Association study between the dopamine receptor D(4) gene and obsessive-compulsive disorder.

Pharmacological and neuroanatomical evidence suggest the involvement of the dopaminergic system in obsessive-compulsive disorder (OCD). Analysis of the 48-bp dopamine receptor D(4) (DRD4) gene polymorphism in a sample of 210 OCD patients and 202 healthy control subjects showed a significant association (chi(2)=27.5, df=6, p=0.0003). This difference was attributable to a lower frequency of allele 4R in OCD patients compared with the control group (chi(2)=9.33, p=0.0027). However, we did not replicate previous findings of an association between the 7R allele and OCD patients with tics. Finally, we analyzed a sub-sample of 86 OCD families. E-TDT analysis in 70 informative parents did not confirm the association observed in our case-control analysis. In conclusion, the current study cannot exclude an association between DRD4 gene and OCD in the largest sample analyzed. However, further studies will be required to confirm if the DRD4 gene is involved in the pathogenesis of this disorder.     

Cocaine use disorders and suicidal ideation

The goal of this study was to determine the contribution of substance abuse to the expression of suicidal ideation in a sample of patients referred for evaluation of chemical dependency in a large urban Psychiatric Emergency Service (PES). Records from 777 consecutive patients referred to the chemical dependency service of the PES were analyzed. Of this sample, 43.7% of the patients with only a cocaine use disorder expressed suicidal ideation compared to 38% of those with both cocaine and alcohol use disorders, 24.3% with only an alcohol use disorder and 17% with other drug use disorders (chi(2)=24.768; df=3; P<0.0001). More than half of the patients (55.26%) with a substance-induced mood or psychotic disorder expressed suicidal ideation (chi(2)=23.174, df=1, P<0.0001), and the majority (85%) of these patients had a cocaine use disorder (chi(2)=12.309, df=1, P<0.0005). In this sample of patients served by an urban PES, cocaine use is associated with suicidal ideation, more so than other substances of abuse.     

Association between three functional polymorphisms of the dopamine D2 receptor gene and polydipsia in schizophrenia

The underlying pathophysiology of polydipsia in schizophrenia is poorly understood. However, several studies suggest there may be a genetic predisposition to polydipsia, including our previous study demonstrating familial concordance of polydipsia among first-degree relatives with schizophrenia. Antipsychotic medications may contribute to the development of polydipsia and studies show that dopamine D2 receptors are involved in drinking behaviour pathophysiology. Our hypothesis is that polymorphisms in the dopamine D2 receptor gene (DRD2) may confer susceptibility to polydipsia in schizophrenia. We tested for an association between polydipsia in schizophrenia and three functional polymorphisms of DRD2. The three polymorphisms, -141C Ins/Del, Ser311Cys, and TaqIA, were genotyped in patients with polydipsia (n = 64) and in those without polydipsia (n = 91). Of the three polymorphisms, TaqIA was significantly associated with polydipsia [genotype: chi2 = 6.59, df = 2, p = 0.037; allele: chi2 = 6.52, df = 1, p = 0.011, OR 1.81, 95% CI 1.15-2.86]. Haplotype analysis of the three markers found increased significance of the association (global, p = 0.00091). Although based on a relatively small portion of the sample, individual comparison of the common haplotypes showed that haplotype Ins-Cys-A1 was significantly less frequent in patients with polydipsia (p = 0.00082). The present data suggests polymorphisms in DRD2 may confer susceptibility to polydipsia in schizophrenia. To confirm our findings, further studies are warranted on larger samples using more extensive biological measures for diagnosing the polydipsia phenotype.     

