Association study of serotonin 2A receptor (5-HT2A) and serotonin transporter (5-HTT) gene polymorphisms with schizophrenia

OBJECTIVE: To investigate (i) the association between four serotonergic polymorphisms (A-1438G and T102C of the 5-HT2A receptor gene, and 5-HTT VNTR and 5-HTTLPR of the 5-HT transporter gene) and schizophrenia and (ii) the potential interaction of those polymorphisms in the development of schizophrenia. SUBJECTS AND METHODS: 227 outpatients with schizophrenia (DSM-IV criteria) and 420 unrelated healthy controls from Asturias (Northern Spain) were genotyped using standard methods. RESULTS: Both groups showed Hardy-Weinberg equilibrium for the analyzed genetic variability. A-1438G and T102C polymorphisms are in complete linkage disequilibrium in our population. There was an apparent difference in the distribution of genotypes for the A-1438G (or T102C) polymorphisms (p=0.018, not significant after a Bonferroni correction). The 5-HT2A -1438A (or 102T) allele was significantly more frequent in patients than controls (0.53 and 0.45, respectively; corrected p=0.028, OR=1.39 (95% CI=1.11-1.75)). Genotype and allele distributions for 5-HTT polymorphisms were similar in both groups. However, assessment of the combined influence of 5-HT2A A-1438G and 5-HTTLPR polymorphisms demonstrated a significant effect (chi(2) (3)=11.51, p=0.009), whereby the combination of -1438A and 5-HTTLPR S alleles was associated with schizophrenia. CONCLUSIONS: Our findings support a possible synergistic effect of genetic factors influencing serotonergic neurotransmission on susceptibility to schizophrenia.     

5-羟色胺1A受体基因C（-1019）G多态性与精神分裂症的关联分析

目的:探讨云南地区汉族人群中5-羟色胺1A(5-HT1A)受体基因C(-1019)G多态性与精神分裂症的关联,及其对症状组成、前额叶执行功能的可能影响. 方法:应用阳性与阴性症状量表(PANSS)、简明精神病评定量表(BPRS)、外显攻击量表(OAS)等评定患者症状,威斯康星卡片分类测验(WCST)评定精神分裂症和正常人前额叶执行功能.142例精神分裂症患者和84名正常对照分别用聚合酶链式反应-限制性片段长度多态性(PCR-RFLP)方法进行基因分型. 结果:云南地区汉族人群中,5-HT1A受体基因启动子区C(-1019)G多态性在精神分裂症和正常人之间的各量表分差异有显著性(P=0.001).C(-1019)G多态性对PANSS中因子被动淡漠性社会退缩(N4)(P=0.010)、言语缺乏主动性和流畅性(N6)(P=0.004)、阴性症状总分(NT)(P=0.013)、紧张(G4)(P=0.005)、自发社交回避(G16)(P=0.013),以及BPRS中的因子4激活性(P=0.026)等条目得分的形成影响有显著性.C(-1019)G多态性与WCST各条目不相关. 结论:云南地区汉族人群中,5-HT1A受体基因启动子区C(-1019)G多态性与精神分裂症显著相关,对精神分裂症症状组成可能起一定作用,但与WCST反映的前额叶执行功能状态并无显著相关.     

Association of muscarinic m1 receptor genetic polymorphisms with psychiatric symptoms and cognitive function in schizophrenic patients

OBJECTIVE: The cholinergic system is important in the search for the pathophysiology of schizophrenia due to its role in cognitive function, interaction with the dopamine system in brain regions relevant to schizophrenia, side effects of antipsychotic medication and potential antipsychotic effect of muscarinic receptor antagonists. This study investigated the association of type I muscarinic receptor (CHRM1) genetic polymorphisms with the clinical characteristics of chronic schizophrenic inpatients. METHODS: We determined the genotype of CHRM1 genetic polymorphisms in 243 schizophrenic patients hospitalized in chronic care wards. Psychotic symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS), and cognitive function was assessed using the Folstein Mini-Mental Status Examination (MMSE) test. Sixty of the 243 subjects also completed the Wisconsin Card Sorting Test (WCST). RESULTS: There was a significant difference in the number of correct responses and the percentage of perseverative errors in the WCST in the CHRM1 C267A genotype group of schizophrenia patients. There was no significant association between age at onset, chlorpromazine equivalents, BPRS scores, MMSE or schizophrenia per se in patients with the CHRM1 C267A genotype. The full exon of the CHRM1 gene was screened out with single-strand conformation polymorphism, and 2 single nucleotide polymorphisms (C267A and C1353T) were identified in our patients and control subjects. These 2 single nucleotide polymorphisms were linked together without exception. CONCLUSION: This study demonstrated that in schizophrenic patients, the heterozygote group of CHRM1 C267A polymorphism (267C/A) had more correct responses and less perseverative errors on the WCST performance than the 267C/C homozygote group, implicating that this polymorphism may be related to prefrontal cortical function. Our results also suggested that the C267A polymorphism plays no major role in the susceptibility to and clinical manifestations of schizophrenia.     

