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Objective Overactivity of dopaminergic neurotransmission is a putative mechanism of tardive dyskinesia (TD). Dopamine beta-hydroxylase (DBH) is a key enzyme in the conversion of dopamine to norepinephrine, and plasma DBH activity is altered in TD patients. This study examined whether the functional DBH 5'-Ins/Del polymorphism was associated with TD severity in Chinese patients with schizophrenia. Methods We compared the rate of this polymorphism in patients with (n = 312) and without TD (n = 435), and healthy controls (n = 625). The severity of TD was assessed using the Abnormal Involuntary Movement Scale (AIMS) and psychopathology using the Positive and Negative Syndrome Scale (PANSS). Results There were no significant differences in the distribution of the allele and genotype frequencies between the patients and controls, or between the patients with and without TD. Also, there was no significant difference in the AIMS total score between the three genotype groups. However, the PANSS positive symptom subscore was significantly higher in patients with Del/Del genotype (13.2 ± 5.2) than those with Ins/Del (11.2 ± 4.9) and Ins/Ins (11.1 ± 3.1) genotypes (both p

Aims: Some of the well-known functional alcohol dehydrogenase (ADH) gene variants (e.g. ADH1B *2, ADH1B *3 and ADH1C *2) that significantly affect the risk of alcohol dependence are rare variants in most populations. In the present study, we comprehensively examined the associations between rare ADH variants [minor allele frequency (MAF)

Sex differences are observed in both epidemiological and clinical aspects of major depressive disorder (MDD). The cortico-limbic-striatal neural system, including the prefrontal cortex, amygdala, hippocampus, and striatum, have shown sexually dimorphic morphological features and have been implicated in the dysfunctional regulation of mood and emotion in MDD. In this study, we utilized a whole-brain, voxel-based approach to examine sex differences in the regional distribution of gray matter (GM) morphological abnormalities in medication-naive participants with MDD. Participants included 29 medication-naive individuals with MDD (16 females and 13 males) and 33 healthy controls (HC) (17 females and 16 males). Gray matter morphology of the cortico-limbic-striatal neural system was examined using voxel-based morphometry analyzes of high-resolution structural magnetic resonance imaging scans. The main effect of diagnosis and interaction effect of diagnosis by sex on GM morphology were statistically significant (p

Patients suffering from major depressive disorder (MDD) have been reported to have substantial long-lasting limitations in multiple domains of health-related quality of life (HRQoL). The thoughtful assessment of HRQoL and the impact of treatment response on HRQoL are emerging as important issues in the care of patients with major depressive disorder.One hundred and three patients meeting Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria for MDD took fluoxetine (20 mg/d) for 6 weeks and were assessed by the Short Form 36 Health Survey (SF-36), the 17-item Hamilton Depression Rating (HAMD-17) and the Clinical Global Impression (CGI) scales. Relationships between SF-36 scores and depressive symptom severity and early change of these symptoms were tested.SF-36 component scores at week 6 were higher than those at baseline (all P ≤ 0.0058). Scores for general health were significantly higher in responders than non-responders (P = 0.0009). The overall HAMD-17 and CGI scores at 2- and 6-week follow-up were significantly lower than those at baseline (P ≤ 0.0001). Higher scores for anxiety/somatization were significantly associated with poorer SF-36 scores at baseline (P = 0.0001); role-physical scores at week 6 were positively correlated with reduction rate of anxiety/somatization in 2-week follow-up (P = 0.0002).Depressive symptom severity was associated with HRQoL in patients with MDD. HRQoL may vary with severity of depression and/or anxiety-somatization at baseline.

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.

Alcohol dependence (AD) is a complex disorder characterized by psychiatric and physiological dependence on alcohol. AD is reflected by regular alcohol drinking, which is highly inheritable. In this study, to identify susceptibility genes associated with alcohol drinking, we performed a genome-wide association study of copy number variants (CNVs) in 2,286 Caucasian subjects with Affymetrix SNP6.0 genotyping array. We replicated our findings in 1,627 Chinese subjects with the same genotyping array. We identified two CNVs, CNV207 (combined p-value 1.91E-03) and CNV1836 (combined p-value 3.05E-03) that were associated with alcohol drinking. CNV207 and CNV1836 are located at the downstream of genes LTBP1 (870 kb) and FGD4 (400 kb), respectively. LTBP1, by interacting TGFB1, may down-regulate enzymes directly participating in alcohol metabolism. FGD4 plays a role in clustering and trafficking GABA(A) receptor and subsequently influence alcohol drinking through activating CDC42. Our results provide suggestive evidence that the newly identified CNV regions and relevant genes may contribute to the genetic mechanism of alcohol dependence.

