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>35kg/m 2) and never-overweight (BMI<25kg/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.
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