Epistasis between COMT Val158Met and DRD3 Ser9Gly polymorphisms and cognitive function in schizophrenia: genetic influence on dopamine transmission

Abstract

Objective: To assess the relationship between cognitive function, a proposed schizophrenia endophenotype, and two genetic polymorphisms related to dopamine function, catechol-O-methyl transferase (COMT) Val 158 Met and dopamine receptor 3 (DRD3) Ser 9 Gly. Methods: Fifty-eight outpatients with schizophrenia/schizoaffective disorder and 88 healthy controls underwent neurocognitive testing and genotyping. Analyses of covariance (ANCOVAs) using age, sex, and years of education as covariates compared cognitive performance for the proposed genotypes in patients and controls. ANCOVAs also tested for the epistatic effect of COMT and DRD3 genotype combinations on cognitive performance. Conclusion: Combined genetic polymorphisms related to dopamine neurotransmission might influence executive function in schizophrenia. Looking at the effects of multiple genes on a single disease trait (epistasis) provides a comprehensive and more reliable way to determine genetic effects on endophenotypes.

Effects of aripiprazole on pupillometric parameters related to pharmacokinetics and pharmacogenetics after single oral administration to healthy subjects

“…In case of -141C Ins/Del (rs1799732) polymorphism, Del allele carriers were associated with lower antipsychotic drug response, compared to Ins/Ins genotype (Zhang et al, 2010). Another study showed that Gly/Gly genotype was more common among schizophrenia patients than Ser/Ser genotype for DRD3 Ser9Gly (rs6280) polymorphism in comparison with healthy controls, therefore, Gly/Gly can be considered as a risk factor for the disease (Loch et al, 2015). Moreover, between paediatric patients under antipsychotic treatment the ATP Binding Cassette Subfamily B Member 1 ( ABCB1 , coding for P-glycoprotein) T allele carriers for G2677T/A and C3435T polymorphisms had significantly lower plasma concentration/dose ratio for ARI related to patients with other ABCB1 genotypes (Rafaniello et al, 2017).…”

The Role of Dopaminergic Genes in Probabilistic Reinforcement Learning in Schizophrenia Spectrum Disorders

“…Moreover, it should be noted that there are several other dopaminergic receptors that should be investigated in the future [ 99 ], especially D3 receptors, which has been involved in pathophysiological mechanisms underlying cognitive impairment observed in patients with SZ [ 100 ] as well as in RL [ 101 ]. Finally, epistatic interactions between dopaminergic genes should be given more attention, since looking at the effects of multiple genes on a single trait provides a comprehensive and more reliable way to determine genetic effects on endophenotype, as shown for example in a study on the combined effect of COMT (rs4680) and DRD3 (rs6289) on cognition in SZ [ 102 ] or response to treatment [ 103 ]. It should also be mentioned that considering the candidate gene approach, we included relatively small sample of participant.…”

Diversity matters: opportunities in the study of the genetics of psychotic disorders in low- and middle-income countries in Latin America

“…The authors made all the results available, which comprised the raw data of every study, including the country of origin and ethnicity of each sample. Among the 1,188 eligible publications, only 19 were from Latin America, which represents 1.5% of the included reports: Brazil (13 studies [48][49][50][51][52][53][54][55][56][57][58][59] ), Mexico (four studies [60][61][62][63], and Costa Rica (two studies 64,65 ), although the samples overlapped considerably. Overall, the 19 studies assessed seven cohorts, all with relatively small sample sizes, totaling 1,426 cases (range = 69-421; standard deviation [SD] = 120.1) and 2,020 controls (range = 85-834; SD = 298.0), whose ethnicities were described as ''Mixed.…”