Abstract
BackgroundVariation in the COMT gene has been implicated in a number of psychiatric disorders, including psychotic, affective and anxiety disorders. The majority of these studies have focused on the functional Val108/158Met polymorphism and yielded conflicting results, with limited studies examining the relationship between other polymorphisms, or haplotypes, and psychiatric illness. We hypothesized that COMT variation may confer a general risk for psychiatric disorders and have genotyped four COMT variants (Val158Met, rs737865, rs165599, and a SNP in the P2 promoter [-278A/G; rs2097603]) in 394 Caucasian cases and 467 controls. Cases included patients with schizophrenia (n = 196), schizoaffective disorder (n = 62), bipolar disorder (n = 82), major depression (n = 30), and patients diagnosed with either psychotic disorder NOS or depressive disorder NOS (n = 24).ResultsSNP rs2097603, the Val/Met variant and SNP rs165599 were significantly associated (p = 0.004; p = 0.05; p = 0.035) with a broad "all affected" diagnosis. Haplotype analysis revealed a potentially protective G-A-A-A haplotype haplotype (-278A/G; rs737865; Val108/158Met; rs165599), which was significantly underrepresented in this group (p = 0.0033) and contained the opposite alleles of the risk haplotype previously described by Shifman et al. Analysis of diagnostic subgroups within the "all affecteds group" showed an association of COMT in patients with psychotic disorders as well as in cases with affective illness although the associated variants differed. The protective haplotype remained significantly underrepresented in most of these subgroups.ConclusionOur results support the view that COMT variation provides a weak general predisposition to neuropsychiatric disease including psychotic and affective disorders.
Highlights
Variation in the COMT gene has been implicated in a number of psychiatric disorders, including psychotic, affective and anxiety disorders
The role of Catechol-O-Methyltransferase (COMT) in dopamine metabolism has led to investigation of its variants in the etiology of numerous psychiatric disorders including psychotic, affective and anxiety disorders
COMT is located in the region on chromosome 22q11 commonly deleted in velo-cardio-facial/DiGeorge syndrome (VCFS/ DGS) whose phenotypic spectrum includes severe psychiatric disease that has been described as schizophrenia by some [3,4,5] and bipolar disorder by others [6] and 3
Summary
Variation in the COMT gene has been implicated in a number of psychiatric disorders, including psychotic, affective and anxiety disorders. The majority of these studies have focused on the functional Val108/158Met polymorphism and yielded conflicting results, with limited studies examining the relationship between other polymorphisms, or haplotypes, and psychiatric illness. The role of Catechol-O-Methyltransferase (COMT) in dopamine metabolism has led to investigation of its variants in the etiology of numerous psychiatric disorders including psychotic, affective and anxiety disorders. In addition to schizophrenia and bipolar disorder, evidence for a contribution of COMT variants exists for panic disorder [10,11], attention deficit hyperactivity disorder [12], obsessive compulsive disorder [13], phobic anxiety [14] and anorexia nervosa [15]
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