NEW SUSCEPTIBILITY LOCUS FOR NIDDM IS LOCALIZED TO HUMAN-CHROMOSOME 20Q

To test the hypothesis that a gene (or genes) in the ''MODY1 region'' of the long arm of chromosome 20 contributes to the development of NID DM, we conducted linkage studies in 29 extended Caucasian families in which many members were affected with NIDDM. A total of 498 individual s, including 159 NIDDM patients with an average age at diagnosis of 47 years, were genotyped for eight highly polymorphic microsatellite mar kers spanning a 31-cM region on chromosome 20q12-13.1. Using affected sib-pair analysis, we obtained evidence suggesting linkage between NID DM and markers D20S119, D20S178, and D20S197 (allele sharing identical -by-descent [IBD], 0.56 for all three; P = 0.005, P = 0.009, and P = 0 .004, respectively). Multipoint nonparametric linkage (NPL) analysis a lso showed evidence for linkage of NIDDM with the same three markers. The evidence for linkage was much stronger (allele sharing IBD by affe cted sibpairs, 0.64 [P < 0.0001]; maximum NPL score, 3.3 [P = 0.009]) in the 14 families whose average age at diagnosis of NIDDM was above t he median (47 years) for all families. In these 14 families, one parti cular allele of the microsatellite D20S197 was transmitted from hetero zygous parents to NIDDM offspring more frequently than expected (P < 0 .01). This indicates that the marker allele and the disease allele are in linkage disequilibrium, implying that they are in close proximity. Consequently, the recently identified MODY1 gene (hepatocyte nuclear factor 4) is an unlikely candidate gene for NIDDM in our families, sin ce it is located about 8 cM centromeric of D20S197. In conclusion, we have identified a new region on chromosome 20q that contains one or mo re NIDDM genes distinct from the recently identified MODY1 gene.