Association of THR105Ile, a functional polymorphism of histamine N-methyltransferase (HNMT), with alcoholism in German Caucasians

BACKGROUND: CNS histamine has been shown to have an inhibitory effect on reward and it is implicated in the etiology of addiction and stress. Histamine N-methyltransferase (HNMT) is believed to be the sole pathway for termination of the neurotransmitter action of histamine in mammalian brain. A common, functional polymorphism, a C314T transition in the HNMT gene, results in a Thr105Ile substitution of the protein encoded. A recent study has shown that the frequency of the Ile105 allele was significantly lower in alcoholics compared to that in non-alcoholics in Finns and Plains American Indians. Following up these results, we tested whether the Thr105Ile polymorphism was associated with alcoholism in German Caucasians. METHODS: Thr105Ile was genotyped in n=366 psychiatrically interviewed German Caucasian ICD-10 lifetime alcoholics, along with n=200 ethnically matched controls. RESULTS: No significant difference was found in the frequency of the Ile105 allele between alcoholics (0.11) and controls (0.10) (chi(2)=0.21, d.f.=1, p=0.647). Likewise, genotype distributions did not differ significantly. However, the frequency of the Ile105 allele was significantly lower in male alcoholics with a family history of alcoholism compared to that in male alcoholics without a family history of alcoholism (chi(2)=4.07, d.f.=1, p=0.044). CONCLUSIONS: In German Caucasians the association of the HNMT Thr105Ile polymorphism with alcoholism was not replicated per se, but a congruent association was found between the Ile105 allele and family history of alcoholism supporting the protective role of the Ile105 allele against alcoholism.     

Human 5-HT1A receptor C(-1019)G polymorphism and psychopathology

Dysfunction of the serotonin (5-HT1A) receptor (5-HTR1A) has been implicated in mood disorders, anxiety disorders, psychosis and the action of antidepressants. A common C(-1018)G [C(-1019)G] functional polymorphism in the promoter region of the human 5-HT1A receptor gene has been reported, which may be useful in identifying psychopathology associated with altered function of the human 5-HT1A receptor. We studied the relationship of this polymorphism to psychopathology and 5-HT1A binding in prefrontal cortex. The 5-HT1A receptor genotype for the C(-1019)G polymorphism was typed in 696 unrelated psychiatric subjects, 107 unrelated healthy volunteers, and in post-mortem brain samples from 241 cases. 5-HT1A receptor binding was assayed in post-mortem prefrontal cortex using [3H]8-OH-DPAT, and specific binding determined by 1 microM 5-HT. An association of genotype distribution and allele frequency of the 5-HTR1A C(-1019)G locus was observed in schizophrenia (chi2=9.51, d.f.=2, p=0.009; chi2=9.52, d.f.=1, p=0.002; Armitage's trend test: chi2=9.07, d.f.=1, p=0.003), in substance use disorder (chi2=8.41, d.f.=2, p=0.015; chi2=8.35, d.f.=1, p=0.004; Armitage's trend test: chi2=6.27, d.f.=1, p=0.0012), and in panic attack (chi2=6.31, d.f.=2, p=0.043; chi2=6.14, d.f.=1, p=0.013; Armitage's trend test: chi2=6.27, d.f.=1, p=0.012). An association of the 5-HTR1A C(-1019)G locus with schizophrenia, substance use disorder, and panic attack was suggested by our results. In post-mortem brain samples, 5-HT1A receptor binding in prefrontal cortex and suicide were not associated with genotype. The relationship does not appear to be explained by binding differences, although we cannot rule out altered receptor affinity and transduction.     

Substance abuse disorder and major depression are associated with the human 5-HT1B receptor gene (HTR1B) G861C polymorphism.

The 5-HT(1B) receptor has been implicated in several psychopathologies, including pathological aggression, alcoholism and suicide. To test these and related potential genetic relationships in a single population, the human 5-HT(1B) receptor (h5-HTR(1B)) genotype for the G861C polymorphism was determined in 394 psychiatric patients and 96 healthy volunteers. Structured clinical interviews generated DSM III-R diagnoses. No significant association of the genotype or allele frequencies of the h5-HTR(1B) G861C locus was observed with diagnoses of alcoholism, bipolar disorder, schizophrenia or a history of a suicide attempt. Exploratory analyses indicated an association of the genotype and allele frequencies of the h5-HTR(1B) G861C locus with a history of substance abuse disorder (chi(2) = 9.51, df = 2, p = 0.009; chi(2) = 7.31, df = 1, p = 0.007, respectively) and with a diagnosis of a major depressive episode (chi(2) = 6.83, df = 2, p = 0.033; chi(2) = 5.81, df = 1, p = 0.016, respectively). Significant gene dose effects on the risk for substance abuse disorder and a major depressive episode were observed with the 861C allele (Armitage linearity tendency test: chi(2) = 7.20, df = 1, p = 0.008; chi(2) = 6.80, df = 1, p = 0.009, respectively). Substance abuse disorder and major depression appear to be associated with the h5-HTR(1B) G861C locus in the patient population, but other psychopathologies such as bipolar disorder, schizophrenia, alcoholism, and suicide attempts were not found to be associated with this polymorphism. This preliminary result will need replication, given the limitations of association studies.     