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 p0.05). 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.

Several genome-wide association studies (GWASs) reported tens of risk genes for alcohol dependence, but most of them have not been replicated or confirmed by functional studies. The present study used a GWAS to search for novel, functional and replicable risk gene regions for alcohol dependence. Associations of all top-ranked SNPs identified in a discovery sample of 681 African-American (AA) cases with alcohol dependence and 508 AA controls were retested in a primary replication sample of 1,409 European-American (EA) cases and 1,518 EA controls. The replicable associations were then subjected to secondary replication in a sample of 6,438 Australian family subjects. A functional expression quantitative trait locus (eQTL) analysis of these replicable risk SNPs was followed-up in order to explore their cis-acting regulatory effects on gene expression. We found that within a 90 Mb region around PHF3-PTP4A1 locus in AAs, a linkage disequilibrium (LD) block in PHF3-PTP4A1 formed the only peak associated with alcohol dependence at p

Human personality traits are strong predictors or characteristics of many psychiatric disorders including substance dependence (SD). Recently, significant associations between alcohol dehydrogenase type 1A gene (ADH1A) and SD have been reported, which led us to investigate the impact of ADH1A variation on personality traits and risk of SD. Five hundred fifty-eight subjects with SD [398 European-Americans (EAs) and 160 African-Americans (AAs)], 517 college students (384 EAs and 133 European-origin Hispanics), and 448 healthy subjects (385 EAs, 48 AAs, and 15 European-origin Hispanics) participated. Personality traits were assessed in 247 subjects with SD (179 EAs and 68 AAs), all 517 college students, and 332 healthy subjects (285 EAs, 40 AAs, and 7 European-origin Hispanics). The relationships between ADH1A and personality traits were comprehensively examined using stepwise multivariate analysis of covariance (MANCOVA), and then decomposed by stepwise analysis of covariance (ANCOVA). The relationship between ADH1A and SD was examined using stepwise logistic regression analysis. Admixture effects on analyses were considered. Overall, Agreeableness and Conscientiousness were associated with the diplotypes, haplotypes, genotypes, and/or alleles of ADH1A in three of four phenotype groups including EA SD subjects, healthy subjects, and AA SD subjects (1.7 × 10−4 ≤ P ≤ 0.055), but not college students. Neuroticism was associated with diplotype, haplotypes and genotypes in AA SD subjects (0.001 ≤ P ≤ 0.031). In addition, SD was associated with diplotypes, haplotypes, genotypes, and/or alleles of ADH1A (0.008 ≤ P ≤ 0.060). The present study demonstrates that the ADH1A variation may contribute to the genetic component of variation in personality traits and SD. © 2009 Wiley-Liss, Inc.

The admixture of different ancestral populations in America may have important implications for the risk for psychiatric disorders, as it appears to have for other medical disorders. The present study investigated the role of population admixture in risk for several psychiatric disorders in European-Americans (EAs) and African-Americans (AAs). This is a multisite study with 3,792 subjects recruited from across the United States, including 3,119 EAs and 673 AAs. These subjects included healthy controls and those with substance dependence (SD) [including alcohol dependence (AD), cocaine dependence, and opioid dependence], social phobia, affective disorders, and schizophrenia. In addition, DNA was included from 78 West Africans. The degree of admixture for each subject was estimated by analysis of a set of ancestry-informative genetic markers using the program STRUCTURE, and was compared between cases and controls. As noted previously, the degree of admixture in AAs was higher than EAs. In EAs, the degree of admixture (with African ancestry) was significantly lower in patients with SD (mainly AD) than controls (P = 0.009 for SD; P = 0.008 for AD). This finding suggests that population admixture may modulate risk for alcohol dependence. Population admixture might protect against alcohol dependence by increasing average heterozygosity and reducing the risk of deleterious recessive alleles. We cannot exclude the possibility that the results might have been influenced by selection bias due to the multisite nature of the study.

