COMT genetic variation confers risk for psychotic and affective disorders: a case control study

Behavioral and Brain Functions BioMed Central Research Open Access COMT genetic variation confers risk for psychotic and affective disorders: a case control study Birgit Funke*1, Anil K Malhotra2, Christine T Finn1, Alex M Plocik1, Stephen L Lake3, Todd Lencz2, Pamela DeRosse2, John M Kane2 and Raju Kucherlapati1 Address: 1Harvard Partners Center for Genetics and Genomics, Boston, USA, 2Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, NY, USA and 3Channing Laboratory, Brigham and Women's Hospital, Boston, USA Email: Birgit Funke* - ; Anil K Malhotra - ; Christine T Finn - ; Alex M Plocik - ; Stephen L Lake - ; Todd Lencz - ; Pamela DeRosse - ; John M Kane - ; Raju Kucherlapati - * Corresponding author Published: 18 October 2005 Behavioral and Brain Functions 2005, 1:19 doi:10.1186/1744-9081-1-19 Received: 25 August 2005 Accepted: 18 October 2005 This article is available from: http://www.behavioralandbrainfunctions.com/content/1/1/19 © 2005 Funke et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Background: 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. 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). Results: SNP 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. Conclusion: Our results support the view that COMT variation provides a weak general predisposition to neuropsychiatric disease including psychotic and affective disorders. Page 1 of 9 (page number not for citation purposes) Behavioral and Brain Functions 2005, 1:19 http://www.behavioralandbrainfunctions.com/content/1/1/19 Background are widely expressed at varying levels, MB-COMT appears to be the predominant from in brain [42,43]. It has therefore been suggested that disease pre-disposing variant/s may be located in the P2 promoter, acting in cis to alter COMT protein levels via enhancement or suppression of transcription [44]. Several recent studies have investigated the effect of previously associated variants on COMT expression levels [16,45-47]. Interestingly, some showed reduced expression levels of Valine-coding COMT mRNAs [45,47]. Although this contrasts with the higher enzyme activity of Val-COMT, the net result of these two effects seems to be a 40% higher enzyme activity in human dorsolateral prefrontal cortex samples homozygous for ValCOMT [16]. A variant located in the P2 promoter (-278A/ G) showed a small effect on enzyme activity, suggesting that it may indeed influence brain dopamine levels [16]. 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. The largest body of work exists for schizophrenia and bipolar disorder because 1. Imbalance of dopamine is thought be key to the pathogenesis of psychosis [1,2], 2. 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 [3-5] and bipolar disorder by others [6] and 3. Genetic variation in COMT has been implicated in prefrontal cortical function [7,8], which is commonly impaired in both disorders [9]. 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]. Most studies focused on a common functional SNP (Val108/158Met) because the Methionine-containing variant shows a significant reduction in enzyme activity [16-18]. However, despite their large number, these studies have generated controversial and confusing results: For schizophrenia, initial studies have reported an association of the A (Met) allele [19-21]. However, current evidence favors an association of the of the G (Val) allele [22-27]. Similarly, for bipolar disorder, several studies reported an association of Met-COMT [[28-31], reviewed in: [32]]; but a recent study by Shifman et al. showed evidence of an association of Val-COMT [33]. As with schizophrenia and bipolar disorder, the associations remain controversial for other psychiatric illnesses including ADHD, OCD, anorexia nervosa, and anxiety disorder [34-37]. In all cases, likely contributing factors are small sample sizes and/or diagnostic differences as the absence of objective biomarkers in psychiatric disorders potentially hampers consistent classification of disease [38,39]. Although Shifman et al. saw an association of the Valine allele in their cohort, its moderate effect combined with highly significant p-values for two SNPs located in intron 1 and the 3'UTR (rs737865 and rs165599) has led to the hypothesis that the Val/Met variant may not contribute to disease but may simply be in strong LD with the actual, as of yet unidentified pre-disposing variant [40]. A recent study by Handoko et al. supports this view [41]. The COMT gene is transcribed from two promoters resulting in a cytoplasmatic form (soluble; S-COMT, transcribed from P1) and a membrane bound form (MBCOMT, transcribed from P2) [42]. Although both variants Taken together, current evidence suggests (...truncated)