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G30, DISCI AND BDNF CANDIDATE GENES WITH COGNITION IN PATIENTS WITH SCHIZOPHRENIA AND HEALTHY CONTROLS
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Abstracts of the 3rd Biennial Schizophrenia International Research Conference / Schizophrenia Research 136, Supplement 1 (2012) S1–S375
(22 MZ and 14 DZ pairs) and 12 sibling pairs discordant for BD-I, and 203 healthy controls (105 MZ, 50 DZ, 48 siblings). The subjects completed the Hassles and Uplifts Scale, Response Styles to Depression Questionnaire and Coping Responses Inventory. Variables that showed statistically significant differences from the controls in both bipolar patients and the MZ discordant co-twins, but not (or less so) in the DZ discordant co-twins/siblings were identified as potential endophenotypes. Twin modelling was used to estimate the heritability and genetic correlation with BD-I of candidate endophenotypes. Results: Scores for ruminative (RUM) coping and emotional discharge (ED) were increased in both the bipolar patient groups and the MZ discordant co-twins, but not in the discordant DZ co-twins/siblings, relative to controls (RUM scores: MZ and DZ patients>controls, p=0.001, MZ cotwins>controls, p=0.05; ED scores: MZ patients>controls, p=0.001, DZ patients>controls, p=0.01, MZ co-twins>controls, p=0.05). Twin modelling gave further support for the endophenotypic status of RUM, but not for ED. RUM has significant low-moderate heritability with 23% of the total variance accounted for by additive genetic effects (h2 =0.23, 95% CI: 0.02-0.59), whereas ED was found to not even be heritable (h2 = 0.09, 95% CI: 0.00-0.52). Shared environment did not substantially explain inter-individual differences in coping responses, but unique environmental effects accounted for a significant proportion of the variance in both responses: RUM (e2 = 0.50, 95% CI: 0.36-0.67) and ED (e2 = 0.69, 95% CI: 0.47-0.90). RUM has a significant moderate-high total phenotypic correlation with BD-I (rph=0.46, 95% CI: 0.35-0.56) and a significant total phenotypic correlation with BD due to additive genetic effects (rph-a=0.43, 95% CI: 0.12-0.53). RUM has a significantly large genetic correlation, with all of its genes found to be shared with BD-I (rg=1.00, 95% CI: 0.32-1.00). Genetic influences account for 93% of the phenotypic correlation between RUM and BD-I. Discussion: This study has implications for clinical research, suggesting that future studies should focus on identifying how psychological variables predispose individuals to, and subsequently maintain, bipolar affective states. Data from this study suggests that a ruminative coping response may be an early indicator of BD-I in twins and siblings at risk for illness, and potentially in other individuals with a genetic propensity to develop this disorder. The significant shared genetic variance between BD-I and rumination adds support to its endophenotypic potential and the next step will be to identify specific genes that influence both this coping response and the disorder.
Poster #102 THE ASSOCIATION OF NRG1, DTNBP1, RGS4, G72/G30, DISC1 AND BDNF CANDIDATE GENES WITH COGNITION IN PATIENTS WITH SCHIZOPHRENIA AND HEALTHY CONTROLS János M. Réthelyi, Patrícia Polgár, Judit Benkovits, Kinga Farkas, Attila J. Pulay, Pál Czobor, István Bitter Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary Background: Previous studies have indicated association of schizophrenia candidate genes with neurocognition both in patients with schizophrenia and healthy individuals. Earlier in the same sample we have shown differential association of candidate genes with symptom severity in patients. The objective of this study was to test the most extensively researched schizophrenia candidate genes for association with domain-specific cognitive functions. Methods: Cognitive functioning was assessed in a subsample of 263 patients with a DSM-IV diagnosis of schizophrenia and 135 healthy controls by a neuropsychological test-battery measuring the domains of sustained vigilance/attention, working memory, short-term memory, verbal memory, cognitive flexibility, and ideation fluency. Using the raw neuropsychological measures we calculated a global index of cognitive impairment and domain-specific composite z-scores. Clinical assessment was performed using the Schedule for Deficit Syndrome and the Positive and Negative Symptom Scale. DNA samples were genotyped for polymorphisms of the candidate genes NRG1, DTNBP1, RGS4, G72/G30, DISC1 and BDNF. Association between the above composite scores and the SNPs was examined using the General Linear Model (GLM) analysis. Results: The preliminary analyses uncovered statistically significant associations between DTNBP1 rs909706 and the global index of cognitive
impairment (F=3,39; p=0,03), and cognitive flexibility (F=4,81; p=0,01), and DTNBP1 rs1011313 and short-term memory (F=3,66; p=0,02). RGS4 rs10917670 was associated with working-memory (F=4,28; p=0.01). We found significant association between global cognitive impairment and rs821616 in DISC1 (F=3.02, p=0.05) and rs6265 in BDNF (F=4.47, p=0.01); moreover rs6265 was associated with working memory (F=6.22, p=0.002) and attention (F=7.27, p=0.0074). We found no association of NRG1and G72/G30 with the domains of cognitive functioning. Discussion: Using neurocognition as an endophenotype for psychotic disorders in genetic studies has the potential to determine common and separate genetic factors influencing disease risk and neurocognition.