Background Opioidergic neurotransmission is critical in many, possibly all, forms of substance dependence. Several opioid-system genes have been shown to be associated with substance dependence disorders. The pro-opiomelanocortin gene ( POMC ) encodes several peptides important for endogenous opioidergic neurotransmission. We tested whether POMC genetic variation affects risk for substance dependence. Methods Five single nucleotide polymorphisms spanning POMC were examined in independent family and case-control samples. Family-based studies included 854 subjects from 319 African American (AA) families and 761 subjects from 313 European American (EA) families. Each family had a pair of siblings affected with cocaine and/or opioid dependence. Case-control studies included 791 cases (455 AAs and 336 EAs) affected with alcohol, cocaine, and/or opioid dependence and 682 control subjects (199 AAs and 483 EAs). Results Family-based analyses revealed an association of rs6719226 with opioid dependence in AA families and rs6713532 with cocaine dependence in EA families ( p = .010–.044). Case-control analyses demonstrated an association of rs6713532 with alcohol or cocaine dependence in EAs ( p allele-wise = .003–.008). Moreover, the minor allele of rs1866146 was found to be a risk factor for cocaine or opioid dependence in AAs ( p allele-wise = .010–.017) and for alcohol, cocaine, or opioid dependence in EAs ( p allele-wise = .001–.003). Logistic regression analyses in which sex and age were considered and population stratification analyses confirmed these findings. Additionally, specific haplotypes increased risk for cocaine dependence ( p = .023) in AAs and opioid dependence ( p = .012) in EAs. Conclusions Given these replicated results, we conclude that variation in POMC confers vulnerability to multiple forms of substance dependence.

Each gene in the chromosome 11q23 cluster of NCAM1, TTC12, ANKK1, and DRD2 is functionally linked to dopamine in brain. Many association studies of DRD2 and substance dependence (SD), including alcohol dependence (AD) and drug dependence (DD), have been reported; the results have been inconsistent. Recent association studies have considered this cluster more comprehensively, examining the association of SD with several risk variants mapped to the other genes in the cluster. Because comorbid AD with DD (AD+DD) is common, we hypothesized that heterogeneity of the SD diagnoses studied might have contributed to the inconsistency of prior results.We conducted 2 separate association studies of AD+DD and AD without DD (AD-only) in 1,090 European-Americans using family-based and case-control designs and 43 single nucleotide polymorphisms mapped to this cluster. We used a generalized linear model and haplotype score tests for the case-control sample, and the family-based association test for the family sample.For AD+DD, the risk regions centered on TTC12 exon 3 [optimal individual haplotype simulated p (p(oihs)) = 0.000015], and another extended from ANKK1 exon 8 to DRD2;C957T (p(oihs) = 0.0028), in both samples. NCAM1 exon 12 markers showed global significance in both designs, but were significant for specific haplotypes (p(oihs) = 0.0029) only for the family sample. For AD-only, NCAM1 intron 14 to 18 and the junction of ANKK1 and DRD2 were associated globally. Population stratification was excluded as the basis for these results. Linkage disequilibrium contrast tests supported selection at TTC12 exon 3 and ANKK1 exon 2.We conclude that variants in TTC12 exon 3, NCAM1 exon 12, and the two 3'-ends of ANKK1 and DRD2 co-regulate risk for comorbid AD and DD.

BackgroundIn our previous studies, we reported positive associations between sevenADH4polymorphisms and substance dependence [i.e., alcohol dependence (AD) and/or drug dependence (DD)] in European-Americans (EAs). In the present study, we address the relationship betweenADH4variation and substance dependence in an African-American (AA) population, and report evidence that supports an association between a differentADH4polymorphism (rs2226896) and these phenotypes in AAs.MethodsTwo family-based association study methods, i.e., TDT and FBAT, were applied to test the relationship betweenADH4variation and substance dependence in Sample 3 (112 small nuclear families) and in Sample 4 (632 pedigrees), respectively. A population-based case-control association study method was also applied to test this relationship in 1303 unrelated subjects, with and without controlling for admixture effects. Finally, a Hardy-Weinberg Disequilibrium (HWD) test was applied to examine the association in the case-only sample, infer the genetic disease models, and distinguish the disease and non-disease factors contributing to HWD.ResultsThe marker examined was found to be in significant HWD in AA alcoholics (p = 0.0071) and drug dependent subjects (p = 0.0341), but in Hardy-Weinberg Equilibrium (HWE) in all other subgroups. Other association methods failed to detect any association between this variation and phenotypes. The best-fit genetic disease model for this marker is a recessive genetic model.ConclusionADH4variation might play a role in risk for substance dependence in AAs, potentially via a recessive mechanism. Under certain conditions, the HWD test could be a more powerful association method than conventional family-based and population-based case-control association analyses, for which, the present study provides an extreme example.

