogenetics Division, Brigham and Women’s Hospital, Boston, Massachusetts 3 Department of Medicine, Harvard Medical School, Boston, Massachusetts 4 Department of Pathology, Harvard Medical School, Boston, Massachusetts 5 Department of Public Health Sciences, Wake Forest University Medical School, Winston-Salem, North Carolina Address correspondence and reprint requests to Alessandro Doria, MD, PhD, Section on Genetics & Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: alessandro.doria{at}joslin.harvard.edu Abstract Maturity-onset diabetes of the young (MODY) is a subtype of diabetes defined by an autosomal dominant inheritance and a young onset. Six MODY genes have been discovered to date. To identify additional MODY loci, we conducted a genome scan in 21 extended U.S. families (15 white and 6 from minorities, for a total of 237 individuals) in which MODY was not caused by known MODY genes. Seven chromosomal regions (1q42, 2q24, 2q37, 4p13, 8p23, 11p15, and 19q12) had a parametric heterogeneity logarithm of odds (HLOD) ≥1.00 or a nonparametric logarithm of odds (LOD) ≥0.59 ( P ≤ 0.05) in the initial screen. After typing additional markers at these loci to reduce the spacing to 2–3 cM, significant linkage was detected on 8p23 (HLOD = 3.37 at D8S1130 and nonparametric LOD = 3.66; P = 2 × 10 −5 at D8S265), where a 4.7-Mb inversion polymorphism is located. Thirty percent of the families (6 of 21) were linked with this region. Another linkage peak on chromosome 2q37 with an HLOD of 1.96 at D2S345/D2S2968 accounted for diabetes in an additional 25% of families (5 of 21). All 6 minority families were among the 11 families linked to these loci. None of the other loci followed up had an HLOD exceeding 1.50. In summary, we have identified a MODY locus on 8p23 that accounts for diabetes in a substantial proportion of MODY cases unlinked to known MODY genes. Another novel MODY locus may be present on 2q37. Cloning these new MODY genes may offer insights to disease pathways that are relevant to the cause of common type 2 di