Computational protocol: A Conserved BDNF, Glutamate- and GABA-Enriched Gene Module Related to Human Depression Identified by Coexpression Meta-Analysis and DNA Variant Genome-Wide Association Studies

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Protocol publication

[…] Eight neuropsychiatry-related candidate gene lists and three gene lists from presumably unrelated disorders or traits were identified from relevant GWAS. Individual genes were identified by the presence of GWAS significant SNPs within a given nucleotide distance from the coding region of that gene (UCSC hg18 with build 36.3 was used for all GWAS).The first gene list was obtained from a published GWAS for neuroticism . Neuroticism is a personality trait that reflects a tendency toward negative mood states, and that is linked to several internalizing psychiatric conditions. That GWAS involved 1,227 healthy individuals with self-report of no diagnosis or treatment for schizophrenia, schizoaffective disorder or bipolar disorder and personality measures of neuroticism. Genotyped data were generated from Affymetrix GeneChip Human Mapping 500 K using BRLMM algorithm. 449 SNPs were selected by p-value less than 0.001, and 155 genes were identified to have contained one or more selected SNPs in the 10 kilobases (kb) up- and down-stream extension of the coding regions.The second gene list was obtained from the MDD 2000+ project that included a meta-analysis of MDD studies with 2,431 MDD cases and 3,673 controls . Similarly, 532 SNPs with p-value less than 0.001 were mapped to gene coding regions (including 10 kb upstream and downstream regions) and 159 genes were identified.The third gene list was obtained from a mega-analysis of GWAS for MDD . The associated 202 SNPs’ p-values were less than 10−5 and 52 genes were identified using the University of California Santa Cruz Human Genome Browser, hg18 assembly (UCSC hg18) with build 36.3. Gene symbols from the build version 36.3 in the National Center for Biotechnology Information (NCBI) database were used.The fourth candidate gene list was obtained from a mega-GWAS of bipolar disease which contained 7,481 patients and 9,250 controls . 6,887 SNPs were identified when p-value less than 0.001. By mapping the SNPs to gene coding region using SNPnexus software (http://snp-nexus.org/), 602 genes were obtained.For the fifth to eighth gene lists, we interrogated the Catalog of Published Genome-Wide Association Studies (http://www.genome.gov/gwastudies/). The database (as of 01/31/13; time of the latest data analysis update) contained 10,183 entries of disease- or trait-associated SNPs with p-values smaller than 10−5 in 1,491 GWAS studies. We manually regrouped the disorders and traits into 4 categories: (1) all MDD-related studies, (2) all neuropsychiatric disorder studies, (3) all neurological disorder and brain phenotypes studies, (4) all medical illnesses sharing increased risk with MDD. Note that the genes in the list #3 were included in the list #2, and genes in the list #2 were included in the list #1, which is the larger category (see more detail list in ). Lists #4 is independent and non-overlapping with others. The associated four gene lists were then compiled, and genes were uniquely included when the mapped SNP was within the gene region including a 100 kb upstream and downstream.As negative controls, we identified in the catalog of published GWAS three gene sets presumably not related to psychiatric diseases: (a) 65 publications (270 genes) of cancer GWAS studies; (b) 42 publications (459 genes) of human body indices GWAS studies (HBI: genetic phenotypes for human, for example: height, weight, eye color, etc.); and (c) 33 publications (187 genes) of GWAS studies for common disease traits not related to brain function or major mental illnesses (). […]

Pipeline specifications

Software tools BRLMM, SNPnexus
Application GWAS
Organisms Homo sapiens
Diseases Brain Diseases
Chemicals gamma-Aminobutyric Acid, Glutamic Acid