Poster #103 COMT MET158 ALLELE IS ASSOCIATED WITH VIOLENCE IN SCHIZOPHRENIA: A META-ANALYSIS Savita G. Bhakta 1 , Jian-Ping Zhang 1 , Anil K. Malhotra 1,2 1 Hofstra-NSLIJ School of Medicine/The Zucker Hillside Hospital, Glen Oaks, New York, USA; 2 Feinstein Institute for Medical Research, Manhasset, New York, USA Background: Several studies have shown a higher incidence of aggression and violent behavior including homicide in schizophrenia, estimated at 2-10 times that of general population. However, the etiology of violence is complex and multi-factorial. While substance abuse, delusions, medication compliance are associated with aggressive behavior, certain genetic factors may put schizophrenic patients at higher risk of violence. Several studies have examined the association of Catechol-O-methyl transferase (COMT) gene and risk for violence and aggressive behavior in patients with schizophrenia. A common functional COMT polymorphism, rs4680, changes a valine (val) residue to methionine (met) in codon 158 of COMT resulting in 3-4 fold higher enzymatic activity in the Val/Val than in Met/Met homozygotes. The Met158 allele of COMT gene is associated with increased levels of catecholamines in the frontal cortex and may increase the likelihood of aggressiveness. We conducted a meta-analysis to test the hypothesis that Met158 allele of COMT gene is associated with aggressive and violent behavior in schizophrenia. Methods: MEDLINE search (10/4/11) yielded 14 studies of the association of the COMT gene and aggression in schizophrenia. Data was available for all identified studies encompassing a cohort of 2219 patients with schizophrenia with or without history of violence. Meta-analyses were conducted for the Met158Val polymorphism (rs4680) using a random effects model. Three separate analyses were conducted for Met allele carriers vs. Val/Val homozygotes, Met/Met homozygotes vs. Val allele carriers, and Met allele vs. Val allele, respectively. Primary outcome was frequency of patients with aggressive behavior and odds ratio (OR) was the effect size measure. Heterogeneity among studies was assessed by Q test and I-square. Publication bias was examined using the “Trim and Fill” method and Egger’s regression test. Sensitivity analysis was conducted for each meta-analysis to assess the influence of any single study. Results: The total sample included mostly men (80%) and Asians (65%), with an average age of 38 years. The frequency of violent patients in the sample ranged from 20% to 75%. The pooled effect size for the Met homozygotes vs. Val allele carriers was highly significant (OR=1.85, 95% confidence interval [CI]=1.20-2.83, p=0.005), suggesting that homozygotes for the Met allele are at greater risk for violence in schizophrenia. There was evidence of publication bias by the “trim and fill” method, however, the adjusted OR was still significant (OR=1.65, CI=1.05-2.59). Similarly, pooled OR for the Met allele carriers vs. Val homozygotes was also significant (OR=1.54, CI=1.07-2.22, p=0.021) without evidence of publication bias, suggesting that the Met158 allele carrier of the COMT gene is associated with increased risk for violence in schizophrenia. The pooled OR for the Met allele vs. Val allele (N=13, n=4174) was also significant (OR=1.35, CI=1.04-1.77, p=0.023), again suggesting that the Met allele of rs4680 is associated with risk for violence in schizophrenia. There were substantial heterogeneity across studies, but moderator analysis did not reveal any significant moderators. Sensitivity analysis after removing one study at a time from each meta-analysis did not significantly alter the results. Discussion: The results of our meta-analysis support the hypothesis that the Met158 allele of the COMT gene confers a significantly increased risk for aggressive and violent behavior in schizophrenia. These data may pro-
Abstracts of the 3rd Biennial Schizophrenia International Research Conference / Schizophrenia Research 136, Supplement 1 (2012) S1–S375