Eleven single-nucleotide polymorphisms (SNPs) spanning OPRD1 were examined in 1063 European Americans (EAs) (620 cases with substance dependence (SD), including 557 with alcohol dependence (AD), 225 with cocaine dependence (CD) and 111 with opioid dependence (OD), and 443 controls). Nominally significant associations (P < 0.05) of five SNPs with SD were observed; only the association of the non-synonymous variant G80T with OD remained significant after correction for multiple testing using SNPSpD. Haplotype analyses with six tag SNPs indicated that a specific haplotype GCAACT, which harbors G80T G-allele and C921T C-allele, was significantly associated with AD (χ2 = 14.82, degrees of freedom (d.f.) = 1, P < 0.001), CD (χ2 = 9.19, d.f. = 1, P=0.002) and OD (χ2 = 20.68, d.f. = 1, P < 0.001). Logistic regression analyses, with sex and age being considered, demonstrated that this haplotype had a risk effect on AD (P = 0.03, β = 1.86, odds ratio (OR) = 6.43) and especially on OD (P< 0.001, β = 3.92, OR= 50.57). Moreover, seven SNPs covering OPRK1 were examined in the majority of the above subjects (390 cases, including 327 AD, 177 CD and 97 OD subjects, and 358 controls). Although no significant differences in allele, genotype or haplotype frequency distributions were seen between cases and controls, a specific OPRK1 haplotype, GGCTTCT, was significantly associated with AD (χ2 = 8.12, d.f. = 1, P=0.004). Logistic regression analyses also revealed its risk effect on AD (P = 0.009, β = 1.06, OR= 2.90). Population stratification artifact was not observed in the sample. Taken together, our findings supported a positive association between OPRD1 variants and SD, and a positive haplotypic association between OPRK1 and AD in EAs.

Background The apolipoprotein E (APOE) and tau proteins play important roles in the pathological development of Alzheimer's disease (AD). Many studies have shown an association between the APOE gene and AD. Association between AD and the newly discovered saitohin (STH) gene, nested within the intron of the tau gene, has been reported. The present study aimed to elucidate the association between APOE and AD, and between STH and AD in our sample. Methods The functional polymorphisms, rs429358 and rs7412, in the APOE gene (which together define the ε 2, ε 3, and ε 4 alleles), and the Q7R SNP in the STH gene, were genotyped in 369 patients with AD and 289 healthy European-Americans. The associations between these two genes and AD were analyzed in a case-control design. Results Consistent with previously reported results, the frequencies of the APOE ε 4 allele, ε 4/ε 4 genotype and ε 3/ε 4 genotype were significantly higher in AD cases than controls; the ε 4/ε 4 genotype frequency was significantly higher in early-onset AD (EOAD) than late-onset AD (LOAD); the frequencies of the ε 2 allele, ε 3 allele, ε 3/ε 3 genotype and ε 2/ε 3 genotype were significantly lower in AD cases than controls. Positive likelihood ratios (LRs+) of APOE alleles and genotypes increased in a linear trend with the number of ε 4 alleles and decreased in a linear trend with the number of ε 2 or ε 3 alleles. There was no significant difference in the STH allele and genotype frequency distributions between AD cases and controls. Conclusion This study confirmed that the ε 4 allele is a dose-response risk factor for AD and the ε 4/ε 4 genotype was associated with a significantly earlier age of onset. Moreover, we found that the ε 2 allele was a dose-response protective factor for AD and the ε 3 allele exerted a weaker dose-response protective effect for risk of AD compared with ε 2. In a clinical setting, APOE genotyping could offer additional biological evidence of whether a subject may develop AD, but it is not robust enough to serve as an independent screening or predictive test in the diagnosis of AD. STH variation was not significantly associated with AD in our sample.

