Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia

Department of Psychiatry and Behavioral Sciences, Evanston Northwestern Healthcare Research Institute, Center for Psychiatric Genetics, Northwestern University, Evanston, IL 60201, USA.
Molecular Psychiatry (Impact Factor: 14.5). 05/2005; 10(4):353-65. DOI: 10.1038/
Source: PubMed


Catechol-O-methyltransferase (COMT) has been implicated in schizophrenia by its function through its roles in monoamine neurotransmitter metabolism and its impact on prefrontal cognition, and also by its position through linkage scans and a strong cytogenetic association. Further support comes from association studies, especially family-based ones examining the COMT variant, Val(108/158)Met. We have studied eight markers spanning COMT and including portions of the two immediately adjacent genes, thioredoxin reductase 2 and armadillo repeat deleted in velocardiofacial syndrome (ARVCF), using association testing in 136 schizophrenia families. We found nominal evidence for association of illness to rs165849 (P=0.051) in ARVCF, and a stronger signal (global P=0.0019-0.0036) from three-marker haplotypes spanning the 3' portions of COMT and ARVCF, including Val(108/158)Met with Val(108/158) being the overtransmitted allele, consistent with previous studies. We also find Val(108/158)Met to be in linkage disequilibrium with the markers in ARVCF. These findings support previous association signals of schizophrenia to COMT markers, and suggest that ARVCF might contribute to this signal. ARVCF, a member of the catenin family, besides being a positional candidate, is also one due to its function, that is, its potential role in neurodevelopment, which is implicated in schizophrenia pathogenesis by several lines of evidence.

