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OBJECTIVES Escitalopram (S-CT) is used widely to treat patients with panic disorder (PD) and the CYP2C19 enzyme is responsible for S-CT metabolism. We hypothesized that CYP2C19 polymorphisms were associated with S-CT treatment response in Chinese patients with PD. PATIENTS AND METHODS Seventy-eight patients with PD completed the assessment by the Panic Disorder Severity Scale - Chinese Version (PDSS-CV) and the Hamilton Anxiety Scale (HAMA-14) during an 8-week period. All patients were administered a fixed dose of 10 mg/day S-CT. Three CYP2C19 metabolizer phenotypes were analyzed by PCR-genotyping microarray, including extensive metabolizer (EM), intermediate metabolizer, and poor metabolizer (PM). RESULTS This prospective, open-label and observational study showed that the proportion of EM (43.6%) was higher than that of PM (10.2%). There were higher response ratios of PDSS-CV in PM (the second to fourth week: 62.5-100%) than in EM (the second to fourth week: 23.5-55.9%) (Ps

Background Schizotypal personality disorder (SPD) is linked to schizophrenia in terms of shared genetics, biological markers and phenomenological characteristics. In the current study, we aimed to determine whether the previously reported altered functional connectivity (FC) with precuneus in patients with schizophrenia could be extended to individuals with SPD. Methods Twenty subjects with SPD and 19 healthy controls were recruited from 4461 freshmen at a university in Shanghai and received a resting-state scan of MRI. All participants were evaluated by the Chinese version of Schizotypal Personality Questionnaire (SPQ) and the Chinese version of Symptom Checklist (SCL-90). The imaging data were analysed using the seed-based functional connectivity method. Results Compared with the controls, SPD subjects exhibited reduced FC between bilateral precuneus and contralateral parahippocampus. In SPD group, SPQ total score was negatively correlated with FC between right precuneus and left parahippocampus (r = −0.603, p = 0.006); there was a negative trend between SPQ subscale score of suspiciousness and FC between left precuneus and right parahippocampus (r = −0.553, p = 0.014); and a positive trend was found between SPQ subscale score of odd or eccentric behaviour and FC between left precuneus and right superior temporal gyrus (r = 0.543, p = 0.016). As for the SCL-90 score, a similar negative trend was found between SCL-90 subscale score of suspiciousness and FC between right precuneus and left parahippocampus (r = −0.535, p = 0.018) in SPD group. Conclusions Our findings suggest that the decreased functional connectivity between precuneus and contralateral parahippocampus might play a key role in the pathophysiology of schizophrenia spectrum disorder.

Alzheimer's disease (AD) is a multifactorial neurological condition associated with genetic profiles that are still not completely understood. We performed a family-based low-density genome-wide association analysis of age at onset (AAO) in AD (244 patients and their relatives) using Illumina 6 K single-nucleotide polymorphisms (SNPs) panel and the FBAT-logrank statistic. We observed 10 SNPs associated with AAO in AD with p 2 × 10(-3). The most significant hit within a known gene, the neuronal protein astrotactin 2 (ASTN2), was SNP rs1334071 (p = 8.74 × 10(-4)). ASTN2 has been implicated in several neuropsychiatric disorders, including cognitive disorders, autism and schizophrenia. We then conducted a replication study focusing on ASTN2 gene in a Canadian sample of 791 AD patients and 782 controls using the logrank test. Five ASTN2 SNPs (highest association is rs16933774 with p = 0.0053) showed associations with AAO in this Canadian sample (p 0.05). Furthermore, Kaplan-Meier survival analysis of SNP rs16933774 showed that the AAO of AD in individuals heterozygous for AG genotype of rs16933774 (median of AAO = 68.5 years) was approximately 4.5 years earlier than those individuals having the AA genotype (median of AAO = 73 years). In conclusion, a significant association of ASTN2 genetic variants with AAO of AD in two independent samples demonstrates a role for ASTN2 in the pathogenesis of AD. Future functional studies of this gene may help to characterize the genetic architecture of the AAO of AD. Genetic factors in AAO may be a critical factor for early AD intervention and prevention efforts.