(22 MZ and 14 DZ pairs) and 12 sibling pairs discordant for BD-I, and 203 healthy controls (105 MZ, 50 DZ, 48 siblings). The subjects completed the Hassles and Uplifts Scale, Response Styles to Depression Questionnaire and Coping Responses Inventory. Variables that showed statistically significant differences from the controls in both bipolar patients and the MZ discordant co-twins, but not (or less so) in the DZ discordant co-twins/siblings were identified as potential endophenotypes. Twin modelling was used to estimate the heritability and genetic correlation with BD-I of candidate endophenotypes. Results: Scores for ruminative (RUM) coping and emotional discharge (ED) were increased in both the bipolar patient groups and the MZ discordant co-twins, but not in the discordant DZ co-twins/siblings, relative to controls (RUM scores: MZ and DZ patients>controls, p=0.001, MZ cotwins>controls, p=0.05; ED scores: MZ patients>controls, p=0.001, DZ patients>controls, p=0.01, MZ co-twins>controls, p=0.05). Twin modelling gave further support for the endophenotypic status of RUM, but not for ED. RUM has significant low-moderate heritability with 23% of the total variance accounted for by additive genetic effects (h2 =0.23, 95% CI: 0.02-0.59), whereas ED was found to not even be heritable (h2 = 0.09, 95% CI: 0.00-0.52). Shared environment did not substantially explain inter-individual differences in coping responses, but unique environmental effects accounted for a significant proportion of the variance in both responses: RUM (e2 = 0.50, 95% CI: 0.36-0.67) and ED (e2 = 0.69, 95% CI: 0.47-0.90). RUM has a significant moderate-high total phenotypic correlation with BD-I (rph=0.46, 95% CI: 0.35-0.56) and a significant total phenotypic correlation with BD due to additive genetic effects (rph-a=0.43, 95% CI: 0.12-0.53). RUM has a significantly large genetic correlation, with all of its genes found to be shared with BD-I (rg=1.00, 95% CI: 0.32-1.00). Genetic influences account for 93% of the phenotypic correlation between RUM and BD-I. Discussion: This study has implications for clinical research, suggesting that future studies should focus on identifying how psychological variables predispose individuals to, and subsequently maintain, bipolar affective states. Data from this study suggests that a ruminative coping response may be an early indicator of BD-I in twins and siblings at risk for illness, and potentially in other individuals with a genetic propensity to develop this disorder. The significant shared genetic variance between BD-I and rumination adds support to its endophenotypic potential and the next step will be to identify specific genes that influence both this coping response and the disorder.
Poster #102 THE ASSOCIATION OF NRG1, DTNBP1, RGS4, G72/G30, DISC1 AND BDNF CANDIDATE GENES WITH COGNITION IN PATIENTS WITH SCHIZOPHRENIA AND HEALTHY CONTROLS János M. Réthelyi, Patrícia Polgár, Judit Benkovits, Kinga Farkas, Attila J. Pulay, Pál Czobor, István Bitter Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary Background: Previous studies have indicated association of schizophrenia candidate genes with neurocognition both in patients with schizophrenia and healthy individuals. Earlier in the same sample we have shown differential association of candidate genes with symptom severity in patients. The objective of this study was to test the most extensively researched schizophrenia candidate genes for association with domain-specific cognitive functions. Methods: Cognitive functioning was assessed in a subsample of 263 patients with a DSM-IV diagnosis of schizophrenia and 135 healthy controls by a neuropsychological test-battery measuring the domains of sustained vigilance/attention, working memory, short-term memory, verbal memory, cognitive flexibility, and ideation fluency. Using the raw neuropsychological measures we calculated a global index of cognitive impairment and domain-specific composite z-scores. Clinical assessment was performed using the Schedule for Deficit Syndrome and the Positive and Negative Symptom Scale. DNA samples were genotyped for polymorphisms of the candidate genes NRG1, DTNBP1, RGS4, G72/G30, DISC1 and BDNF. Association between the above composite scores and the SNPs was examined using the General Linear Model (GLM) analysis. Results: The preliminary analyses uncovered statistically significant associations between DTNBP1 rs909706 and the global index of cognitive
impairment (F=3,39; p=0,03), and cognitive flexibility (F=4,81; p=0,01), and DTNBP1 rs1011313 and short-term memory (F=3,66; p=0,02). RGS4 rs10917670 was associated with working-memory (F=4,28; p=0.01). We found significant association between global cognitive impairment and rs821616 in DISC1 (F=3.02, p=0.05) and rs6265 in BDNF (F=4.47, p=0.01); moreover rs6265 was associated with working memory (F=6.22, p=0.002) and attention (F=7.27, p=0.0074). We found no association of NRG1and G72/G30 with the domains of cognitive functioning. Discussion: Using neurocognition as an endophenotype for psychotic disorders in genetic studies has the potential to determine common and separate genetic factors influencing disease risk and neurocognition.