According to the five-factor model of personality (Digman 1990), the full range of personality traits can be well defined in terms of five basic dimensions. These dimensions are: factor I (extraversion or surgency), which contrasts such traits as talkativeness, assertiveness, and activity level with silence, passivity, and reserve; factor II (agreeableness or pleasantness), which contrasts kindness, trust, and warmth with hostility, selfishness, and distrust; factor III (conscientiousness or dependability), which contrasts organization, thoroughness, and reliability with carelessness, negligence, and unreliability; factor IV (neuroticism versus emotional stability), which includes nervousness, moodiness, and temperamentality; and factor V (openness to experience or intellect), which contrasts imagination, curiosity, and creativity with shallowness and imperceptiveness (Goldberg 1993). This structure of traits in the five-factor model is consistent among highly diverse cultures with distinct languages and between men and women, older and younger adults, and European Americans (EAs) and non-European Americans (Costa et al 1991; McCrae and Costa 1997). This universality could reflect a common biological basis of personality traits across distinct cultures, populations, ages, and sexes. Based on its wide applicability and consistency, the five-factor model has been widely accepted. Genetic factors have been implicated as contributing to individual difference in major dimensions of personality traits, evidenced by a linkage study and many association studies. A genomewide-scan linkage study mapped five trait-influencing sites for neuroticism at chromosomes 1q, 4q, 7p, 12q, and 13q (Fullerton et al 2003). Subjects expressing one or both S alleles of a regulatory region polymorphism at the serotonin transporter gene (SLC6A4) tended to score lower on the NEO Five-Factor Inventory factor of agreeableness than subjects homozygous for the L allele; within this factor, the facet subscale of tendermindedness was lower for subjects expressing one or both S alleles compared with subjects homozygous for the L allele (p = .003) (Wand et al 2002). There have also been reports of an association between this polymorphism and harm avoidance (Wiesbeck et al 2004), neuroticism (Du et al 2000; Lesch et al 1996), violent behavior (Retz et al 2004), or other anxiety-related personality traits (Melke et al 2001). Many other studies have also reported on the relationship of personality traits with other candidate loci, such as variation at the 5-HT2C gene (Ebstein et al 1997), the 5-HT2A gene (Golimbet et al 2002), the DRD2 gene (Jonsson et al 2003; Lee et al 2003; Ponce et al 2003; Rosmond et al 2001), the DRD3 gene (Thome et al 1999), the DRD4 gene (Bau et al 1999; Gelernter et al 1997; Lee et al 2003), the COMT gene (Rujescu et al 2003; Tsai et al 2004), the BDNF gene (Itoh et al 2004; Lang et al 2004, 2005; Sen et al 2003), the OPRM1 gene (Wand et al 2002), the TFAP2B gene (Damberg et al 2000), and the ESR1 gene (Westberg et al 2003). These findings provide additional support for the hypothesis that personality traits are influenced by genetic factors. Personality traits may play a central role in the development of substance dependence (SD; including alcohol dependence and opioid dependence in the studies by Caspi et al 1997; Cloninger 1987; Cloninger et al 1988; Loper et al 1973; Verheul et al 2004; Zucker and Lisansky Gomberg 1986). Specifically, some premorbid personality traits, such as “behavioral under-control” (including impulsivity, thrill seeking, rebelliousness, irresponsibility, nonconformity, and aggressiveness) (Sher et al 1991), rejection of societal values, antisocial behavior, and hyperactivity, are robust predictors of alcohol dependence (Cox et al 1983; Otter and Martin 1996). In contrast, it has been argued that personality traits, especially “negative emotionality” (anxiousness, inhibition, moodiness, and unhappiness), may be a consequence rather than a cause of alcohol dependence (Schuckit 1986). Common genetic factors may largely underlie the association between personality traits and alcohol dependence. For example, in a community sample of 2682 twins, Slutske et al (1998) found that 70% of the association between antisociality and alcohol dependence was explained by common genetic factors; this study also showed that alcohol dependence and conduct disorder shared many personality traits (also confirmed by Krueger et al 2000; Sher and Trull 1994) that could be accounted for by common genetic risk factors. In a follow-up study, these authors confirmed the finding that these personality dimensions shared genetic risk factors with alcohol dependence (Slutske et al 2002). Studies of the offspring of alcoholics suggested that behavioral undercontrol might be related to the familial diathesis underlying alcohol dependence risk (e.g., Finn et al 2000; Sher et al 1991, 1999). There is also direct evidence that personality traits and alcohol dependence are linked to polymorphisms in the serotonin transporter gene (SLC6A4) and the μ-opioid receptor gene (OPRM1) (Sander et al 1998a, 1998b). These findings support the idea of a shared genetic basis for personality features and alcohol dependence. The development of alcohol dependence depends on heavy ethanol consumption, which appears to be influenced by alcohol dehydrogenase (ADH) activity. Increased ADH activity can increase the rate of alcohol metabolism, thereby increasing the production of the toxin acetaldehyde. If acetaldehyde is not metabolized quickly, it accumulates, resulting in an aversive “flushing reaction,” which can limit alcohol consumption and, hypothetically, thereby reduce the risk for alcohol dependence (Hasin et al 2002; Muramatsu et al 1995; Thomasson et al 1994). Conversely, decreased ADH activity may increase the risk for alcohol dependence (Hasin et al 2002; Thomasson et al 1994). Human ADH4 enzyme mainly contributes to liver ADH activity, and at intoxicating levels of alcohol, it may account for as much as 40% of the total ethanol oxidation rate (Ditlow et al 1984). A polymorphism mapped to the promoter region of the ADH4 locus at 4q22 (e.g., single nucleotide polymorphism [SNP]6: −75A/C [rs1800759]) could modulate ADH activity (Edenberg et al 1999). Guindalini et al (2005) reported that promoter variants, including −75A/C and −159A/G, were significantly associated with alcohol dependence in European Brazilians and African Brazilians. We (Luo et al 2006a) found that seven ADH4 markers (including −75A/C) were in strong linkage disequilibrium (LD) to form a haplotype block in EA and African American (AA) substance dependent subjects and healthy control subjects. The genotype frequency distributions of the seven ADH4 markers were in Hardy-Weinberg Disequilibrium (HWD) in the EA patients with SD but were in Hardy-Weinberg Equilibrium (HWE) in the EA healthy control subjects and the AA cases and control subjects. The genotypes of seven ADH4 markers were significantly associated with alcohol and/or drug dependence in EAs. Among these markers in EAs, SNP6 and SNP2 (rs1042364) were most significant HWD in cases with alcohol dependence and drug dependence, respectively; also, these two markers were most significantly associated with alcohol dependence and drug dependence, respectively. Fine mapping the risk loci with an HWD measure (Feder et al 1996) revealed that these two markers were closest to the risk loci for alcohol dependence and drug dependence, respectively. After correcting for the effects of allele frequencies of markers on HWD (Jiang et al 2001), SNP6 was the marker closest to the risk loci for both alcohol dependence and drug dependence. We hypothesized that personality traits would also be associated with ADH4 variation, due to their strong genetic link to SD and the strong association between SD and ADH4. The present study aimed to investigate the role of these seven ADH4 markers in determining differences in personality traits among individuals.

