Association study of a functional catechol-o-methyltransferase polymorphism and cognitive function in patients with dementia

A functional catechol-o-methyltransferase (COMT Val158/108Met) polymorphism, a valine (Val) to methionine (Met) substitution, has been associated with cognitive processing in the normal brain, older age, mild cognitive impairment and in various dementias. COMT is involved in the breakdown of dopamine and other catecholamines, especially in the frontal cortex; hence the carriers of Met allele, with the lower enzymatic activity, are expected to perform better on particular neuro-cognitive tests. The study included 46 patients with dementia and 65 healthy older subjects. The neurological status was assessed, using the Mini Mental Status Examination (MMSE), and the batery of different neurological tests. In DNA samples COMT polymorphism was genotyped. Patients with dementia exhibited significant genotype-induced differences in scores for MMSE, Visual Association Test (VAT) duration of numbers test, VAT time of response to numbers test, VAT average response to numbers test and WPLCR/PPLR unanswered. Carriers of Met/Met genotype had significantly lower scores of MMSE, significantly longer time to respond to VAT duration of numbers test, VAT time of response to numbers test and VAT average response to numbers test, and significantly greater number of unanswered questions to WPLCR/PPLR when compared to Met/Val or Val/Val genotypes. Our preliminary data showed significantly impaired performance in several neuro-cognitive tests in carriers of Met/Met genotype in patients with dementia compared to either Met/Val or Val/Val genotype carriers. Although Met/Met genotype with more dopamine available in the frontal cortex should be associated with better neuro-cognitive test results than Met/Val or Val/Val genotype, our data on patients with dementia did not confirm this hypothesis. Further study on larger sample of patients is needed to clarify the role of COMT polymorphism in cognitive functions.     

A preliminary study suggests that nicotine and prefrontal dopamine affect cortico‐striatal areas in smokers with performance feedback

Nicotine and tonic dopamine (DA) levels [as inferred by catechol‐O‐methyl tranferase (COMT) Val158Met genotype] interact to affect prefrontal processing. Prefrontal cortical areas are involved in response to performance feedback, which is impaired in smokers. We investigated whether there is a nicotine × COMT genotype interaction in brain circuitry during performance feedback of a reward task. We scanned 23 healthy smokers (10 Val/Val homozygotes, 13 Met allele carriers) during two fMRI sessions while subjects were wearing a nicotine or placebo patch. A significant nicotine × COMT genotype interaction for BOLD signal during performance feedback in cortico‐striatal areas was seen. Activation in these areas during the nicotine patch condition was greater in Val/Val homozygotes and reduced in Met allele carriers. During negative performance feedback, the change in activation in error detection areas such as anterior cingulate cortex (ACC)/superior frontal gyrus on nicotine compared to placebo was greater in Val/Val homozygotes compared to Met allele carriers. With transdermal nicotine administration, Val/Val homozygotes showed greater activation with performance feedback in the dorsal striatum, area associated with habitual responding. In response to negative feedback, Val/Val homozygotes had greater activation in error detection areas, including the ACC, suggesting increased sensitivity to loss with nicotine exposure. Although these results are preliminary due to small sample size, they suggest a possible neurobiological mechanism underlying the clinical observation that Val/Val homozygotes, presumably with elevated COMT activity compared to Met allele carriers and therefore reduced prefrontal DA levels, have poorer outcomes with nicotine replacement therapy .     

COMT Val158Met and cognition: main effects and interaction with educational attainment

Studies in children have shown that the genetic influence on cognition is positively correlated with socioeconomic status. Catechol- O -methyltransferase (COMT) Val158Met, a common, functional polymorphism, has been implicated in executive cognition and working memory. Imaging studies have shown that the variant Met allele is associated with more efficient prefrontal cortical processing and better attention but also emotional vulnerability to stress. We hypothesized that COMT Val158Met genotype would interact with years of education (yrs ed), one indicator of socioeconomic adversity, to predict cognitive task performance. We therefore administered the Wechsler Adult Intelligence Scale-Revised (WAIS-R) to 328 community-derived, genotyped, Plains American Indians (mean yrs ed = 12; range = 5–18). We found significant genotypic effects on WAIS-R measures of long-term memory, working memory and attention. The Met allele was associated with improved performance in the Information and Picture Completion subscales; Met/Met homozygotes performed the best. COMT genotype interacted with yrs ed to influence Information and Block Design scores: Met allele carriers' scores improved markedly with increasing yrs ed, whereas the scores of Val/Val individuals were only marginally influenced by yrs ed. There was a crossover of effects at 11–12 yrs ed: in the less educated group, Met allele carriers actually performed worse than Val/Val individuals perhaps because of emotional vulnerability to educational adversity, but in the better educated group, Met allele carriers excelled. Our study in Plains American Indians has shown that COMT Val158Met influences several aspects of cognition and some of its effects are moderated by educational adversity.     

