Originally published as Genetics Published Articles Ahead of Print on September 1, 2006.

Genetics, Vol. 174, 1565-1572, November 2006, Copyright © 2006
doi:10.1534/genetics.106.062208

High-Resolution Quantitative Trait Locus Analysis Reveals Multiple Diabetes Susceptibility Loci Mapped to Intervals <800 kb in the Species-Conserved Niddm1i of the GK Rat

Charlotte Granhall*, Hee-Bok Park*, Hossein Fakhrai-Rad{dagger},{ddagger} and Holger Luthman*,{ddagger},1

* Lund University, Department of Clinical Sciences, SE-205 02 Malmö, Sweden, {dagger} ParAllele BioScience, South San Francisco, California 94080 and {ddagger} Karolinska Institutet, Department of Molecular Medicine, SE-171 76 Stockholm, Sweden

1 Corresponding author: Department of Clinical Sciences, Lund University, CRC, Bldg. 91, Floor 11, SE-205 02 Malmö, Sweden.
E-mail: holger.luthman{at}med.lu.se

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 = 5 x 10–6). Two adjacent loci were also detected, and the GK allele at Niddm1i2 (500 kb) showed a glucose-raising effect, whereas it had a glucose-lowering effect at Niddm1i3 (400 kb). Most proximally, Niddm1i1 (800 kb) affecting body weight was identified. Experimental data from subcongenics supported the four loci. Sorcs1, one of the two known diabetes susceptibility genes in the region, resides within Niddm1i3, while Tcf7l2 maps outside all four loci. Multiple-marker QTL analysis incorporating the effect of cosegregating QTL as cofactors together with genetically selected progeny can remarkably enhance resolution of QTL. The data demonstrate that the species-conserved Niddm1i is a composite of at least four QTL affecting type 2 diabetes susceptibility and that two adjacent QTL (Niddm1i2GK and Niddm1i3GK) act in opposite directions.