5-羟色胺2A受体基因多态性与抑郁症的关联研究

目的探讨5-羟色胺2A（5-HT2A）受体基因T102C和A-1438G多态性与抑郁症的关系。方法采用聚合酶链式反应（PCR）和限制性片断长度多态性（RFLP）技术检测123例抑郁症患者和122名健康对照的T102C和A-1438G基因多态性分布,病例-对照关联分析法分析两组间基因型频率和等位基因频率的差异。结果5-HT2A基因T102C多态性等位基因频率和A-1438G等位基因频率在患者组和对照组间的分布均有显著性差异（P〈0．05）,患者组C102等位基因频率（30．1％）明显低于对照组（41．0％）,在分层分析中,男性患者组中频率（26．2％）明显低于男性对照组（50．0oA）;患者组A-1438等位基因型频率（69．1％）明显高于对照组（56．6％）,A-1438等位基因在女性患者组中频率（69．1％）明显高于女性对照组（55．2％）。患者组中TT／AA（T102T／A-1438A）基因型组合频率（43．9％）明显高于对照组（20．5％）。结论5-HT2A基因T102C和A-1438G多态性可能与抑郁症的发病有关,其中C102等位基因可能是男性罹患抑郁症的保护因子,A-1438等位基因可能是抑郁症特别是女性抑郁症患病的危险因子,T102T和A—1438A基因型同时出现可能是抑郁症发病的重要危险因素。     

精神分裂症患者多巴胺D1受体基因-48A/G多态性与认知功能的关系

目的探讨精神分裂症患者多巴胺D1受体基因-48A／G多态性与认知功能的关系。方法应用聚合酶链反应-限制性片段长度多态性方法(PCR-RFLP),检测103例精神分裂症患者多巴胺D1受体基因-48A／G多态性。采用威斯康星卡片分类测验(Wiscosin Card Sorting Test,WCST)和韦氏成人智力量表修订版(Wechsler Adult Intelligence Scale-RC,WAIS-RC)评估患者的认知功能。结果其中分类数、错误应答数、持续应答数、非持续错误数、算术、数字广度(顺)、数字符号及木块图得分在AA基因型和AG+GG基因型两组患者间均无显著性差异(P>0．05),但持续错误数(t=2．321,P<0．05)和数字广度(逆)(t=3．042,P<0．01)在两组间有显著性差异,AA基因型患者持续错误数和数字广度(逆)得分明显高于AG+GG基因型患者。结论精神分裂症患者D1受体基因-48A／G多态性与持续性错误数及数字广度(逆)相关,AA基因型精神分裂症患者较AG+GG基因型患者工作记忆受损更严重,但短时记忆能力要强于后者。     

Association of 5-HT2A receptor gene polymorphisms with gastrointestinal disorders in Egyptian children with autistic disorder

Gastrointestinal disturbances (GID) are frequently reported in children with autism spectrum disorders (ASD). Recently, mounting evidence suggests that there may be a genetic link for autism with gastrointestinal disturbances.We aimed to investigate whether there were any association between the -1438A/G, 102T/C and His452Tyr polymorphisms of the serotonin 2A receptor gene (5-HT2A) in Egyptian children with ASD and GID. Eighty children with autistic disorder and 100 healthy control children were examined. -1438A/G, 102T/C and His452Tyr polymorphisms of 5-HT2A were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Significant increase of the G allele and the GG genotype of the -1438A/G polymorphism was observed in children with autism than control, but there were no significant differences in the frequencies either of the 102T/C genotype or His452Tyr genotype between the two groups. There was a significant increase of homozygote A allele of the -1438A/G and CC genotype of the 102T/C polymorphism in ASD children with GID. This study supports the possible involvement of the 5-HT2A receptor in the development of ASD and associated GID.     