Cognitive and serum BDNF correlates of BDNF Val66Met gene polymorphism in patients with schizophrenia and normal controls

Studies suggest that a functional polymorphism of the brain-derived neurotrophic factor gene (BDNF Val66Met) may mediate hippocampal-dependent cognitive functions. A few studies have reported its role in cognitive deficits in schizophrenia including its association with peripheral BDNF levels as a mediator of these cognitive deficits. We assessed 657 schizophrenic inpatients and 445 healthy controls on the repeatable battery for the assessment of neuropsychological status (RBANS), the presence of the BDNF Val66Met polymorphism and serum BDNF levels. We assessed patient psychopathology using the Positive and Negative Syndrome Scale. We showed that visuospatial/constructional abilities significantly differed by genotype but not genotype?×?diagnosis, and the Val allele was associated with better visuospatial/constructional performance in both schizophrenic patients and healthy controls. Attention performance showed a significant genotype by diagnosis effect. Met allele-associated attention impairment was specific to schizophrenic patients and not shown in healthy controls. In the patient group, partial correlation analysis showed a significant positive correlation between serum BDNF and the RBANS total score. Furthermore, the RBANS total score showed a statistically significant BDNF level?×?genotype interaction. We demonstrated an association between the BDNF Met variant and poor visuospatial/constructional performance. Furthermore, the BDNF Met variant may be specific to attentional decrements in schizophrenic patients. The association between decreased BDNF serum levels and cognitive impairment in schizophrenia is dependent on the BDNF Val66Met polymorphism.     

Differential Effects of the Catechol-O-Methyltransferase Val158Met Genotype on the Cognitive Function of Schizophrenia Patients and Healthy Japanese Individuals

Background

The functional polymorphism Val158Met in the catechol-O-methyltransferase (COMT) gene has been associated with differences in prefrontal cognitive functions in patients with schizophrenia and healthy individuals. Several studies have indicated that the Met allele is associated with better performance on measures of cognitive function. We investigated whether the COMT Val158Met genotype was associated with cognitive function in 149 healthy controls and 118 patients with schizophrenia.

Methods

Cognitive function, including verbal memory, working memory, motor speed, attention, executive function and verbal fluency, was assessed by the Brief Assessment of Cognition in Schizophrenia (BACS-J). We employed a one-way analysis of variance (ANOVA) and a multiple regression analysis to determine the associations between the COMT Val158Met genotype and the BACS-J measurements.

Results

The one-way ANOVA revealed a significant difference in the scores on the Tower of London, a measure of executive function, between the different Val158Met genotypes in the healthy controls (p = 0.023), and a post-hoc analysis showed significant differences between the scores on the Tower of London in the val/val genotype group (18.6 ± 2.4) compared to the other two groups (17.6 ± 2.7 for val/met and 17.1 ± 3.2 for met/met; p = 0.027 and p = 0.024, respectively). Multiple regression analyses revealed that executive function was significantly correlated with the Val158Met genotype (p = 0.003). However, no evidence was found for an effect of the COMT on any cognitive domains of the BACS-J in the patients with schizophrenia.

Conclusion

These data support the hypothesis that the COMT Val158Met genotype maintains an optimal level of dopamine activity. Further studies should be performed that include a larger sample size and include patients on and off medication, as these patients would help to confirm our findings.     