The alcohol dehydrogenase (ADH) family constitutes one of the key sets of enzymes responsible for the oxidation of alcohol. The ADH4 gene, an important member of this family, is a functional and positional candidate for alcohol dependence. The present study aimed to investigate the relationship between ADH4 gene variation and alcohol dependence and drug dependence in European-Americans (EAs) and African-Americans (AAs). Seven single nucleotide polymorphisms (SNPs) spanning the ADH4 gene were genotyped in 365 healthy controls (317 EAs and 48 AAs) and 561 subjects (400 EAs and 161 AAs) affected with alcohol dependence and/or drug dependence (436 with alcohol dependence; 356 with drug dependence). Hardy–Weinberg equilibrium (HWE) for the genotype frequency distributions of these markers was tested in all phenotype groups to evaluate association between ADH4 gene variation and phenotypes and to fine-map the disease risk locus. The allele, genotype, and haplotype frequency distributions of these markers were compared between cases and controls to confirm the associations. The genotype frequency distributions of ADH4 markers were in HWE in EA controls, but were in Hardy–Weinberg disequilibrium (HWD) (ie, deviation from HWE) in EA cases. Among all markers, SNP2 (rs1042363) at exon 9 or SNP6 (rs1800759) at the promoter showed the greatest degree of HWD, among patients with either alcohol dependence or drug dependence. Significant differences between EA cases and controls were seen for genotype (10−6

Cholinergic muscarinic 2 receptor (CHRM2) is implicated in memory and cognition, functions impaired in many neuropsychiatric disorders. Wang et al. [Wang, J.C., Hinrichs, A.L., Stock, H., Budde, J., Allen, R., Bertelsen, S., Kwon, J.M., Wu, W., Dick, D.M., Rice, J. et al. (2004) Evidence of common and specific genetic effects: association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome. Hum. Mol. Genet., 13, 1903-1911] reported that variation in CHRM2 gene predisposed to alcohol dependence (AD) and major depressive syndrome. We examined the relationships between variation in CHRM2 and AD, drug dependence (DD) and affective disorders, using a novel extended case-control structured association (SA) method. Six markers at CHRM2 and 38 ancestry-informative markers (AIMs) were genotyped in a sample of 871 subjects, including 333 healthy controls [287 European-Americans (EAs) and 46 African-Americans (AAs)] and 538 AD and/or DD subjects (415 with AD and 346 with DD and 382 EAs and 156 AAs). The same CHRM2 markers were genotyped in a sample of 137 EA subjects with affective disorders. All of the six markers were in Hardy-Weinberg equilibrium in controls, but SNP3 (rs1824024) was in Hardy-Weinberg disequilibrium in the AD and DD groups. Using conventional case-control comparisons, some markers were nominally significantly or suggestively associated with phenotypes before or after controlling for population stratification and admixture effects, but these associations were not significant after multiple test correction. However, regression analysis identified specific alleles, genotypes, haplotypes and diplotypes that were significantly associated with risk for each disorder. We conclude that variation in CHRM2 predisposes to AD, DD and affective disorders. One haplotype block within the 5'-UTR of CHRM2 may be more important for the development of these disorders than other regions. Interaction between two specific alleles within this block and interaction between two specific diplotypes covering this block multiplicatively increased risk for AD and DD. Although interaction between these two diplotypes also increased risk for affective disorders, the magnitude of the increased risk was less than the sum of the individual risks. In addition, a specific diplotype might inversely affect risk for AD and DD and risk for affective disorders.

