On the Use of Variance per Genotype as a Tool to Identify Quantitative Trait Interaction Effects: A Report from the Women's Genome Health Study

Testing for genetic effects on mean values of a quantitative trait has been a very successful strategy. However, most studies to date have not explored genetic effects on the variance of quantitative traits as a relevant consequence of genetic variation. In this report, we demonstrate that, under plausible scenarios of genetic interaction, the variance of a quantitative trait is expected to differ among the three possible genotypes of a biallelic SNP. Leveraging this observation with Levene's test of equality of variance, we propose a novel method to prioritize SNPs for subsequent gene–gene and gene–environment testing. This method has the advantageous characteristic that the interacting covariate need not be known or measured for a SNP to be prioritized. Using simulations, we show that this method has increased power over exhaustive search under certain conditions. We further investigate the utility of variance per genotype by examining data from the Women's Genome Health Study. Using this dataset, we identify new interactions between the LEPR SNP rs12753193 and body mass index in the prediction of C-reactive protein levels, between the ICAM1 SNP rs1799969 and smoking in the prediction of soluble ICAM-1 levels, and between the PNPLA3 SNP rs738409 and body mass index in the prediction of soluble ICAM-1 levels. These results demonstrate the utility of our approach and provide novel genetic insight into the relationship among obesity, smoking, and inflammation.Author Summary: Finding gene–gene and gene–environment interactions is a major challenge in genetics. In this report, we propose a novel method to help detect these interactions. This method works by first identifying a subset of genetic variants more likely to be involved in genetic interactions and then testing these variants for interaction effects. Using this method, we were able to identify three previously unknown genetic interactions. The first interaction involves a measure of body fat and a genetic variant of the LEPR gene in the prediction of C-reactive protein concentration, a marker of inflammation. The second interaction involves the same measure of body fat and a genetic variant of the PNPLA3 gene in the prediction of ICAM-1 levels, also a marker of inflammation. These results are significant because both LEPR and PNPLA3 are linked to the biological response to increased body fat, and inflammation itself is known to be increased in obesity and is thought to contribute to its adverse health effect. Finally, a third interaction was identified between a genetic variant of the ICAM1 gene and smoking in the prediction of ICAM-1 levels. The ICAM1 gene encodes ICAM-1 itself and smoking is known to be an important determinant of ICAM-1 concentrations.