Alcohol dependence and conduct disorder among Navajo Indians

OBJECTIVE: The purpose of this study is to examine the association between conduct disorder before age 15 and subsequent alcohol dependence, and to describe the lifetime prevalence of alcohol dependence among Navajo Indian women and men. METHOD: This was a case-control design which included both men (n = 735) and women (n = 351) and in which the Diagnostic Interview Schedule was used for the diagnosis of the lifetime history of alcohol dependence and conduct disorder. Alcohol dependent cases were selected from inpatient and outpatient treatment programs (204 men, 148 women). Whenever possible, controls were matched for age, sex and community of residence and were randomly selected and interviewed until a nonalcohol dependent individual was found. Among the men, there were 374 alcohol dependent controls and 157 nonalcohol dependent controls. Among the women, the figures were 60 and 143, respectively. When combined, the controls comprise samples of the adult male and female populations from which estimates of lifetime prevalence of alcohol dependence, and of the amount of alcohol dependence in the population attributable to conduct disorder, may be inferred. RESULTS: Conduct disorder is a risk factor for alcohol dependence among both men and women. Lifetime prevalence of alcohol dependence in this population is high (70.4% for men and 29.6% for women), but the amount of alcohol dependence in the population attributable to conduct disorder is low. On the other hand, among the alcohol dependent, those with conduct disorder had the most severe alcohol- and nonalcohol-related problems. CONCLUSIONS: The potential limitations of the study are those common to case-control designs, especially biased recall by cases. There are also potential sampling biases among the controls. It is shown that none of the potential biases invalidate the findings, which support the hypothesis that in this population conduct disorder is a risk for alcohol dependence. The implications for primary prevention of alcohol dependence are discussed.     

Early adolescent psychopathology as a predictor of alcohol use disorders by young adulthood

Few prospective studies have examined the relation between early adolescent conduct disorder (CD) symptoms and the development of alcohol use disorders (AUD) by young adulthood. The relative contribution of other forms of adolescent psychopathology (i.e., attention-deficit hyperactivity disorder, depression, anxiety/withdrawal) to the development of AUD also remains poorly understood. There is some suggestion that the co-occurrence of conduct disorder symptoms with other forms of psychopathology may interact synergistically in predicting later alcohol use problems. The current study explores these issues using data on 506 boys from the oldest sample of the Pittsburgh Youth Study (PYS). Consistent with prior research, early conduct disorder symptoms emerged as a consistent predictor of increased AUD symptoms and an alcohol dependence diagnosis by young adulthood. In contrast, adolescent boys with high levels of anxiety/withdrawal had lower levels of AUD symptoms and were less likely to develop alcohol dependence by young adulthood. Increased depression in early adolescence was associated with higher AUD symptoms and alcohol abuse and dependence diagnoses by young adulthood, but only for boys with high levels of conduct disorder symptoms. No evidence was found for a relation between attention-deficit hyperactivity disorder symptoms and AUD symptoms or diagnoses after controlling for co-occurring psychopathology.     

Possible association between the gamma-aminobutyric acid type B receptor 1 (GABBR1) gene and schizophrenia.

