Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci.
Walford GA., Gustafsson S., Rybin D., Stančáková A., Chen H., Liu CT., Hong J., Jensen RA., Rice K., Morris AP., Mägi R., Tönjes A., Prokopenko I., Kleber ME., Delgado G., Silbernagel G., Jackson AU., Appel EV., Grarup N., Lewis JP., Montasser ME., Landenvall C., Staiger H., Luan J., Frayling TM., Weedon MN., Xie W., Morcillo S., Martínez-Larrad MT., Biggs ML., Chen YD., Corbaton-Anchuelo A., Færch K., Gómez-Zumaquero JM., Goodarzi MO., Kizer JR., Koistinen HA., Leong A., Lind L., Lindgren C., Machicao F., Manning AK., Martín-Núñez GM., Rojo-Martínez G., Rotter JI., Siscovick DS., Zmuda JM., Zhang Z., Serrano-Rios M., Smith U., Soriguer F., Hansen T., Jørgensen TJ., Linnenberg A., Pedersen O., Walker M., Langenberg C., Scott RA., Wareham NJ., Fritsche A., Häring HU., Stefan N., Groop L., O'Connell JR., Boehnke M., Bergman RN., Collins FS., Mohlke KL., Tuomilehto J., März W., Kovacs P., Stumvoll M., Psaty BM., Kuusisto J., Laakso M., Meigs JB., Dupuis J., Ingelsson E., Florez JC.
Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci.