Genome-wide association study of comorbid depressive syndrome and alcohol dependence

Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia 23298-0126, USA.
Psychiatric genetics (Impact Factor: 1.94). 11/2011; 22(1):31-41. DOI: 10.1097/YPG.0b013e32834acd07
Source: PubMed


Depression and alcohol dependence (AD) are common psychiatric disorders that often co-occur. Both disorders are genetically influenced, with heritability estimates in the range of 35-60%. In addition, evidence from twin studies suggests that AD and depression are genetically correlated. Herein, we report results from a genome-wide association study of a comorbid phenotype, in which cases meet the Diagnostic and Statistical Manual of Mental Disorders-IV symptom threshold for major depressive symptomatology and the Diagnostic and Statistical Manual of Mental Disorders-IV criteria for AD.
Samples (N=467 cases and N=407 controls) were of European-American descent and were genotyped using the Illumina Human 1M BeadChip array.
Although no single-nucleotide polymorphism (SNP) meets genome-wide significance criteria, we identified 10 markers with P values less than 1 × 10(-5), seven of which are located in known genes, which have not been previously implicated in either disorder. Genes harboring SNPs yielding P values less than 1 × 10(-5) are functionally enriched for a number of gene ontology categories, notably several related to glutamatergic function. Investigation of expression localization using online resources suggests that these genes are expressed across a variety of tissues, including behaviorally relevant brain regions. Genes that have been previously associated with depression, AD, or other addiction-related phenotypes - such as CDH13, CSMD2, GRID1, and HTR1B - were implicated by nominally significant SNPs. Finally, the degree of overlap of significant SNPs between a comorbid phenotype and an AD-only phenotype is modest.
These results underscore the complex genomic influences on psychiatric phenotypes and suggest that a comorbid phenotype is partially influenced by genetic variants that do not affect AD alone.

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    • "The gene coding for IP3 receptor type 1 (ITPR1) is enriched in pathways of the G1 and G2 component. A recent GWAS report of comorbid depression and alcoholism subjects (from the Consortium on the Genetics of Alcoholism , COGA) reported clusters of potential riskconferring alleles similar to those described here (Edwards et al. 2012) including glutamatergic genes (GRIN2C (Edwards et al. 2012), GRIN2B (G1,G2), GRIN2A (G3; Edwards et al. 2012), GRIA1 (Edwards, Aliev et al.), GRIA4 (Edwards, Aliev et al.), and GRM1 (G1,G2)). CTNNA2 is enriched in G2 and G3, while CTNNA3 is enriched in pathways from our G2 component. "
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