The Role of the Val66Met Polymorphism of the Brain Derived Neurotrophic Factor Gene in Coping Strategies Relevant to Depressive Symptoms

Disturbances of brain derived neurotrophic factor (BDNF) signalling have been implicated in the evolution of depression, which likely arises, in part, as a result of diminished synaptic plasticity. Predictably, given stressor involvement in depression, BDNF is affected by recent stressors as well as stressors such as neglect experienced in early life. The effects of early life maltreatment in altering BDNF signalling may be particularly apparent among those individuals with specific BDNF polymorphisms. We examined whether polymorphisms of the Val66Met genotype might be influential in moderating how early-life events play out with respect to later coping styles, cognitive flexibility and depressive features. Among male and female undergraduate students (N = 124), childhood neglect was highly related to subsequent depressive symptoms. This outcome was moderated by the BDNF polymorphism in the sense that depressive symptoms appeared higher in Met carriers who reported low levels of neglect than in those with the Val/Val allele. However, under conditions of high neglect depressive symptoms only increased in the Val/Val individuals. In effect, the Met polymorphism was associated with depressive features, but did not interact with early life neglect in predicting later depressive features. It was further observed that among the Val/Val individuals, the relationship between neglect and depression was mediated by emotion-focused styles and diminished perceived control, whereas this mediation was not apparent in Met carriers. In contrast to the more typical view regarding this polymorphism, the data are consistent with the perspective that in the presence of synaptic plasticity presumably associated with the Val/Val genotype, neglect allows for the emergence of specific appraisal and coping styles, which are tied to depression. In the case of the reduced degree of neuroplasticity expected in the Met carriers, early life adverse experiences are not tied to coping styles, and hence less likely to be translated into depressive states.     

Catechol-<Emphasis Type="Italic">O</Emphasis>-methyltransferase (COMT) Val158Met polymorphism and risk of osteoporotic fracture

Catechol-O-methyltransferase (COMT) is an estrogen degrading enzyme. The COMT Val158Met polymorphism is associated with bone mineral density. The aim of this study was to investigate associations between COMT Val158Met and osteoporotic fractures in Chinese Han patients. Case-control study of 320 patients with osteoporotic fractures and 320 healthy controls were conducted. The COMT Val158Met polymorphism was analyzed by polymerase chain reaction-restriction fragment length polymorphism assay. Patients with osteoporotic fracture had a significantly lower frequency of Val/Val genotype [odds ratio (OR) = 0.62, 95% confidence interval (CI) 0.39–0.99, P = 0.04] than controls. When stratified by the fracture type, there was a significantly lower frequency of Val/Val genotype in patients with vertebral fracture (OR = 0.58, 95% CI 0.36–0.94, P = 0.03) than controls. There was no significant difference in the distribution of each genotype between patients with hip fracture and the control group. Our findings suggest that COMT Val/Val genotype was associated with a lower risk of osteoporotic fracture in Chinese population, especially to vertebral fracture.     

The association between catechol-O-methyl-transferase Val108/158Met polymorphism and suicide

One of the candidate genes for suicide is also a gene in the pathway for catecholamine degradation encoding an enzyme catechol-O-methyl-transferase (COMT). It harbors a common functional polymorphism, a G to A nucleotide transition resulting in amino acid substitution from valine (Val) to methionine (Met) at position 158 (COMT Val(108/158) Met; rs4680), that has been associated with psychiatric disorders characterized with an increased risk of suicidal behavior. We have performed the first study on Caucasian population examining the association between completed suicide and the COMT Val(108/158) Met polymorphism. The study population consisted of 356 suicide victims and 198 control subjects. Significant difference in COMT Val(108/158) Met variants' (genotypes, alleles and Val carriers) distribution was found only in male groups, between controls and suicide victims (P = 0.018, P = 0.031, P = 0.005), and between controls and violent suicide victims (P = 0.026, P = 0.042, P = 0.010). The r value from the standardized residuals showed that the Met/Met genotype (r = 2.03) in the control group contributed to these significant differences. In contrast to male subjects, no significant differences in the frequency of the COMT Val(108/158) Met variants were detected between female control and female suicide groups; however, the power of calculation (range 0.161-0.680) was below the desired 0.800. In addition, the logistic regression analysis confirmed these significant differences. In conclusion, our results showed the overpresentation of the Met/Met genotype in male control subjects compared with male suicide victims, suggesting that this genotype of the COMT Val(108/158) Met might be a protective factor against suicide.     