Schizophrenia (SCZ) is a severe neuropsychiatric disorder with a genetic component. The major inhibitory GABA-(gamma-aminobutyric acid) ergic system may be involved. The GABA type B receptor 1 (GABBR1) gene has been localized to 6p21.3, a region linked to SCZ. We therefore investigated five polymorphisms (A-7265G, C10497G, Ser-491-Ser-T1473C, Phe-659-Phe-T1977C, and 3'-UTR A33795G substitutions) in the GABBR1 gene in a sample of 101 DSM-IV SCZ probands and their families, 150 unrelated affected individuals matched with 150 healthy controls, using the transmission disequilibrium test (TDT) and case-control analysis. We did not observe biased transmission of alleles in any of the polymorphisms individually and haplotypes within the gene to SCZ probands. However, a weak significant difference was observed in the A-7265G polymorphism between the allelic frequency (chi2 = 4.310, P = 0.038) and a trend was observed between the genotype frequency (chi2 = 4.970, 2 df, P = 0.083) of SCZ individuals and controls. Further investigations of the role of GABBR1 in SCZ are warranted.     

Additive independent factors that predict risk for alcoholism

Pedigree and adoption studies have supported a genetic heterogeneity model for alcoholism. Lifetime alcoholism diagnosis in medical-surgical inpatients was reported to increase additively with the presence of Antisocial Personality Disorder (ASP) diagnosis, male gender and family history of alcoholism (FHA). These three risk factors have been shown to have separate genetic transmission. This study tested the predictive strength of these factors in a prospective sample of untreated, nonhospitalized young male (n = 98, mean = 25.2 years) and female (n = 121, mean = 25.5 years) offspring of alcoholic (n = 131) and nonalcoholic (n = 88) parents. NIMH-Diagnostic Interview Schedule items were used to diagnose blindly DSM-III alcohol or drug abuse or dependence. No alcohol- or drug-related behavioral items were used in ASP diagnosis. Parental alcoholism was rated using proband information and Family History Research Diagnostic Criteria. ASP, then gender and finally FHA but not age were significant predictors of DSM-III alcoholism. The log linear analysis improvement chi square was significant at p less than .05 for each variable and the overall goodness of fit of the model was substantial (chi 2 = 13.3, p = .78). Prediction of lifetime alcohol abuse/dependence rates for young adults in a prospective sample was highly significant. These three factors with separate genetic vulnerability increased risk over a lifetime. Male gender increased the risk for alcoholism 1.5 times, FHA 1.5 times and ASP diagnosis 3 times in an independent and additive manner.     

Caffeine and 35% carbon dioxide challenge tests in panic disorder

Our aim was to compare the demographic and clinical features of panic disorder (PD) patients with agoraphobia-DSM-IV-who had a panic attack after both an oral caffeine and the 35% carbon dioxide (CO2) challenge tests (responsive group) and compare them with PD patients who did not have a panic attack after both tests (non-responsive group). We examined 83 PD patients submitted to a 35% CO2 test and to an oral caffeine (480 mg) intake within 1 week interval. A panic attack was induced in 51 (61.4%) patients during the CO2 test (chi2=31.67, df=1, p<0.001) and in 38 (45.8%) patients during the caffeine test (chi2=18.28, df=1, p=0.023). All patients who had a panic attack during the caffeine test also had a panic attack during the CO2 test (n=38)-responsive group. The responsive had more (chi2=24.55, df=1, p=0.008) respiratory PD subtype, disorder started earlier (Mann-Whitney, p<0.001) had a higher familial prevalence of PD (chi2=20.34, df=1, p=0.019), less previous alcohol abuse (chi2=23.42, df=1, p<0.001), and had more previous depressive episodes (chi2=27.35, df=1, p<0.001). Our data suggest that there is an association between respiratory PD subtype and hyperreactivity to challenge tests: CO2 and oral caffeine.     

Test of association between GABRA2 (SNP rs279871) and adolescent conduct/alcohol use disorders utilizing a sample of clinic referred youth with serious substance and conduct problems,controls and available first degree relatives

