title: Genomewide analysis of inherited variation associated with phosphorylation of PI3K/AKT/mTOR signaling proteins.
abstract: While there exists a wealth of information about genetic influences on gene expression, less is known about how inherited variation influences the expression and post-translational modifications of proteins, especially those involved in intracellular signaling. The PI3K/AKT/mTOR signaling pathway contains several such proteins that have been implicated in a number of diseases, including a variety of cancers and some psychiatric disorders. To assess whether the activation of this pathway is influenced by genetic factors, we measured phosphorylated and total levels of three key proteins in the pathway (AKT1, p70S6K, 4E-BP1) by ELISA in 122 lymphoblastoid cell lines from 14 families. Interestingly, the phenotypes with the highest proportion of genetic influence were the ratios of phosphorylated to total protein for two of the pathway members: AKT1 and p70S6K. Genomewide linkage analysis suggested several loci of interest for these phenotypes, including a linkage peak for the AKT1 phenotype that contained the AKT1 gene on chromosome 14. Linkage peaks for the phosphorylated:total protein ratios of AKT1 and p70S6K also overlapped on chromosome 3. We selected and genotyped candidate genes from under the linkage peaks, and several statistically significant associations were found. One polymorphism in HSP90AA1 was associated with the ratio of phosphorylated to total AKT1, and polymorphisms in RAF1 and GRM7 were associated with the ratio of phosphorylated to total p70S6K. These findings, representing the first genomewide search for variants influencing human protein phosphorylation, provide useful information about the PI3K/AKT/mTOR pathway and serve as a valuable proof of concept for studies integrating human genomics and proteomics.
authors.affiliation: Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Janna E
authors.initials: JE
authors.lastname: Hutz
authors.forename: W Aaron
authors.initials: WA
authors.lastname: Manning
authors.forename: Michael A
authors.initials: MA
authors.lastname: Province
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D002893:Chromosomes, Human, Pair 3 / Q000378:metabolism; D056726:Genetic Association Studies; D008040:Genetic Linkage; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics*; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010750:Phosphoproteins; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C087000:EIF4EBP1 protein, human