COMT Val158Met多态型青年在数字工作记忆任务中的视觉事件相关电位的研究

目的:针对不同COMT基因型健康青年被试,进行连续3-back任务1h共12Block,探讨健康成人数字工作记忆能力变化情况。方法:将112名健康青年分组抽取出18名不同基因型作为被试,利用视觉事件相关电位P3来观测被试连续工作记忆任务中COMT基因多态型与脑皮层电生理的关系。结果:Val/Val基因型的被试P3波幅显著高于Val/Met基因型(P<0.01),但和Met/Met基因型被试的波幅无差异。结论:Val/Met基因型被试关联着最差的工作记忆任务的成绩,被试者的P3波幅和3-back任务成绩成正相关。     

Modulating effect of Val66Met polymorphism of brain-derived neurotrophic factor gene on clinical and psychological characteristics of patients with schizophrenia

The brain-derived neurotrophic factor (BDNF) gene is an important candidate gene for schizophrenia. The association of BDNF with schizophrenia has been extensively analyzed using the polymorphism Val66Met. There is accumulating evidence that Val66Met is associated with clinical presentations of schizophrenia rather than with the disease itself. In this study, BDNF allele and genotype distributions were compared in patients (n = 1785) and healthy controls (n = 1092). There was no association between the Val66Met polymorphism and schizophrenia. The marker was not associated with the presence of the affective syndrome either. At the same time, the ValVal genotype was associated with higher anxiety levels in male patients as assessed with PANSS. Patients’ personality traits were characterized using the personality inventories EPI, MMPI, and STAI (n = 363), and their cognitive functions, attention (n = 282) and verbal fluency (n = 392), were evaluated. Patients with the ValVal genotype showed higher levels of anxiety (by MMPI) and better performance on neurocognitive tests. The genotype and trait anxiety (by STAI score) had an interaction effect on cognitive functions. In patients with higher anxiety, performance on cognitive tests did not depend on the genotype, while in patients with lower levels of anxiety, the ValVal genotype was associated with significantly better performance. This effect should be taken into account when studying associations of the Val66Met polymorphism with cognitive functions in patients with schizophrenia.     

BDNF Val66Met Variant and Smoking in a Chinese Population

Several recent studies have supported the hypothesis that brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, might be associated with nicotine addiction. Association studies have also suggested that the BDNF gene might play a role in the susceptibility to nicotine dependence but results appear contradictory. The present work was therefore undertaken to examine the association of smoking with the BDNF Val66Met gene polymorphism in Chinese population. The BDNF Val66Met gene polymorphism was examined in 628 healthy male volunteers including 322 smokers and 306 non-smokers. Also, the BDNF serum levels were measured in 136 smokers and 97 nonsmokers. Our results showed no significant association between the BDNF Val66Met polymorphism or serum levels among smokers and non-smokers. Smokers with the Met allele however started smoking significantly earlier than those with the Val/Val genotype (mean age at smoking initiation of 17.4, 17.9 and 21.2 years for Met/Met, Met/Val, and Val/Val, respectively; both p<0.05). No other significant differences between other variables such as number of cigarettes per day, smoking severity as measured by the Fagerstrom Test for Nicotine Dependence (FTND) score and carbon monoxide (CO) levels (all p>0.05). In addition, there was no main effect of genotype on serum BDNF levels. Our findings suggest that the BDNF Val66Met polymorphism may not be involved in susceptibility to smoking among the Chinese male population, but may influence the age at which smoking is initiated. However, the findings must be interpreted with caution because of the relatively small sample size for an association study. Results should be confirmed in a larger cohort.     

Affect-modulated startle: interactive influence of catechol-O-methyltransferase Val158Met genotype and childhood trauma

The etiology of emotion-related disorders such as anxiety or affective disorders is considered to be complex with an interaction of biological and environmental factors. Particular evidence has accumulated for alterations in the dopaminergic and noradrenergic system--partly conferred by catechol-O-methyltransferase (COMT) gene variation--for the adenosinergic system as well as for early life trauma to constitute risk factors for those conditions. Applying a multi-level approach, in a sample of 95 healthy adults, we investigated effects of the functional COMT Val158Met polymorphism, caffeine as an adenosine A2A receptor antagonist (300 mg in a placebo-controlled intervention design) and childhood maltreatment (CTQ) as well as their interaction on the affect-modulated startle response as a neurobiologically founded defensive reflex potentially related to fear- and distress-related disorders. COMT val/val genotype significantly increased startle magnitude in response to unpleasant stimuli, while met/met homozygotes showed a blunted startle response to aversive pictures. Furthermore, significant gene-environment interaction of COMT Val158Met genotype with CTQ was discerned with more maltreatment being associated with higher startle potentiation in val/val subjects but not in met carriers. No main effect of or interaction effects with caffeine were observed. Results indicate a main as well as a GxE effect of the COMT Val158Met variant and childhood maltreatment on the affect-modulated startle reflex, supporting a complex pathogenetic model of the affect-modulated startle reflex as a basic neurobiological defensive reflex potentially related to anxiety and affective disorders.     

