title: Identifying consensus disease pathways in Parkinson's disease using an integrative systems biology approach.
abstract: Parkinson's disease (PD) has had six genome-wide association studies (GWAS) conducted as well as several gene expression studies. However, only variants in MAPT and SNCA have been consistently replicated. To improve the utility of these approaches, we applied pathway analyses integrating both GWAS and gene expression. The top 5000 SNPs (p<0.01) from a joint analysis of three existing PD GWAS were identified and each assigned to a gene. For gene expression, rather than the traditional comparison of one anatomical region between sets of patients and controls, we identified differentially expressed genes between adjacent Braak regions in each individual and adjusted using average control expression profiles. Over-represented pathways were calculated using a hyper-geometric statistical comparison. An integrated, systems meta-analysis of the over-represented pathways combined the expression and GWAS results using a Fisher's combined probability test. Four of the top seven pathways from each approach were identical. The top three pathways in the meta-analysis, with their corrected p-values, were axonal guidance (p = 2.8E-07), focal adhesion (p = 7.7E-06) and calcium signaling (p = 2.9E-05). These results support that a systems biology (pathway) approach will provide additional insight into the genetic etiology of PD and that these pathways have both biological and statistical support to be important in PD.
authors.affiliation: John P Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida, United States of America.
authors.forename: Yvonne J K
authors.initials: YJ
authors.lastname: Edwards
authors.forename: Gary W
authors.initials: GW
authors.lastname: Beecham
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.forename: Sawsan
authors.initials: S
authors.lastname: Khuri
authors.forename: Guney
authors.initials: G
authors.lastname: Bademci
authors.forename: Demet
authors.initials: D
authors.lastname: Tekin
authors.forename: Eden R
authors.initials: ER
authors.lastname: Martin
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Jiang
authors.forename: Deborah C
authors.initials: DC
authors.lastname: Mash
authors.forename: Jarlath
authors.initials: J
authors.lastname: ffrench-Mullen
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
authors.forename: Nicholas
authors.initials: N
authors.lastname: Tsinoremas
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Vance
mesh_terms: D002874:Chromosome Mapping / Q000379:methods / Q000706:statistics & numerical data; D032921:Consensus; D020869:Gene Expression Profiling / Q000379:methods / Q000706:statistics & numerical data; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods / Q000706:statistics & numerical data; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000502:physiology; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008954:Models, Biological; D010300:Parkinson Disease / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D020239:Receptor Cross-Talk / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D049490:Systems Biology / Q000379:methods*; D018511:Systems Integration