Genetic influences on frontal brain function: WCST performance in twins

The Wisconsin Card Sorting Test (WCST) is one of the most widely used assessments of executive functioning related to prefrontal cortex. However, little is known about genetic and environmental determinants of individual differences in WCST performance. This study assessed heritability of standard WCST scores in a sample of 168 young female twins including 58 monozygotic and 25 dizygotic pairs. Several WSCT indices, including the number and percentage of errors, the number of perseverative responses, and the number and percent of perseverative errors, showed significant heritability ranging from 37 to 46%. The results suggest that selected aspects of frontal executive functioning measured by the WCST are moderately influenced by genetic factors.     

T102C and -1438 G/A polymorphisms of the 5-HT2A receptor gene in Turkish patients with obsessive-compulsive disorder.

OBJECTIVE: This study aimed to investigate the possible association between T102C and -1438 G/A polymorphism in the 5-HT2A receptor gene and susceptibility to and clinical features of obsessive-compulsive disorder (OCD). METHOD: Fifty-eight patients with OCD and 83 healthy controls were included in the study. All patients were interviewed and rated by Yale-Brown Obsessive-Compulsive Scale. T102C and -1438 G/A polymorphisms of 5-HT2A receptor gene were determined by PCR technique in DNAs of peripheral leucocytes. RESULTS: OCD patients and healthy controls did not show significant differences in genotype distribution for both polymorphisms investigated. We found that frequencies of the TT genotype for T102C polymorphism and the AA genotype for -1438 G/A polymorphism were significantly higher in patients with severe OCD compared to those with moderate or moderate-severe OCD. CONCLUSION: The -1438 G/A and T102C polymorphisms of the 5-HT2A receptor gene are not associated with an increased risk of OCD. Our data suggest that the TT genotype of T102C and the AA genotype of -1438 G/A polymorphism might be a factor in clinical severity of OCD.     

5-羟色胺2A受体基因多态性与抑郁症的关联

目的：探讨中国汉族人群难治性抑郁症患者与5-羟色胺2A(5-HT2A)受体基因的T102C多态性之间的关系。方法：抽取79例难治性抑郁症患者作研究，以102名正常人作对照。应用聚合酶链式反应(PCR)扩增技术及限制性片段长度多态性(RFLP)分别测定所有研究对象的5-HT2A受体基因的基因型和等位基因。结果：5-HT2A受体基因的3种基因型(A1／A1，A1／A2和A2／A2)在难治性抑郁症组的分布分别为31．6％、54．4％和13．9％，在对照组分别为29．4％、45．1％和25．5％，两组间差异无显著性。结论：5-HB。受体基因的T102C多态性与难治性抑郁症之间无显著关联。     

Association of the 5-HT2A receptor gene polymorphism 102 T/C with ischemic stroke

Serotonin (5-HT) has been implicated in a number of cardiovascular disorders due to its ability to induce vascular contraction and platelet aggregation through activation of the 5-HT2 receptor family. In this study, we investigated the association of stroke in a Scandinavian population with two common polymorphisms in the 5-HT2A receptor gene. The two polymorphisms under investigation, namely the 102T/C and the −1438A/G variations of the 5-HT2A receptor gene, were examined in a case control association study involving 99 stroke patients and a comparable number of controls. Among patients, the prevalence of the homozygous 102T/T genotype was significantly higher than in controls (28.3% vs 13.5%; p<0.01). The allelic frequency of 102T carriers was also significantly higher in stroke patients than in controls (p=0.002, OR=1.88, 95%CI, 1.27–2.80). The association between the 102T allele and stroke was significant in both males and females. There was no association between stroke and the −1438A/G polymorphism. Taken together, this study indicates that the 102T/C polymorphism in the 5-HT2A receptor gene could be an independent risk factor for developing stroke.     