Association between the Val66Met polymorphism of brain-derived neurotrophic factor gene and schizophrenia in Russians

Recent studies have demonstrated a role of the brain-derived neurotrophic factor (BDNF) in schizophrenia. An association between the Val66Met BDNF polymorphism has been reported but the results of different studies are inconsistent. An aim of the present article is to study the allele and genotype distribution in patients with schizophrenia (783) and mentally healthy controls (633). No statistically significant between-group differences have been found. When the group of patients has been stratified by sex and form of schizophrenia, the higher frequency of the Val/Val genotype is observed in the subgroup of men with continuous (chronic) schizophrenia as compared to men with attack-like form (p = 0.047). Clinical symptoms assessed with the PANSS were more severe in male patients with the Val/Val genotype. The Val66Met polymorphism was not associated with forms of schizophrenia or clinical symptoms in female patients. The results obtained suggest that the association between the BDNF gene and schizophrenia may be related to sex and clinical heterogeneity of disease. The Val/Val genotype is associated with severer form of schizophrenia in men.     

偏执型精神分裂症与4个涉及多巴胺代谢的基因之间的关联分析

精神分裂症是由多基因相互作用导致的复杂疾病。对其易感基因,儿茶酚氧位甲基转移酶基因（COMT）的众多报道充满了矛盾。在对偏执型精神分裂症研究中,我们用多基因座关联分析法研究了4个涉及神经递质多巴胺代谢的基因之间的相互作用。分析结果支持如下假说：COMT-136-BclI对Val^108/158Met有调控作用。当前者的基因型是CC时,后者的易感等位基因型是Met（A）;而当前者的基因型是GG时,后者的易感等位基因型是Val（G）。这一新的假说可以解释此前单基因座分析对Val^108/158Met(COMT)的截然相反的报道,同时也显示了多基因座分析对复杂疾病研究的必要性。      

Association of the Val66Met polymorphism of the brain-derived neurotrophic factor gene with schizophrenia in Russians

According to recent data, the brain-derived neurotrophic factor (BDNF) is involved in schizophrenia. An association of the Val66Met polymorphism of the BDNF gene has been reported, but the results of different studies are discrepant. The allele and genotype frequency distributions of BDNF were studied in 783 schizophrenics and 633 mentally healthy controls. Significant between-group differences were not detected. When the patients were stratified by sex and schizophrenia form, men with continuous (chronic) schizophrenia were found to have a significantly higher frequency of the Val/Val genotype as compared to men with the episodic form (P = 0.047). Clinical symptoms assessed by the PANSS in men with the Val/Val genotype were more severe than in men with the Met/Met genotype (P = 0.044). No difference in BDNF genotype frequency distribution was observed between female groups differing in disease form or the severity of clinical symptoms. It was concluded that the association of the Val66Met polymorphism with schizophrenia is affected by the sex of patients and clinical heterogeneity of the disease and that the Val/Val genotype is associated with more severe schizophrenia in males.     

Genetic Variation in the Catechol-O-Methyl Transferase Val108/158Met Is Linked to the Caudate and Posterior Cingulate Cortex Volume in Healthy Subjects: Voxel-Based Morphometry Analysis of Brain Magnetic Resonance Imaging

The effect of the catechol-O-methyltransferase (COMT) Val158Met polymorphism on brain morphology has been investigated but remains controversial. We hypothesized that a comparison between Val/Val and Val/Met individuals, which may represent the most different combinations concerning the effects of the COMT genotype, may reveal new findings. We investigated the brain morphology using 3-Tesla magnetic resonance imaging in 27 Val/Val and 22 Val/Met individuals. Voxel-based morphometry revealed that the volumes of the bilateral caudate and posterior cingulate cortex were significantly smaller in Val/Val individuals than in Val/Met individuals [right caudate: false discovery rate (FDR)-corrected p = 0.048; left caudate: FDR-corrected p = 0.048; and bilateral posterior cingulate cortex: FDR-corrected p = 0.048]. This study demonstrates that interacting functional variants of COMT affect gray matter regional volumes in healthy subjects.     

