Amihai Rigbi

Why do young women smoke? III. Attention and impulsivity as neurocognitive predisposing factors

Since nicotine has been shown to facilitate sustained attention and control of impulsivity, impairment in these domains may influence individuals who initiate smoking for various reasons to continue to smoke cigarettes. The purpose of this study was to determine whether young women who smoke regularly but are not abstinent at the time of testing, differ in their cognitive functioning from non-smokers and whether they resemble women who smoked in the past but quit. Female undergraduate students aged 20-30 years were recruited by advertisement from institutes of higher education in the Jerusalem area. The study sample consisted of 91 current smokers (CS), 40 past smokers (PS) and 151 non-smokers (NS). 46 occasional smokers (OS) were also tested. Confounding by withdrawal state was neutralized by including only CS and OS who smoked their last cigarette less than 90 min before testing. Subjects performed a computerized neurocognitive battery, which tests the domains of attention, memory, impulsivity, planning, information processing and motor performance. Analyses were controlled for age. The results showed that CS made significantly more errors than NS on the Continuous Performance Task (CPT), Matching Familiar Figures Test (MFFT) and Tower of London (TOL) test. PS were significantly worse than NS on the MFFT and TOL test. PS did not differ significantly from CS on any test. No association was found between duration of smoking and performance. These findings suggest that a neurocognitive profile characterized by impairments in sustained attention and control of impulsivity may be one of the factors that predispose young women who initiate cigarette smoking to maintain the habit.

Why do young women smoke? V. Role of direct and interactive effects of nicotinic cholinergic receptor gene variation on neurocognitive function

Previous work suggests that young women who smoke cigarettes regularly, or did so in the past, manifest a neurocognitive profile that is characterized by small but significant impairments of response inhibition and attention. The present study sought to determine whether variation in nicotinic cholinergic receptor (nAchR) genes impacts upon cognitive function in these domains by overall or differential effects on the performance of current, former and non‐smokers. The study sample consisted of 100 female college students, current or past smokers, and 144 who had never smoked. All performed a computerized neurocognitive test battery and were genotyped for 39 single nucleotide polymorphisms in 11 nAchR genes. The results, derived from linear or logistic regression, show significant direct and interactive relationships between single nucleotide polymorphisms and haplotypes in several nAchR genes and performance on the Matching Familiar Figures Test (MFFT) Stroop test, Continuous Performance Task (CPT) and Tower of London (TOL) test. Response inhibition (MFFT, Stroop, CPT Loading Phase, TOL) was associated with variants in CHRNA2, CHRNA4, CHRNA5, CHRNA7, CHRNA9, CHRNA10, CHRNB2 and CHRNB3. Selective attention (Stroop) was associated with CHRNA4, CHRNA5, CHRNA9 and CHRNB2. Sustained attention (CPT Boring Phase) was associated with CHRNA4, CHRNA5, CHRNA7, CHRNA10 and CHRNB3. Up to 37% of the variance among the smokers and up to 47% of the variance among the non‐smokers on the test measures was explained. Differences between smokers and non‐smokers in neurocognitive function, putatively implicated in susceptibility to nicotine dependence, may be modulated by variants in nAchR genes, with potential implications for prevention and treatment.

Further evidence for association of the RGS2 gene with antipsychotic-induced parkinsonism: protective role of a functional polymorphism in the 3′-untranslated region

RGS2 (regulator of G-protein signaling 2) modulates dopamine receptor signal transduction. Functional variants in the gene may influence susceptibility to extrapyramidal symptoms (EPS) induced by antipsychotic drugs. To further investigate our previous report of association of the RGS2 gene with susceptibility to antipsychotic-induced EPS, we performed a replication study. EPS were rated in 184 US patients with schizophrenia (115 African Americans, 69 Caucasian) treated for at least a month with typical antipsychotic drugs (n=45), risperidone (n=46), olanzapine (n=50) or clozapine (n=43). Six single nucleotide polymorphisms (SNPs) within or flanking RGS2 were genotyped (rs1933695, rs2179652, rs2746073, rs4606, rs1819741 and rs1152746). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. Our results indicate association of SNP rs4606 with antipsychotic-induced parkinsonism (AIP), as measured by the Simpson Angus scale, in the overall sample and in the African-American subsample, the G (minor) allele having a protective effect. ORs for AIP among rs4606 G-allele carriers were 0.23 (95% CI 0.10–0.54, P=0.001) in the overall sample, and 0.20 (0.07–0.57, P=0.003) in the African-American subsample. In the previously studied Israeli sample the OR was 0.31 (0.11–0.84, P=0.02). We completely sequenced the RGS2 gene in nine patients with AIP and nine patients without, from the Israeli sample. No common coding polymorphisms or additional regulatory variants were revealed, suggesting that association of the rs4606 C/G polymorphism with AIP is biologically meaningful and not a consequence of linkage disequilibrium with another functional variant. Taken together, the findings of the current study support the association of RGS2 with AIP and focus on a possible protective effect of the minor G allele of SNP rs4606. This SNP is located in the 3′-regulatory region of the gene, and is known to influence RGS2 mRNA levels and protein expression.