Background The identification of genetic factors controlling stress-responsiveness should advance the understanding of susceptibility to psychiatric illness. Methods Rat strains, F344/NHsd and LEW/NHsd, which differ in measures of stress-responsiveness and behaviors modeling psychiatric disorders, were bred to generate F 2 progeny that were used in a quantitative trait loci (QTL) analysis to identify genomic regions influencing late-afternoon corticosterone levels. Results Regions on chromosomes 4 and 10 previously identified as influencing autoimmune phenomena were the most significant QTL observed, reaching suggestive significance at the genome-wide level. Congenic animals targeting these regions with F344/NHsd deoxyribonucleic acid on a DA/Bkl genomic background demonstrated corticosterone levels approximating those of F344/NHsd rats and differing significantly from DA/Bkl rats. Conclusions Specific genomic regions influence both corticosterone levels and stress-related disease susceptibility. These findings not only represent the first identification of QTL controlling corticosterone levels but also suggest a mechanism underlying genetic differences in stress-responsiveness.

Our objective was to investigate the relationship between the gene encoding the μ-opioid receptor (OPRM1) and susceptibility to substance dependence in European-American (EA) and African-American (AA) subjects. Eight single nucleotide polymorphisms (SNPs) at the OPRM1 locus, i.e., −2044C/A, −1793T/A, −1699insT, −1469T/C, −1320A/G, −111C/T, +17C/T (Ala6Val), and +118A/G (Asn40Asp) were genotyped in 676 subjects: 318 EA subjects and 124 AA subjects with substance dependence, and 179 EA normal controls, and 55 AA normal controls. Affection status was defined by each unique combination of alcohol, cocaine, and opioid dependence and analysis of association examined in relation to the possible combinations. We used a newly implemented permutation method to evaluate statistical significance. In EAs, a significant difference in haplotype frequency distributions was found between controls and “alcohol + opioid” dependent patients (P = 0.0036). This finding is also supported by logistic regression analysis and a simulation method. The frequencies of allele −2044A and haplotypes including −2044A are higher in these patients than in controls. In AAs, no allele, haplotype, or genotype frequencies were significantly different between cases and controls. There were highly significant differences in the allele, haplotype, and genotype frequencies between EA and AA controls. Four of the variants [−1793T/A, −1699insT, −1320A/G, and −111C/T] are in virtually complete linkage disequilibrium (LD) to compose a sequence pattern, which does not associate with any of the seven categories of substance dependence. In EAs, allele −2044A and haplotypes that include −2044A are the susceptibility allele and haplotypes for substance dependence. These findings suggest that OPRM1 may play a role in the pathophysiology of substance dependence and this role is population- and diagnosis-specific. © 2003 Wiley-Liss, Inc.

Correction to: Neuropsychopharmacology advance online publication, 28 September 2011; doi:10.1038/npp.2011.229 In this article, the incorrect version of Figure 1 was published. The correct version is shown in the next page.

The set of alcohol-metabolizing enzymes has considerable genetic and functional complexity. The relationships between some alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) genes and alcohol dependence (AD) have long been studied in many populations, but not comprehensively. In the present study, we genotyped 16 markers within the ADH gene cluster (including the ADH1A, ADH1B, ADH1C, ADH5, ADH6, and ADH7 genes), 4 markers within the ALDH2 gene, and 38 unlinked ancestry-informative markers in a case-control sample of 801 individuals. Associations between markers and disease were analyzed by a Hardy-Weinberg equilibrium (HWE) test, a conventional case-control comparison, a structured association analysis, and a novel diplotype trend regression (DTR) analysis. Finally, the disease alleles were fine mapped by a Hardy-Weinberg disequilibrium (HWD) measure (J). All markers were found to be in HWE in controls, but some markers showed HWD in cases. Genotypes of many markers were associated with AD. DTR analysis showed that ADH5 genotypes and diplotypes of ADH1A, ADH1B, ADH7, and ALDH2 were associated with AD in European Americans and/or African Americans. The risk-influencing alleles were fine mapped from among the markers studied and were found to coincide with some well-known functional variants. We demonstrated that DTR was more powerful than many other conventional association methods. We also found that several ADH genes and the ALDH2 gene were susceptibility loci for AD, and the associations were best explained by several independent risk genes.