Association between the serotonin 2A receptor gene and tardive dyskinesia in chronic schizophrenia

Tardive dyskinesia (TD) is a long-term adverse effect of antipsychotic drugs that are dopamine D2 receptor blockers.(1) Serotonin receptor antagonism has been proposed as a common mechanism contributing to the low extrapyramidal effects profile of atypical antipsychotic drugs.(2) We examined the association of three polymorphisms in the 5-HT2A receptor gene (HTR2A) with TD susceptibility--T102C(3) and his452tyr(4) in the coding region and A-1438G(5) in the promoter--in matched schizophrenia patients with (n = 59, SCZ-TD-Y) and without TD (n = 62, SCZ-TD-N) and normal control subjects (n = 96). The T102C and the A-1438G polymorphisms are in complete linkage disequilibrium but not his452tyr. There was a significant excess of 102C and -1438G alleles (62.7%) in the SCZ-TD-Y patients compared to SCZ-TD-N patients (41.1%) and controls (45.9%; chi(2) = 12.8, df = 2, P = 0.002; SCZ-TD-Y vs SCZ-TD-N, chi(2) = 11.4, df = 1, P = 0.0008, OR 2.41, 95% CI 1.43-3.99) and of 102CC and -1438GG genotypes (SCZ-TD-Y 42.4%, SCZ-TD-N, 16.1%, controls 20.8%, chi(2) = 13.3, df = 4, P = 0.01). The 102CC and the -1438GG genotypes were associated with significantly higher AIMS trunk dyskinesia scores (F = 3.9; df = 2, 116; P = 0.02) and more incapacitation (F = 5.0; df = 2, 115; P = 0.006). The his452tyr polymorphism showed no association with TD. These findings suggest that the 5-HT2A receptor gene is significantly associated with susceptibility to TD in patients with chronic schizophrenia. Previously reported association of the T102C and A-1438G polymorphisms with schizophrenia(6) may reflect association of a sub-group of patients with a susceptibility to abnormal involuntary movements related to antipsychotic drug exposure.     

Inter-relationships of intermediate phenotypes for serotonin function, impulsivity, and a 5-HT2A candidate allele: His452Tyr

Central serotonin (5-hydroxytryptamine, 5-HT) function has a role in a range of genetically influenced psychiatric diagnoses and behaviors. Several human 5-HT receptor polymorphisms are 'candidate alleles', altering in vitro function, and potentially affecting behavior and drug response. The 5-HT(2A) His452Tyr polymorphism alters signal transduction, and has been associated with diminished efficacy of clozapine in schizophrenia. Another 5-HT(2A) receptor polymorphism consists of the silent thymidine-cytosine substitution (102T>C), which has been controversially associated with schizophrenia. We investigated the role of His452Tyr and the 102T>C in behavior and in vivo intermediate biochemical phenotypes. Intracellular 5-HT-induced Ca(2+) release by platelets and fenfluramine-induced prolactin release by pituitary were evaluated in 27 psychiatrically interviewed subjects (including both impulsive patients and controls) stratified by His452Tyr genotype and also genotyped for a second 5-HT(2A) polymorphism, 102T>C. Subjects with increased measures of impulsivity showed decreased postreceptor 5-HT function, as indicated by reduced 5-HT-induced Ca(2+) release, but no alteration in net 5-HT function, as measured by fenfluramine response. No significant effects of either polymorphism were associated with altered 5-HT-induced calcium response or fenfluramine-stimulated prolactin release. One available Tyr452/Tyr452 homozygote had diminished Ca(2+) release and one of the highest levels of fenfluramine response. Although not statistically significant, the effect of the T102C, but not the His452Tyr, genotype on prolactin level change over time was associated with a medium to large strength of association (treatment magnitude of T(2)=0.10), suggesting that further study is warranted.     

Family-based association studies between 5-HT5A receptor gene and schizophrenia

BACKGROUND: Pharmacological and neurodevelopmental data support the idea that the gene, which codes for the 5-HT(5A) receptor is an important candidate gene for schizophrenia susceptibility. However, previous genetic studies focusing on this gene yielded conflicting results, potentially because of: (i) stratification biases of case-control association studies, (ii) genetic and phenotypic heterogeneity of schizophrenia, and (iii) variability in the loci analyzed (the 5-HT(5A) gene having many polymorphic sites). METHODS: A transmission disequilibrium test was used in the present study aimed at investigating two polymorphisms in exon 1 of the 5-HT(5A) gene, the A12T silent substitution and the C43T transversion leading to a 15Pro --> Ser substitution, in 103 patients with DSM-IV diagnosis of schizophrenia, and their 206 parents. RESULTS: We found an excess of transmission of the 12T allele from the parents to their affected children (P = 0.02), with evidence for linkage disequilibrium between the 12T-43C haplotype and schizophrenia (P = 0.002). Furthermore, patients with the 12T allele had a significantly later age at onset (P = 0.003), and the Q-TDT approach confirmed that this allele was transmitted with an older age at onset (P = 0.01). CONCLUSIONS: These data provided convergent evidence for a significant role of the 5-HT(5A) gene in schizophrenia and more specifically in patients with later age at onset.     