Recent findings have linked the GABRA2 gene with antisocial personality disorder and alcohol dependence (AD) in adults and conduct disorder (CD), but not AD symptoms, in children and adolescents. We sought to replicate previous findings and test for an association between a single nucleotide polymorphism (SNP) in the GABRA2 gene (rs279871) and CD among adolescents.MethodsAdolescent patients (n = 371), 13–18 years old, were recruited from a university substance abuse treatment program. Patient siblings (n = 245), parents of patients (n = 355), adolescent controls (n = 185), siblings of controls (n = 163) and parents of controls (n = 263) were included in these analyses (total sample n = 1582). Case-control (using only Caucasian and Hispanic probands) and family-based association tests were completed to test for association between rs279871 and several a priori CD and AD phenotypes.ResultsFor case-control association tests, rs279871 was significantly associated with CD (p = 0.02) but not AD phenotypes; the result did not survive strict correction for multiple testing. All family-based association tests were non-significant (CD p = 0.48; CD symptom count age corrected within sex p = 0.91; AD p = 0.84; alcohol use disorder p = 0.52).ConclusionsConsistent with previous findings, the results do not support the association between GABRA2 SNP rs279871 and AD in adolescents. Our results also do not support an association between rs279871 and CD; the study limitations are reviewed.     

Prenatal alcohol use: the role of lifetime problems with alcohol, drugs, depression, and violence.

OBJECTIVE: The purpose of this study was to examine a broader array of lifetime factors that theoretically may be associated with prenatal alcohol use than have previously been studied together, including family history of alcohol-use problems, history of physical or sexual abuse, lifetime major depressive disorder, alcohol-use disorder, illicit-drug-use problems, and partner violence. METHOD: A total of 186 pregnant women, all of whom used alcohol in the year before pregnancy, were initially recruited in prenatal care settings. Women who reported no prenatal alcohol use (n = 96) were compared with women who drank 1-10 standard drinks during pregnancy (n = 75) and with women who drank more than 10 standard drinks during pregnancy (n = 13), considered to be a higher risk group, on the lifetime risk variables. Because of the public health implications, secondary analyses compared women who abstained during pregnancy with those who used any alcohol. RESULTS: Significant intercorrelations were found among most of the lifetime risk factors studied. Multivariate analyses showed that drug-use problems and partner violence were most strongly associated with prenatal alcohol use than any other variable studied. CONCLUSIONS: Consistent with a life span risk framework for alcohol-use problems, results of this study show that childhood abuse, familial alcoholism, lifetime major depressive disorder, and alcohol- and drug-use problems are interrelated. However, when considered together, only lifetime partner violence and drug use are significantly related to various levels of prenatal alcohol use. Identification, assessment, and intervention efforts should integrate these important factors.     

Family harmony as a protective factor against adolescent tobacco and alcohol use in Wuhan,China

PURPOSE: To investigate the association between family harmony (FH) and tobacco and alcohol use (TAU) in Chinese adolescents. METHODS: Participants completed a survey in 1998 as part of a larger study of adolescent health in Wuhan, China. Analyses were performed on subjects for whom complete data were available (n = 183; 50.8% male; mean age = 13.17 yrs, std dev = 0.59). Structural equation modeling was utilized to quantify the relationships between the FH, TAU, depression, and academic aptitude factors. RESULTS: The conceptualized structural equation model was found to have a good fit to the data (CFI = 0.995; chi2 = 39.57 df = 38; p = 40). FH was a significant predictor of TAU (beta = -0.42, p < 0.05) and was protective. FH' was also negatively related to depression (r = -0.24, p < 0.05) and positively related to academic achievement/aptitude (r = 0.35, p < 0.05). CONCLUSIONS: These central findings highlight the value and importance placed on FH within the Chinese culture. Future prevention programs may benefit by taking into account FH as a potential mediator of TAU in adolescents in China.     

Present and lifetime comorbidity of tobacco, alcohol and drug use in eating disorders: a European multicenter study

OBJECTIVES: To assess the differences in comorbid lifetime and current substance use (tobacco, alcohol and drug use) between eating disorder (ED) patients and healthy controls in five different European countries. METHOD: A total of 1664 participants took part in the present study. ED cases (n=879) were referred to specialized ED units in five European countries. The ED cases were compared to a balanced control group of 785 healthy individuals. ASSESSMENT: Participants completed the Substance Use Subscale of the Cross Cultural (Environmental) Questionnaire (CCQ), a measure of lifetime tobacco, alcohol and drug use. In the control group, also the GHQ-28, the SCID-I interview and the EAT-26 were used. RESULTS: ED patients had higher lifetime and current tobacco and general drug use. The only non-significant result was obtained for lifetime and current alcohol use. Significant differences across ED subdiagnoses and controls also emerged, with BN and AN-BP generally presenting the highest and AN-R and controls the lowest rates. The only exception was detected for alcohol use where EDNOS demonstrated the highest values. Only a few cultural differences between countries emerged. CONCLUSIONS: With the exception of alcohol consumption, tobacco and drug use appear to be more prevalent in ED patients than healthy controls. The differential risk observed in patients with bulimic features might be related to differences in temperament or might be the result of increased sensitivity to reward.     

