High-resolution QTL Analysis Reveals Multiple Diabetes Susceptibility Loci Mapped to Intervals less than 800-kb in the Species Conserved Niddm1i of the GK Rat

Niddm1i, a 16 Mb locus within the major diabetes QTL in the diabetic GK rat, causes impaired glucose tolerance in the congenic NIDDM1I strain. Niddm1i is homologous to both human and mouse regions linked with type 2 diabetes-susceptibility. We employed multiple QTL analyses of congenic F2-progeny selected for one recombination event within Niddm1i combined with characterization of subcongenic strains. Fine-mapping located one hyperglycemia locus within 700 kb (Niddm1i4, P=5x10). Two adjacent loci were also detected, the GK allele at Niddm1i2 (500 kb) showed a glucose-raising effect, whereas it had a glucose-decreasing effect at Niddm1i3 (400 kb). Most proximal, Niddm1i1 (800 kb) affecting body weight was identified. Experimental data from subcongenics supported the four loci. Within Niddm1i3 Sorcs1 resides, one of the two known diabetes susceptibility genes in the region, while Tcf7l2 maps outside all four loci. Multiple-marker QTL analysis incorporating the effect of cosegregating QTLs as cofactors together with genetically selected progeny can remarkably enhance resolution of QTLs. The data demonstrate that the species conserved Niddm1i is a composite of at least four QTLs affecting type 2 diabetes susceptibility, and that two adjacent QTLs (Niddm1i2 and Niddm1i3) act in opposite directions.