5-羟色胺2A受体基因多态与海洛因成瘾及渴求程度的关联分析

目的探讨5-HT2A-1438A／G基因多态与海洛因成瘾及线索诱发海洛因渴求程度的关系。方法采 用PCR-RFLP技术对380例海洛因依赖者(依赖组)和275名健康人(对照组)的5-HT2A-1438A／G基因多态进行检 测,并对依赖组行线索诱发海洛因渴求实验。比较依赖组和对照组的5-HT2A-1438A／G多态基因型及等位基因频 率,分析依赖组不同基因型与线索诱发海洛因渴求程度和主观戒断反应的关系。结果 (1)依赖组与对照组的5- HT2A-1438A／G的基因型和等位基因频率均无显著性差异(P>0．05)。(2)依赖组中,5-HT2A-1438A／G的3种多态 基因型诱发渴求和主观戒断反应的差异有统计学意义(P<0．05),G／G基因型诱发渴求和主观戒断反应均小于A／ A(P=0．024,P=0．009)和A／G(P=0．018,P=0．011)基因型。结论未发现5-HT2A-1438A／G基因多态与海洛 因成瘾有关,但该基因多态性与线索诱发海洛因的渴求程度有关,A+(A／A和A／G)携带者线索诱发海洛因的渴求 程度和主观戒断反应明显高于A-(G／G)携带者。     

Genetic association analysis of 5-HT(6) receptor gene polymorphism (267C/T) with tardive dyskinesia

Possible involvement of serotonergic (5-hydroxytryptamine: 5-HT) receptors in the pathophysiology of tardive dyskinesia (TD) has been suggested. In the present study, the relationship between the 5-HT(6) receptor gene (HTR6) polymorphisms and TD was studied in 173 Japanese patients with schizophrenia. The 267C/T allele of HTR6 was genotyped using PCR amplification followed by endonuclease digestion. The patients with the three 267C/T genotypes showed no significant difference in gender, age, duration of illness, or current antipsychotic dose. In addition, there were no significant differences in total AIMS scores among patients with the three genotypes. Moreover, no significant differences in genotypes and allele frequencies were observed between subjects with and without TD. These results suggest that the 267C/T polymorphism of HTR6 does not confer increased susceptibility to TD.     

Mutation and association analysis of the 5' region of the dopamine D3 receptor gene in schizophrenia patients: identification of the Ala38Thr polymorphism and suggested association between DRD3 haplotypes and schizophrenia

Although the association between the Ser9Gly polymorphism of the dopamine D3 receptor gene (DRD3) and schizophrenia has been investigated by many research groups, it is not known whether the Ser9Gly polymorphism alone or a variation in linkage disequilibrium may effect susceptibility to schizophrenia. We searched the 5' region of the DRD3 gene and found three novel polymorphisms: -712G/C, -205A/G, and Ala38Thr. The Ala38Thr polymorphism is located in the first transmembrane region and is conserved in the monkey, mouse, and rat. Case-control comparisons in 153 Japanese schizophrenia patients and 122 Japanese controls did not suggest an association between Ala38Thr and schizophrenia. However, there was a marginally significant association between the Ser9 allele of the Ser9Gly polymorphisms and schizophrenia (P = 0.02). Furthermore, there was a highly significant association between haplotypes of the -712G/C, -205A/G, and Ser9Gly polymorphisms and schizophrenia (P = 0.0007, corrected P = 0.007). These positive findings were replicated in an additional 99 Japanese schizophrenia patients and 132 controls (P = 0.04 and 0.0004, respectively). The most allelic differences of the Ser9Gly polymorphism between patient and control groups arose from the chromosome carrying specific alleles of the other three polymorphisms. This study indicates unknown variant(s) in linkage disequilibrium with the DRD3 haplotypes associated with schizophrenia.     

