Genetic association studies are now routinely used to identify single nucleotide polymorphisms (SNPs) linked with human diseases or traits through single SNP-single trait tests. Here we introduced partial least squares path modeling (PLSPM) for association between single or multiple SNPs and a latent trait that can involve single or multiple correlated measurement(s). Furthermore, the framework naturally provides estimators of polygenic effect by appropriately weighting trait-attributing alleles. We conducted computer simulations to assess the performance via multiple SNPs and human obesity-related traits as measured by body mass index (BMI), waist and hip circumferences. Our results showed that the associate statistics had type I error rates close to nominal level and were powerful for a range of effect and sample sizes. When applied to 12 candidate regions in data (N = 2,417) from the European Prospective Investigation of Cancer (EPIC)-Norfolk study, a region in FTO was found to have stronger association (rs7204609∼rs9939881 at the first intron P = 4.29×10(-7)) than single SNP analysis (all with P>10(-4)) and a latent quantitative phenotype was obtained using a subset sample of EPIC-Norfolk (N = 12,559). We believe our method is appropriate for assessment of regional association and polygenic effect on a single or multiple traits.
Xue, F., Li, S., Luan, J., Yuan, Z., Luben, R. N., Khaw, K. T., … Zhao, J. H. (2012). A latent variable partial least squares path modeling approach to regional association and polygenic effect with applications to a human obesity study. PLoS ONE, 7(2). https://doi.org/10.1371/journal.pone.0031927