Article

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/sj.mp.4001586
Source: PubMed

ABSTRACT

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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    • "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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    • "A Val 158 Met functional polymorphism in the Catechol-O- Methyltransferase (COMT) gene has received much attention as a candidate gene for schizophrenia, given its role in dopamine breakdown and because of its genomic localization in the 22q11 region, a region which is deleted in the velo-cardialefacial syndrome, of which the psychiatric presentation resembles the clinical syndrome of schizophrenia [1] [21]. Whereas earlier studies found an association of schizophrenia with the Met allele [16] [18] and later evidence favored an association with the Val allele [3] [5] [7] [19] [27], two recent meta-analyses found minimal or no evidence for an association between COMT Val158Met and schizophrenia [4] [14]. An interesting approach to overcome problems associated with simple gene-disorder association analyses is the use of smaller samples consisting of pairs of relatives, in order to study the association between allele sharing and a certain illness, or alternatively, the influence of a candidate polymorphism on measures of psychopathology. "

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