Oxytocin and vasopressin genes are significantly associated with schizophrenia in a large Arab-Israeli pedigree.

We have previously studied the genetics of schizophrenia in a large inbred Arab-Israeli pedigree and found evidence for linkage on chromosome 20p13. This locus harbours four strong candidate genes for schizophrenia: atractin (ATRN), pantonate-kinase2 (PANK2), oxytocin (OXT) and arginine-vasopressin (AVP). In this study we further explored the association of these genes with schizophrenia in the pedigree and searched for the disease-causing variants. A mutation screening of affected individuals from the pedigree was performed by using intensive sequencing in these four genes of interest. Then, we studied the prevalence of the identified variants in all family members (n=56) as well as in Arab-Israeli nuclear families (n=276) and a Jewish case-control sample (n=545). We also studied the possible functional role of these variants by examining their association with gene expression in the brain (n=104). We identified seven genetic variants in the OXT-AVP cluster in affected individuals from the pedigree. Three of these variants were significantly associated with schizophrenia in this pedigree. A 7-SNP haplotype was also significantly associated with disease. We found significant association of some of these variants in the two samples from the general population. Expression data analysis showed a possible functional role of two of these variants in regulation of gene expression. Involvement of OXT and AVP in the aetiology of schizophrenia has been suggested in the past. This study demonstrates, for the first time, a significant genetic association of these neuropeptides with schizophrenia and strongly supports this hypothesis.

Evidence for association of the GLI2 gene with tardive dyskinesia in patients with chronic schizophrenia

Tardive dyskinesia (TD) occurs in approximately 20% of patients exposed to long‐term antipsychotic treatment and may be influenced by genetic predisposition, in addition to clinical risk factors. In this study, we implemented a two‐step approach to identify susceptibility genes for TD. First, we performed a secondary analysis of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) genome‐wide association study (GWAS) dataset to identify candidate genes for TD severity. A total of 327 schizophrenia patients treated with antipsychotics who participated in the CATIE trial were included in a TD severity GWAS (approximately 495,000 SNPs). Cases were defined as demonstrating involuntary movements of a mild degree in two or more body regions or of a moderate to severe degree in at least one body region on at least two separate evaluations, whereas controls were completely free of abnormal involuntary movement on all evaluations. Using logistic regression and controlling for population stratification and relevant clinical risk factors, none of the associated SNPs reached GWAS significance; however, several promising SNPs were identified for follow‐up investigation. In the second step, we performed an association study of the top 25 SNPs in an independent sample of 170 Jewish, Israeli, schizophrenia patients (retrospective, cross‐sectional design). Association of the SNP rs3943552 T allele in the GLI2 gene with TD was observed in a subsample of Ashkenazi Jewish patients (N = 96, P = 0.018; P = 6.2 × 10−5 in the CATIE sample). The GLI2 gene encodes a transcription factor that participates in the development of the dopaminergic system during embryogenesis. Taken together, our findings support a possible contribution of GLI2 to TD susceptibility.

Lymphoblast and brain expression of AHI1 and the novel primate-specific gene, C6orf217, in schizophrenia and bipolar disorder

Association with schizophrenia of the Abelson Helper Integration Site 1 (AHI1) gene on chromosome 6q23 and the adjacent primate-specific gene, C6orf217, was demonstrated in an inbred, Arab Israeli family sample and replicated in an Icelandic case control sample. Further support was provided by a second replication in a large European sample and a meta-analysis that supported association with schizophrenia of all seven alleles overtransmitted to affected subjects in the original study. We examined constitutive expression of AHI1 and C6orf217 in immortalized lymphoblasts of patients from the Arab Israeli family sample in which the association with schizophrenia was originally discovered and population-matched normal controls, and in post-mortem brain of patients with schizophrenia and bipolar (BP) disorder and control subjects from the Stanley Medical Research Institute Collection. We found a significant effect of diagnostic group in the lymphoblast sample (F=5.72; df=2,39; p=0.006). Patients with early age of onset had higher AHI1 expression than controls and later onset patients (p=0.002; 0.03 respectively). C6orf217 expression in lymphoblasts was too low to measure. We found no difference in brain expression of AHI1 in schizophrenia or BP patients compared to controls. However, there was a genotypic difference in AHI1 expression for SNP rs9321501, which was strongly associated with schizophrenia in the original study. Genotypes that included the undertransmitted C allele (CC/AC) showed lower expression than the homozygous AA genotype (F=4.73, df=2,83; p=0.028). There was no significant difference in brain expression of C6orf217 between patients and controls and no genotypic effect. This study provides further evidence for involvement of AHI1 in susceptibility to schizophrenia.

