OBJECTIVE—Insulin resistance and disturbed glucose homeostasis are key characteristics of metabolic syndrome, diabetes, and cardiovascular disease. The recent nonlinear computer version of homeostasis model assessment (HOMA)2 provides an appropriate and convenient assessment of glucose metabolism, enabling gene-mapping studies in large population samples.RESEARCH DESIGN AND METHODS—Fasting insulin and glucose concentration were measured in 758 dizygous and 305 monozygous nondiabetic female pairs from the St. Thomas’ U.K. adult twin registry (TwinsUK). Insulin resistance (IR) and pancreatic β-cell function (BCF) were estimated from this data using the HOMA2 model.RESULTS—Genome-wide variance component linkage analysis using 2,231 genetic markers identified a highly significant quantitative trait locus for BCF on chromosome 10p15 (logarithm of odds [LOD] 6.2, P = 0.0001), a region recently shown to contain a functional variant for type 1 diabetes. Both BCF and IR suggested a pleiotropic effect on 17q25 (univariate LOD 3.2, P = 0.0012, and 2.38, P = 0.0087; bivariate LOD 2.66), and one additional region showed linkage for IR on chromosome 22q11 (LOD 3.2, P = 0.0016), providing replication and refining previous findings for diabetes and associated traits.CONCLUSIONS—To our best knowledge, this is the first genome-wide linkage screen for HOMA2 indexes in a large, healthy female sample. These results suggest that loci involved in control of normal glucose homeostasis among nondiabetic individuals might overlap with those involved in the development of diabetes. Linkage replications in independent studies and across populations provide information on important regions of common but potentially heterogeneous variability that can now be used for targeted positional candidate studies.