Childhood inattention and dysphoria and adult obesity associated with the dopamine D4 receptor gene in overeating women with seasonal affective disorder.

There is significant evidence that altered dopamine activity plays a role in seasonal affective disorder (SAD). The current study examined three separate genetic hypotheses for SAD related to the 7-repeat allele (7R) of the dopamine-4 receptor gene (DRD4), a variant associated with decreased affinity for dopamine. We examined the possible contribution of 7R to the overall expression of SAD, attention deficit disorder (ADD) comorbidity, and body weight regulation. As part of an ongoing genetic study of increased eating behavior and mood in female subjects, 108 women with winter SAD and carbohydrate craving/weight gain were administered the Wender-Utah Rating Scale to measure childhood ADD symptomatology, and a questionnaire to assess maximal lifetime body mass index (BMI). To test for an association between 7R and the categorical diagnosis of SAD, the transmission disequilibrium test (TDT) was used in a subsample of probands providing familial DNA. Standard parametric tests were used to compare childhood ADD symptoms and maximal lifetime BMI across the two genotypic groups defined by the presence or absence of 7R. The TDT found no initial evidence for an association between 7R and the categorical diagnosis of SAD. However, 7R carriers reported significantly greater inattention and dysphoria in childhood (p=0.01 and 0.001, respectively) and a higher maximal lifetime BMI (p=0.007) than did probands without this allele. Furthermore, excluding probands with extreme obesity (maximal BMI >40), a strong correlation was found linking childhood inattentive symptoms and maximal lifetime BMI (r=0.35, p=0.001). In overeating women with SAD, the 7R allele of DRD4 may be associated with a unique developmental trajectory characterized by attentional deficits and dysphoria in childhood and mild to moderate obesity in adulthood. This developmental course may reflect different manifestations of the same underlying vulnerability related to central dopamine dysfunction. Given the possibility of population stratification when studying genotype/phenotype relationships, future use of genomic controls and replication of our findings in other overeating and/or ADD populations are needed to confirm these initial results.     

Circadian clock-related polymorphisms in seasonal affective disorder and their relevance to diurnal preference.

Disturbed circadian rhythms have been observed in seasonal affective disorder (SAD). The aim of this study was to further investigate this connection, and to test for potential association between polymorphisms in circadian clock-related genes and SAD, seasonality (seasonal variations in mood and behavior), or diurnal preference (morningness-eveningness tendencies). A total of 159 European SAD patients and 159 matched controls were included in the genetic analysis, and subsets were screened for seasonality (n=177) and diurnal preference (n=92). We found that diurnal preference was associated with both SAD and seasonality, supporting the hypothesis of a link between circadian rhythms and seasonal depression. The complete case-control material was genotyped for polymorphisms in the CLOCK, Period2, Period3, and NPAS2 genes. A significant difference between patients and controls was found for NPAS2 471 Leu/Ser (chi(2)=9.90, Bonferroni corrected P=0.035), indicating a recessive effect of the leucine allele on disease susceptibility (chi(2)=6.61, Bonferroni corrected P=0.050). Period3 647 Val/Gly was associated with self-reported morningness-eveningness scores (n=92, one-way ANOVA: F=4.99, Bonferroni corrected P=0.044), with higher scores found in individuals with at least one glycine allele (t=3.1, Bonferroni corrected P=0.013). A second, population-based sample of individuals selected for high (n=127) or low (n=98) degrees of seasonality, was also genotyped for NPAS2 471 Leu/Ser. There was no significant difference between these seasonality extreme groups, and none of the polymorphisms studied were associated with seasonality in the SAD case-control material (n=177). In conclusion, our results suggest involvement of circadian clock-related polymorphisms both in susceptibility to SAD and diurnal preference.