Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families

Non–insulin dependent diabetes mellitus (NIDDM) affects more than 100 million people worldwide1,2 and is associated with severe metabolic defects, including peripheral insulin resistance, elevated hepatic glucose production, and inappropriate insulin secretion3. Family studies point to a major genetic component4–6, but specific susceptibility genes have not yet been identified — except for rare early–onset forms with monogenic7–10 or mito–chondrial11 inheritance. We have screened over 4,000 individuals from a population isolate in western Finland, identified 26 families (comprising 217 individuals) enriched for NIDDM and performed a genome–wide scan using non–parametric linkage analysis. We found no significant evidence for linkage when the families were analysed together, but strong evidence for linkage when families were classified according to mean insulin levels in affecteds (in oral glucose tolerance tests). Specifically, families with the lowest insulin levels showed linkage (P = 2 × 10−5) to chromosome 12 near D12S1349. Interestingly, this region contains the gene causing the rare, dominant, early–onset form of diabetes MODY3. Unlike MODY3 families, the Finnish families with low insulin have an age–of–onset typical for NIDDM (mean = 58 years). We infer the existence of a gene NIDDM2 causing NIDDM associated with low insulin secretion, and suggest that NIDDM2 and MODY3 may represent different alleles of the same gene.