title: Pathway-Based Genome-wide Association Studies Reveal That the Rac1 Pathway Is Associated with Plasma Adiponectin Levels.
abstract: 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.
authors: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.|Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Wei-Dong
authors: WD
authors: Li
authors: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
authors: Hongxiao
authors: H
authors: Jiao
authors: Zilkha Neurogenetic Institute and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90089, USA.
authors: Kai
authors: K
authors: Wang
authors: Research Center of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China.
authors: Fuhua
authors: F
authors: Yang
authors: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.|Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Struan F A
authors: SF
authors: Grant
authors: Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.|Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Hakon
authors: H
authors: Hakonarson
authors: Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: Rexford
authors: R
authors: Ahima
authors: Center for Neurobiology and Behavior, Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors: R
authors: R
authors: Arlen Price
mesh_terms: D052242:Adiponectin / Q000097:blood*; D015992:Body Mass Index; D016022:Case-Control Studies; D055106:Genome-Wide Association Study; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics*; D044465:White People / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: C499918:ADIPOQ protein, human; D052242:Adiponectin; C107953:RAC1 protein, human; D020830:rac1 GTP-Binding Protein