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    • "duplication [42] spans 29 genes, of which 22 are brain-expressed and at least 9 (MAZ, CDIPT, DOC2A, TBX6, MAPK3, TAOK2, QPRT, MVP, SEZ6L2) have functions of potential relevance to SZ pathogenesis, such as neuronal differentiation, glutamate neurotransmission, synaptic plasticity, and cognition [43] [44] [45] [46] [47] [48] [49] [50] [51]. Similarly, 22qDS spans 51 genes, of which 36 are brainexpressed , and some have been previously studied as SZ candidate genes, including COMT (see review [52], PRODH (see review [53], ARVCF [54], and GNB1L [55]; several (ZDHHC8, PRODH, TBX1, COMT, DGCR8, and GNB1L) have also been suggested to be linked with a range of cognitive and psychiatric phenotypes as demonstrated by mouse models [56] [57] [58] [59] [60]. "
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    ABSTRACT: Schizophrenia (SZ) is a common and severe psychiatric disorder with both environmental and genetic risk factors, and a high heritability. After over 20 years of molecular genetics research, new molecular strategies, primarily genome-wide association studies (GWAS), have generated major tangible progress. This new data provides evidence for: (1) a number of chromosomal regions with common polymorphisms showing genome-wide association with SZ (the major histocompatibility complex, MHC, region at 6p22-p21; 18q21.2; and 2q32.1). The associated alleles present small odds ratios (the odds of a risk variant being present in cases vs. controls) and suggest causative involvement of gene regulatory mechanisms in SZ. (2) Polygenic inheritance. (3) Involvement of rare (<1%) and large (>100kb) copy number variants (CNVs). (4) A genetic overlap of SZ with autism and with bipolar disorder (BP) challenging the classical clinical classifications. Most new SZ findings (chromosomal regions and genes) have generated new biological leads. These new findings, however, still need to be translated into a better understanding of the underlying biology and into causal mechanisms. Furthermore, a considerable amount of heritability still remains unexplained (missing heritability). Deep resequencing for rare variants and system biology approaches (e.g., integrating DNA sequence and functional data) are expected to further improve our understanding of the genetic architecture of SZ and its underlying biology.
    Brain research bulletin 04/2010; 83(3-4):93-102. DOI:10.1016/j.brainresbull.2010.04.009 · 2.72 Impact Factor
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    • "The absence of a COMT Val108/158Met genotype by group interaction observed here is in in line with evidence for a weak or absent association of this polymorphism with schizophrenia (Munafo et al., 2005) and the failure to find a greater effect of this genotype on working memory and prefrontal function in schizophrenic patients (Bertolino et al., 2006; Egan et al., 2001; Ho et al., 2005). It has been suggested that other polymorphisms in the COMT gene (Chen et al., 2004; Handoko et al., 2005; Sanders et al., 2005), interactions with risk alleles of other genes (Lawrie et al., 2008; Nicodemus et al., 2007; Roffman et al., 2008a; Tan et al., 2008) and environmental influences (Caspi et al., 2005) may constitute a background of risk factors that could interact with the COMT Val108/158Met polymorphism to increase schizophrenia susceptibility, which could be manifested, in part, as a structural change in the medial temporal lobe (Job et al., 2005). "
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    ABSTRACT: Abnormalities of the medial temporal lobe have been consistently demonstrated in schizophrenia. A common functional polymorphism, Val108/158Met, in the putative schizophrenia susceptibility gene, catechol-O-methyltransferase (COMT), has been shown to influence medial temporal lobe function. However, the effects of this polymorphism on volumes of medial temporal lobe structures, particularly in patients with schizophrenia, are less clear. Here we measured the effects of COMT Val108/158Met genotype on the volume of two regions within the medial temporal lobe, the amygdala and hippocampus, in patients with schizophrenia and healthy control subjects. We obtained MRI and genotype data for 98 schizophrenic patients and 114 matched controls. An automated atlas-based segmentation algorithm was used to generate volumetric measures of the amygdala and hippocampus. Regression analyses included COMT met allele load as an additive effect, and also controlled for age, intracranial volume, gender and acquisition site. Across patients and controls, each copy of the COMT met allele was associated on average with a 2.6% increase in right amygdala volume, a 3.8% increase in left amygdala volume and a 2.2% increase in right hippocampus volume. There were no effects of COMT genotype on volumes of the whole brain and prefrontal regions. Thus, the COMT Val108/158Met polymorphism was shown to influence medial temporal lobe volumes in a linear-additive manner, mirroring its effect on dopamine catabolism. Taken together with previous work, our data support a model in which lower COMT activity, and a resulting elevation in extracellular dopamine levels, stimulates growth of medial temporal lobe structures.
    NeuroImage 12/2009; 53(3):992-1000. DOI:10.1016/j.neuroimage.2009.12.046 · 6.36 Impact Factor
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    • "However, the results from association studies attempting to examine the COMT Val158Met polymorphism as a specific risk gene for schizophrenia have shown great inconsistency. Earlier studies found an association of schizophrenia with the Met allele (Park et al., 2002; Ohmori et al., 1998; Kotler et al., 1999), whereas later evidence favoured an association with the Val allele (Glatt et al., 2003; Wonodi et al., 2003; Kremer et al., 2003; Chen et al., 2004b; Sanders et al., 2005). Two recent meta-analyses found minimal or no evidence for an association between the COMT Val158Met polymorphism and schizophrenia (Fan et al., 2005; Munafo et al., 2005), comparable to a recent study in two large samples (Williams et al., 2005). "
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    ABSTRACT: Gene-environment interactions involving the catechol-O-methyltransferase Val(158)Met polymorphism (COMT(Val158Met)) have been implicated in the causation of psychosis. Evidence from general population studies suggests that Met/Met subjects are sensitive to stress, a trait associated with psychosis. We hypothesized that the Met allele would moderate the effects of stress on negative affect (NA) in controls, and on NA and psychosis in patients with a psychotic disorder. Thirty-one patients with a psychotic disorder and comorbid cannabis misuse and 25 healthy cannabis users were studied with the experience sampling method (ESM), a structured diary technique assessing current context and emotional and psychotic experiences in daily life. A significant interaction between COMT(Val158Met) genotype and ESM stress in the model of NA was found for patients (interaction chi(2) = 7.4, P = 0.02), but not for controls (interaction chi(2) = 3.8, P = 0.15). In the model of ESM psychosis, a significant interaction between COMT(Val158Met) genotype and ESM stress was also apparent (interaction chi(2) = 11.6, P < 0.01), with Met/Met patients showing the largest increase in psychotic experiences as well as NA in reaction to ESM stress. The findings suggest that the COMT(Val158Met) polymorphism moderates affective and psychotic responses to stress in patients with psychosis, providing evidence for gene-environment interaction mechanisms in the formation of psychotic symptoms.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2008; 147B(1):10-7. DOI:10.1002/ajmg.b.30559 · 3.42 Impact Factor
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