Linkage and Association Mapping of a Chromosome 1q21-q24 Type 2 Diabetes Susceptibility Locus in Northern European Caucasians

Linkage and Association Mapping of a Chromosome 1q21-q24 Type 2 Diabetes Susceptibility Locus in Northern European Caucasians Swapan Kumar Das 1 , Sandra J. Hasstedt 2 , Zhengxian Zhang 1 and Steven C. Elbein 1 3 1 Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 2 Department of Human Genetics, University of Utah Health Sciences Center, Salt Lake City, Utah 3 Department of Medicine, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas Address correspondence and reprint requests to Steven C. Elbein, MD, Professor of Medicine, University of Arkansas for Medical Sciences, Endocrinology 111J-1/LR, John L. McClellan Memorial Veterans Hospital, 4700 W. 7th St., Little Rock, AR 72205. E-mail: elbeinstevenc{at}uams.edu Abstract We have identified a region on chromosome 1q21-q24 that was significantly linked to type 2 diabetes in multiplex families of Northern European ancestry and also in Pima Indians, Amish families, and families from France and England. We sought to narrow and map this locus using a combination of linkage and association approaches by typing microsatellite markers at 1.2 and 0.5 cM densities, respectively, over a region of 37 cM (23.5 Mb). We tested linkage by parametric and nonparametric approaches and association using both case-control and family-based methods. In the 40 multiplex families that provided the previous evidence for linkage, the highest parametric, recessive logarithm of odds (LOD) score was 5.29 at marker D1S484 (168.5 cM, 157.5 Mb) without heterogeneity. Nonparametric linkage (NPL) statistics ( P = 0.00009), SimWalk2 Statistic A ( P = 0.0002), and sib-pair analyses (maximum likelihood score = 6.07) all mapped to the same location. The one LOD CI was narrowed to 156.8–158.9 Mb. Under recessive, two-point linkage analysis, adjacent markers D1S2675 (171.5 cM, 158.9 Mb) and D1S1679 (172 cM, 159.1 Mb) showed LOD scores >3.0. Nonparametric analyses revealed a second linkage peak at 180 cM near marker D1S1158 (163.3 Mb, NPL score 3.88, P = 0.0001), which was also supported by case-control (marker D1S194, 178 cM, 162.1 Mb; P = 0.003) and family-based (marker ATA38A05, 179 cM, 162.5 Mb; P = 0.002) association studies. We propose that the replicated linkage findings actually encompass at least two closely spaced regions, with a second susceptibility region located telomeric at 162.5–164.7 Mb. HLOD, heterogeneity LOD IDB, identical by descent LOD, logarithm of odds MLS, maximum likel