Poster #103 COMT MET158 ALLELE IS ASSOCIATED WITH VIOLENCE IN SCHIZOPHRENIA: A META-ANALYSIS Savita G. Bhakta 1 , Jian-Ping Zhang 1 , Anil K. Malhotra 1,2 1 Hofstra-NSLIJ School of Medicine/The Zucker Hillside Hospital, Glen Oaks, New York, USA; 2 Feinstein Institute for Medical Research, Manhasset, New York, USA Background: Several studies have shown a higher incidence of aggression and violent behavior including homicide in schizophrenia, estimated at 2-10 times that of general population. However, the etiology of violence is complex and multi-factorial. While substance abuse, delusions, medication compliance are associated with aggressive behavior, certain genetic factors may put schizophrenic patients at higher risk of violence. Several studies have examined the association of Catechol-O-methyl transferase (COMT) gene and risk for violence and aggressive behavior in patients with schizophrenia. A common functional COMT polymorphism, rs4680, changes a valine (val) residue to methionine (met) in codon 158 of COMT resulting in 3-4 fold higher enzymatic activity in the Val/Val than in Met/Met homozygotes. The Met158 allele of COMT gene is associated with increased levels of catecholamines in the frontal cortex and may increase the likelihood of aggressiveness. We conducted a meta-analysis to test the hypothesis that Met158 allele of COMT gene is associated with aggressive and violent behavior in schizophrenia. Methods: MEDLINE search (10/4/11) yielded 14 studies of the association of the COMT gene and aggression in schizophrenia. Data was available for all identified studies encompassing a cohort of 2219 patients with schizophrenia with or without history of violence. Meta-analyses were conducted for the Met158Val polymorphism (rs4680) using a random effects model. Three separate analyses were conducted for Met allele carriers vs. Val/Val homozygotes, Met/Met homozygotes vs. Val allele carriers, and Met allele vs. Val allele, respectively. Primary outcome was frequency of patients with aggressive behavior and odds ratio (OR) was the effect size measure. Heterogeneity among studies was assessed by Q test and I-square. Publication bias was examined using the “Trim and Fill” method and Egger’s regression test. Sensitivity analysis was conducted for each meta-analysis to assess the influence of any single study. Results: The total sample included mostly men (80%) and Asians (65%), with an average age of 38 years. The frequency of violent patients in the sample ranged from 20% to 75%. The pooled effect size for the Met homozygotes vs. Val allele carriers was highly significant (OR=1.85, 95% confidence interval [CI]=1.20-2.83, p=0.005), suggesting that homozygotes for the Met allele are at greater risk for violence in schizophrenia. There was evidence of publication bias by the “trim and fill” method, however, the adjusted OR was still significant (OR=1.65, CI=1.05-2.59). Similarly, pooled OR for the Met allele carriers vs. Val homozygotes was also significant (OR=1.54, CI=1.07-2.22, p=0.021) without evidence of publication bias, suggesting that the Met158 allele carrier of the COMT gene is associated with increased risk for violence in schizophrenia. The pooled OR for the Met allele vs. Val allele (N=13, n=4174) was also significant (OR=1.35, CI=1.04-1.77, p=0.023), again suggesting that the Met allele of rs4680 is associated with risk for violence in schizophrenia. There were substantial heterogeneity across studies, but moderator analysis did not reveal any significant moderators. Sensitivity analysis after removing one study at a time from each meta-analysis did not significantly alter the results. Discussion: The results of our meta-analysis support the hypothesis that the Met158 allele of the COMT gene confers a significantly increased risk for aggressive and violent behavior in schizophrenia. These data may pro-