Why do young women smoke? VI. A controlled study of nicotine effects on attention: pharmacogenetic interactions

In prior studies we found that young, female smokers manifest poorer performance than non-smokers on attention-related tasks and that these findings can be moderated by variation in nicotinic acetylcholine receptor (nAChR) genes. We predicted that under controlled conditions (1) nicotine would improve functioning on attentional tasks in smokers who previously manifested relatively poor performance, and that (2) smokers who carry genetic variations associated with poorer attention performance would derive greater benefit from nicotine. To test these hypotheses, 31 young female smokers, who participated in our previous study, performed the Matching Familiar Figures Test (MFFT), Tower of London Test and Continuous Performance Task (CPT) in a double-blind, within-between subject design, placebo or nicotine (4 mg as gum) serving as the within factor and genetic profile as the between factor. Repeated measures ANCOVA controlling for attention deficit symptomatology, substance abuse and nicotine dependence showed better performance under nicotine among participants with higher levels of attention deficit symptoms (MFFT errors: P=0.04; CPT commissions: P=0.01) and nicotine dependence (CPT stability of response: P=0.04) and greater consumption of caffeine (CPT stability of response: P=0.04). An interactive effect of genetic profile was demonstrated for SNP rs2337980 in CHRNA7. These findings suggest that nicotine may have stronger short-term facilitating effects on attention in women who have more attention deficit symptoms and consume more nicotine and caffeine. This effect may be modified by a specific genetic make-up. Such individuals may be at increased risk for nicotine addiction and for greater difficulties in smoking cessation.

Involvement of PTPN5, the gene encoding the striatal-enriched protein tyrosine phosphatase, in schizophrenia and cognition.

Objective Striatal-enriched protein tyrosine phosphatase (STEP) is a brain-specific member of the protein tyrosine phosphatase (PTP) family that has been implicated in learning and memory. In this study, we examined the association of the protein tyrosine phosphatase non-receptor 5 (PTPN5) gene, which encodes for STEP, with both schizophrenia and cognitive functioning in the Israeli Jewish population. Methods A schizophrenia (SZ) case–control study of 868 participants was carried out (286 patients and 582 controls). Eleven PTPN5 tagging single-nucleotide polymorphisms (SNPs) were selected and single markers and haplotype association analyses were carried out. A cognitive variability study included 437 healthy women who completed a computerized cognitive battery. We performed univariate associations between the SNPs and cognitive performance. The possible functional role of these variants was examined by studying their association with gene expression levels in the brain. Results In the SZ study, we found a nominal association in the whole sample between rs4075664 and SZ. Male patients with SZ showed a more significant association for three SNPs (rs4075664, rs2278732, and rs4757710). Haplotypes of the studied SNPs were associated with SZ both in the overall sample and within the male subsample. Expression analysis provided some support for the effects of the associated SNPs on PTPN5 expression level. The cognitive variability study showed positive associations between PTPN5 SNPs and different cognitive subtests. Principal component analysis showed an ‘attention index’ neurocognitive component that was associated with two SNP pairs (rs10832983×rs10766504 and rs7932938×rs4757718). Conclusion The results imply a model in which PTPN5 may play a role in normal cognitive functioning and contribute to aspects of the neuropathology of SZ.

Evidence for an Interaction of Schizophrenia Susceptibility Loci on Chromosome 6q23.3 and 10q24.33-q26.13 in Arab Israeli Families

A genome scan for schizophrenia related loci in Arab Israeli families by Lerer et al. [Lerer et al. ( 2003 ); Mol Psychiatry 8:488–498] detected significant evidence for linkage at chromosome 6q23. Subsequent fine mapping [Levi et al. ( 2005 ); Eur J Hum Genet 13:763–771], association [Amann‐Zalcenstein et al. (2006); Eur J Hum Genet 14:1111–1119] and replication studies [Ingason et al. ( 2007 ); Eur J Hum Genet 15:988–991] identified AHI1 as a putative susceptibility gene. The same genome scan revealed suggestive evidence for a schizophrenia susceptibility locus in the 10q23–26 region. Genes at these two loci may act independently in the pathogenesis of the disease in our homogeneous sample of Arab Israeli families or may interact with each other and with other factors in a common biological pathway. The purpose of our current study was to test the hypothesis of genetic interaction between these two loci and to identify the type of interaction between them. The initial stage of our study focused on the 10q23–q26 region which has not been explored further in our sample. The second stage of the study included a test for possible genetic interaction between the 6q23.3 locus and the refined 10q24.33–q26.13 locus. A final candidate region of 19.9 Mb between markers D10S222 (105.3 Mb) and D10S587 (125.2 Mb) was found on chromosome 10 by non‐parametric and parametric linkage analyses. These linkage findings are consistent with previous reports in the same chromosomal region. Two‐locus multipoint linkage analysis under three complex disease inheritance models (heterogeneity, multiplicative, and additive models) yielded a best maximum LOD score of 7.45 under the multiplicative model suggesting overlapping function of the 6q23.3 and 10q24.33–q26.13 loci.

Why do young women smoke? VII COMT as a risk modifying gene for Nicotine dependence - role of gene-gene interaction, personality, and environmental factors.

Catechol‐O‐methyltransferase (COMT) may be a risk modifying gene for Nicotine dependence (ND) rather than a direct susceptibility gene for this phenotype. Brain nicotinic cholinergic receptors modulate dopaminergic transmission, and several variants within the neighboring CHRNA5–CHRNA3 genes have been associated with ND. Therefore, it is biologically reasonable to study the interactive contribution of COMT and the CHRNA5 and CHRNA3 genes to ND.