Lack of an association between 5-HT receptor gene polymorphisms and suicide victims

An association between serotonergic dysfunction in the brain and suicidal behavior has previously been suggested. The high affinity of some antipsychotic and antidepressant drugs to serotonin 6 (5-HT6) receptors, and the predominant localization of 5-HT6 receptors in some limbic regions, suggest that 5-HT6 receptors play a role in the pathogenesis of suicide. The objective of the present study was to examine the association between suicide victims and two polymorphisms of the 5-HT6 receptor gene: a biallelic polymorphism (267C/T) in exon 1 and a trinucleotide repeat polymorphism ([GCC](2/3)) in the 5'-upstream region of the gene. The two polymorphisms were genotyped in 163 suicide victims and 166 controls, and the distribution of genotype and allele frequencies between the two groups were compared. Haplotype frequencies of these two polymorphisms were estimated from genotypic data by the maximum-likelihood method. In both polymorphisms, there were no significant differences in genotype or allele frequencies between the suicide victims and the controls. Moreover, there were no significant differences in the haplotype distributions of these polymorphisms between the two groups. These findings suggest that it is unlikely that the 5-HT6 receptor gene is involved in the susceptibility to suicide.     

Risperidone response and 5-HT6 receptor gene variance: genetic association analysis with adjustment for nongenetic confounders

Previous genetic-response studies, usually without considering environmental factors, encountered great difficulties in replication of results. Although atypical antipsychotics are becoming the mainstay for schizophrenia treatment which makes an antipsychotic "atypical" remains unclear. Risperidone (a widely used atypical antipsychotic agent) and several other atypicals have high affinities for 5-HT6 and 5-HT7 receptors. This study investigated the effects of the T-->C 267 polymorphism in the 5HT6 receptor gene and two rare Pro279Leu and Thr92Lys substitutions in the 5HT7 receptor gene on risperidone efficacy after rigorous control for nongenetic confounders. We found an association between the T-->C 267 polymorphism of the 5HT6 receptor gene and response to risperidone in 123 acutely ill schizophrenia inpatients after adjustment for confounders. Compared to patients with the T/C 267 genotype, those with T/T 267 showed less severe positive symptoms (p=0.006) and general psychopathology (including anxiety, depression, and cognitive dysfunctions) (p=0.005). The T-->C 267 polymorphism had no influences on negative symptoms. The two rare polymorphisms in the 5HT7 receptor gene were not observed in our sample. In conclusion, the 5HT6 receptor gene variant can affect risperidone response to positive symptoms and general psychopathology (but not negative symptoms) after control for nongenetic factors.     

Association study of the 5-HT(6) receptor polymorphism (C267T) and symptomatology and antidepressant response in major depressive disorders.

The serotonergic neurotransmitter system has been implicated in the pathogenesis of major depressive disorder (MDD). Of the 14 human serotonin (5-HT) receptors, the 5-HT(6) receptor may be a candidate for the study of MDD because of its relative abundance in certain limbic areas and its high affinity to several antidepressants. The present study tested the hypothesis that a 5-HT(6) genetic polymorphism (C267T) is associated with the clinical manifestations of, and/or antidepressant response in, MDD. The Hamilton Depression Rating Scale was used to assess 57 MDD patients before antidepressant treatment, with 34 patients completing the 4-week treatment and evaluation. The results of the association study provide that the 5-HT(6) C267T genetic variant does not play a major role in producing the clinical manifestations or antidepressant response for MDD patients. Further study with a functional 5-HT(6) polymorphism is needed to explore the role of 5-HT(6) in the pathogenesis of MDD.     

Evidence for deficit in tasks of ventral, but not dorsal, prefrontal executive function as an endophenotypic marker for bipolar disorder.

BACKGROUND: Trait functional abnormalities in BD patients have only been reported in the ventral prefrontal cortex (VPFC). We examined whether deficits in VPFC-related inhibitory processes, but not dorsal prefrontal (DPFC) based executive functions, represent an endophenotypic marker for bipolar disorder I (BDI). METHODS: We used the Wisconsin Card Sorting Test (WCST), commonly associated with DPFC function, and the Hayling Sentence Completion Task (HSCT) which engages the VPFC. Performance on these tests of 43 healthy participants was compared to that of 10 remitted BDI patients and 15 of their unaffected offspring. RESULTS: Compared to healthy participants, patients and their offspring made more errors in the HSCT but offspring achieved more categories and made fewer perseverative errors in the WCST. CONCLUSIONS: Impaired response inhibition, predominantly a VPFC related function, may reflect familial predisposition to BDI while deficits in rule attainment, a DPFC based function, may be associated only with the clinical phenotype.