The brain-derived neurotrophic factor Val66Met polymorphism modulates the effects of parental rearing on personality traits in healthy subjects

There is a growing body of data suggesting that gene-environment interaction is critical in the characterization of personality traits; however, previous studies have not taken into consideration variability in parental rearing as an environmental factor. In this study, we examined the effects of the interaction between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and parental rearing on personality traits in 710 healthy Japanese subjects. Perceived parental rearing was assessed by the Parental Bonding Instrument (PBI), which consists of the care and protection factors. Assessment of personality traits was performed by the temperament and character inventory (TCI), which has seven dimensions, i.e. novelty seeking, harm avoidance, reward dependence, persistence, self-directedness, cooperativeness and self-transcendence. Parental rearing has significant main effects on some TCI dimensions, but no significant main effects of the BDNF genotype on the TCI scores were found. The interaction between the BDNF genotype and maternal care of the PBI had significant effects on harm avoidance and self-directedness of the TCI. Post hoc analyses showed that decreased maternal care was correlated with increased harm avoidance and decreased self-directedness, and for both personality traits the partial correlation coefficient was highest in the Met/Met genotype group and lowest in the Val/Val genotype group and the value of the Val/Met genotype group was in the middle. Data from this study suggest that the BDNF Val66Met polymorphism modulates the effects of parental rearing, especially maternal care, on harm avoidance and self-directedness in healthy subjects.     

Brain-derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly

A functional brain-derived neurotrophic factor (BDNF) gene polymorphism (Val66Met) that alters activity-dependent secretion has previously been reported to influence cognitive functioning. A large proportion of these reports suggest that the Met allele, which results in reduced secretion of BDNF, impairs long-term memory as a direct consequence of its influence on hippocampal function but has little influence on working memory. In contrast, other studies have found that the Met allele can also play a protective role in certain neurological conditions and is associated with improved non-verbal reasoning skills in the elderly suggesting effects that appear disease, domain and age specific. We have investigated six haplotype-tagging single nucleotide polymorphisms (SNPs) using a cohort of 722 elderly individuals who have completed cognitive tests that measured the domains of fluid intelligence, processing speed and memory. We found that the presence of the Met allele reduced cognitive performance on all cognitive tests. This reached nominal significance for tests of processing speed ( P  = 0.001), delayed recall ( P  = 0.037) and general intelligence (g) ( P  = 0.008). No association was observed between cognitive tests and any other SNPs once the Val66Met was adjusted for. Our results support initial findings that the Met allele is associated with reduced cognitive functioning. We found no evidence that the Met allele plays a protective role in older non-demented individuals. Magnetic resonance imaging data collected from a subgroup of 61 volunteers showed that the left and right hippocampus were 5.0% and 3.9% smaller, respectively, in those possessing the Met allele, although only a non-significant trend was observed.     

Subtle gene-environment interactions driving paranoia in daily life

It has been suggested that genes impact on the degree to which minor daily stressors cause variation in the intensity of subtle paranoid experiences. The objective of the present study was to test the hypothesis that catechol- O -methyltransferase (COMT) Val¹⁵⁸Met and brain-derived neurotrophic factor (BDNF) Val⁶⁶Met in part mediate genetic effects on paranoid reactivity to minor stressors. In a general population sample of 579 young adult female twins, on the one hand, appraisals of (1) event-related stress and (2) social stress and, on the other hand, feelings of paranoia in the flow of daily life were assessed using momentary assessment technology for five consecutive days. Multilevel regression analyses were used to examine moderation of daily life stress-induced paranoia by COMT Val¹⁵⁸Met and BDNF Val⁶⁶Met genotypes. Catechol- O -methyltransferase Val carriers displayed more feelings of paranoia in response to event stress compared with Met carriers. Brain-derived neurotrophic factor Met carriers showed more social-stress-induced paranoia than individuals with the Val/Val genotype. Thus, paranoia in the flow of daily life may be the result of gene–environment interactions that can be traced to different types of stress being moderated by different types of genetic variation.