title: Evidence for statistical epistasis between catechol-O-methyltransferase (COMT) and polymorphisms in RGS4, G72 (DAOA), GRM3, and DISC1: influence on risk of schizophrenia.
abstract: Catechol-O-methyltransferase (COMT) regulates dopamine degradation and is located in a genomic region that is deleted in a syndrome associated with psychosis, making it a promising candidate gene for schizophrenia. COMT also has been shown to influence prefrontal cortex processing efficiency. Prefrontal processing dysfunction is a common finding in schizophrenia, and a background of inefficient processing may modulate the effect of other candidate genes. Using the NIMH sibling study (SS), a non-independent case-control set, and an independent German (G) case-control set, we performed conditional/unconditional logistic regression to test for epistasis between SNPs in COMT (rs2097603, Val158Met (rs4680), rs165599) and polymorphisms in other schizophrenia susceptibility genes. Evidence for interaction was evaluated using a likelihood ratio test (LRT) between nested models. SNPs in RGS4, G72, GRM3, and DISC1 showed evidence for significant statistical epistasis with COMT. A striking result was found in RGS4: three of five SNPs showed a significant increase in risk [LRT P-values: 90387 = 0.05 (SS); SNP4 = 0.02 (SS), 0.02 (G); SNP18 = 0.04 (SS), 0.008 (G)] in interaction with COMT; main effects for RGS4 SNPs were null. Significant results for SNP4 and SNP18 were also found in the German study. We were able to detect statistical interaction between COMT and polymorphisms in candidate genes for schizophrenia, many of which had no significant main effect. In addition, we were able to replicate other studies, including allelic directionality. The use of epistatic models may improve replication of psychiatric candidate gene studies.
authors.affiliation: Clinical Brain Disorders Branch, National Institute of Mental Health, National Institute of Health, Bethesda, MD 20892, USA.
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Nicodemus
authors.forename: Bhaskar S
authors.initials: BS
authors.lastname: Kolachana
authors.forename: Radhakrishna
authors.initials: R
authors.lastname: Vakkalanka
authors.forename: Richard E
authors.initials: RE
authors.lastname: Straub
authors.forename: Ina
authors.initials: I
authors.lastname: Giegling
authors.forename: Michael F
authors.initials: MF
authors.lastname: Egan
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D020710:RGS Proteins / Q000235:genetics*; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics*; D012307:Risk Factors; D012559:Schizophrenia / Q000201:enzymology* / Q000235:genetics*; D035781:Siblings
chemical_list: D002352:Carrier Proteins; C475071:DAOA protein, human; C412476:DISC1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D020710:RGS Proteins; D018094:Receptors, Metabotropic Glutamate; C102718:metabotropic glutamate receptor 3; C098799:RGS4 protein; D002394:Catechol O-Methyltransferase