We found strong associations between ADH4 gene variation and alcohol and drug dependence by the Hardy-Weinberg Disequilibrium (HWD) test and case-control association analysis in an initial study. The present study aimed to confirm these findings by controlling for population stratification and admixture effects to which the HWD test and case-control association methods may be vulnerable. In addition to 365 unrelated healthy controls and 560 unrelated cases in the initial study, we evaluated 104 small nuclear families with affected offspring who had diagnoses of alcohol and/or drug dependence. Seven single nucleotide polymorphisms (SNPs) at the ADH4 gene locus were genotyped in all subjects, and 38 unlinked ancestry-informative markers were also genotyped in unrelated cases and controls. Structured association analysis demonstrated that the genotypes of six ADH4 markers were associated with alcohol dependence, and all seven ADH4 markers were associated with drug dependence (P=10-0.047). Logistic regression analysis showed that: (i) the genotypes of SNP2 (rs1042363) were significantly associated with alcohol dependence and drug dependence (mainly cocaine dependence), and the genotypes of SNP3 (rs1126671) were also significantly associated with alcohol dependence and (ii) one seven-variant haplotype and one diplotype were significantly associated with alcohol dependence and other seven-variant diplotypes were significantly associated with drug dependence (including cocaine and opioid dependence). Transmission disequilibrium test, haplotype-based haplotype relative risk and genotype-based haplotype relative risk analyses all confirmed the association of the ADH4 markers with alcohol dependence and drug dependence. Using rigorous study designs that account for possible population stratification, these findings confirm and extend our original observations indicating that variation at ADH4 predisposes to alcohol and drug dependence.

Background Glutamate carboxypeptidase II (GCPII) inactivates the peptide co-transmitter N-acetylaspartylglutamate following synaptic release. Inhibition of GCPII elevates extracellular levels of the peptide, inhibits glutamate release and is neuroprotective in an animal model of traumatic brain injury. GCPII gene knockout mice were used to examine the cellular mechanisms underlying the neuroprotective efficacy of this transmitter system. Results Following controlled cortical impact injury, GCPII knockout (KO) mice exhibited reduced TUNEL-positive nuclei in the contusion margin of the cerebral cortex relative to wild type mice. Impact injury reduced glutathione levels and superoxide dismutase and glutathione peroxidase activities and increased malondialdehyde. Each of these effects was moderated in KO mice relative to wild type. Similarly, the injury-induced increases in cleaved caspase-3, cytosolic cytochrome c levels and Bcl-2/Bax ratio observed in wild type mice were attenuated in the knockout mice. Conclusions These data support the hypothesis that the neuroprotective efficacy of GCPII KO in traumatic brain injury is mediated via a reduction in oxidative stress.

Objective: In the present study, we scanned the whole exome in three independent samples to search for replicable risk nonsyn- onymous (ns) variants (ns single-nucleotide polymorphisms (nsSNPs)) for alcohol dependence. Method: A total of 10,554 subjects in three independent samples were analyzed for association with alcohol depen- dence, including one European American sample (1,409 cases with alco- hol dependence and 1,518 controls), one African American sample (681 cases and 508 controls), and one European Australian sample (a total of 6,438 family subjects with 1,645 alcohol-dependent probands). RNA expression of the risk genes in human, mouse, and rat brains was also explored. Results: We identifi ed a total of 70 nsSNPs at 65 genes with nominally replicable associations; 22 nsSNPs at 21 genes among them survived corrections for multiple testing in meta-analysis (α = .0007). By incorporating the information from bioinformatics and RNA expression analyses, we identifi ed at least two of the most promising risk genes for alcohol dependence: APOER2 and UBAP2. Conclusions: The gene cod- ing for apolipoprotein E receptor 2 (APOER2) and the gene coding for ubiquitin-associated protein-2 (UBAP2) are among the most appropriate for follow-up in human and nonhuman species as contributors to risk for alcohol dependence. (J. Stud Alcohol Drugs, 74, 622-625, 2013)

OBJECTIVE: Piwi-interacting RNAs (piRNAs) represent a molecular feature shared by all nonaging biological systems, including the germline and somatic cancer stem cells, which display an indefinite renewal capacity and lifespan-stable genomic integrity and are potentially immortal. Here, we tested the hypothesis that piRNA is a critical genetic determinant of aging in humans. METHODS: Expression of transcriptome-wide piRNAs (n=24k) was profiled in the human prefrontal cortex of 12 subjects (84.9±9.5, range 68–100, years of age) using microarray technology. We examined the correlation between these piRNAs’ expression levels and age, adjusting for covariates including disease status. RESULTS: A total of 9,453 piRNAs were detected in brain. Including seven intergenic and three intronic piRNAs, ten piRNAs were significantly associated with age after correction for multiple testing (|r|=0.9; 1.9×10(−5)≤p≤9.9×10(−5)). CONCLUSION: We conclude that piRNAs might play a potential role in determining the years of survival of humans. The underlying mechanisms might involve the suppression of transposable elements (TEs) and expression regulation of aging-associated genes.