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Pathway-based analysis as an alternative and effective approach to identify disease-related genes or loci has been verified. To decipher the genetic background of plasma adiponectin levels, we performed genome wide pathway-based association studies in extremely obese individuals and normal-weight controls. The modified Gene Set Enrichment Algorithm (GSEA) was used to perform the pathway-based analyses (the GenGen Program) in 746 European American females, which were collected from our previous GWAS in extremely obese (BMI > 35 kg/m 2 ) and never-overweight (BMI<25 kg/m 2 ) controls. Rac1 cell motility signaling pathway was associated with plasma adiponectin after false-discovery rate (FDR) correction (empirical  P  < 0.001, FDR = 0.008, family-wise error rate = 0.008). Other several Rac1-centered pathways, such as cdc42racPathway (empirical  P  < 0.001), hsa00603 (empirical  P  = 0.003) were among the top associations. The RAC1 pathway association was replicated by the ICSNPathway method, yielded a FDR = 0.002. Quantitative pathway analyses yielded similar results (empirical  P  = 0.001) for the Rac1 pathway, although it failed to pass the multiple test correction (FDR = 0.11). We further replicated our pathway associations in the ADIPOGen Consortium data by the GSA-SNP method. Our results suggest that Rac1 and related cell motility pathways might be associated with plasma adiponectin levels and biological functions of adiponectin.

Pathway-Based Genome-wide Association Studies Reveal That the Rac1 Pathway Is Associated with Plasma Adiponectin Levels