There is an increasing interest in the role of intestinal microbiome in human diseases and therapeutic agents' bioavailability, activity and toxicity. Epidemiological data show that the bioavailability of digoxin, a widely used agent for heart disease, varies among individuals. The inactivation of digoxin was found when it was incubated with gut bacterium Eggerthella lenta in vitro decades ago. However, the underlying mechanisms of digoxin inactivation are still unclear. A recent study using animal models uncovered this mystery, which suggested that arginine supplements might be a potential intervention in increasing digoxin activity by inhibiting the expression of cardiac glycoside reductase gene operons that inactivated digoxin. This perspective summarizes the connections among the intestinal microbiome, the digoxin inactivation, the metabolism of arginine. We also discuss several issues yet to be addressed in the future, making better strategies in the application of dietary arginine supplements for digoxin users.

We previously reported a novel, functional and replicable risk gene region [i.e., protein tyrosine phosphatase type IVA gene, member 1 - Plant HomeoDomain (PHD) finger protein 3 gene - eyes shut homolog gene (PTP4A1-PHF3-EYS)] for alcohol dependence in a genome-wide association study (1). This 765kb region (Chr6: 64,066,604-64,831,120) included PTP4A1, PHF3, and their flanking regions, and part of EYS (close to 3’ of PHF3). It was enriched with common risk variants [minor allele frequency (MAF) > 0.05] for alcohol dependence across African-Americans (see Supplementary Figure S1B), European-Americans (Figure S1D) and European-Australians (Figure S1F). Within 90Mb range surrounding this region in the discovery sample, all variants with p 0.05 in both cases and controls] and these disorders, in order to test whether this PTP4A1-PHF3-EYS region is specific for alcohol dependence. The data of these disorders were all of those with neuropsychiatric and neurological disorders available for us from the dbGaP database (http://www.ncbi.nlm.nih.gov/gap/). Table 1 Associations between common PTP4A1-PHF3-EYS variants and different neuropsychiatric disorders A total of 49,268 subjects in these 21 cohorts were analyzed (Table 1), including one African-American discovery cohort [681 cases with alcohol dependence (DSM-IV) and 508 controls], one European-American replication cohort [1,409 alcohol dependent cases and 1,518 controls], and one European-Australian replication cohort [a total of 6,438 family subjects with 1,645 alcohol dependent probands]. 38,714 subjects in other 18 non-alcoholism cohorts served as contrast. Detailed demographic information for these samples has been published (1-9). We imputed the missing SNPs across the entire PTP4A1-PHF3-EYS region using the same reference panels (1,000 Genome Project and HapMap 3). We used the same strategies as previously to maximize the success rate and accuracy of imputation, to stringently clean the phenotype and genotype data, and then to test the variant-disease associations (7). Finally, a total of 477-1,095 SNPs with MAF>0.05 in both cases and controls were extracted for association analysis. The MAFs and minimal p values of the most significant risk SNPs are shown in Table 1. The experiment-wide significance level (α) was set at 1.6×10-5 via correction for the number of the cohorts (i.e., n=21) and the number of effective markers (i.e., n=144) that were calculated from the entire marker set by the adjusted Bonferroni-type program SNPSpD (10). We found that among a total of 1,095 common SNPs in the African-American cohort, 289 SNPs were nominally associated with alcohol dependence (p

OBJECTIVES We have previously reported a top-ranked risk gene [i.e., serine incorporator 2 gene (SERINC2)] for alcohol dependence in individuals of European descent by analyzing the common variants in a genome-wide association study. In the present study, we comprehensively examined the rare variants [minor allele frequency (MAF)

We aimed to identify novel, functional, replicable and genome-wide significant risk regions specific for alcohol dependence using genome-wide association studies (GWASs).A discovery sample (1409 European-American cases with alcohol dependence and 1518 European-American controls) and a replication sample (6438 European-Australian family subjects with 1645 alcohol dependent probands) underwent association analysis. Nineteen other cohorts with 11 different neuropsychiatric disorders served as contrast groups. Additional eight samples underwent expression quantitative locus (eQTL) analysis.A genome-wide significant risk gene region (NKAIN1-SERINC2) was identified in a meta-analysis of the discovery and replication samples. This region was enriched with 74 risk SNPs (unimputed); half of them had significant cis-acting regulatory effects. The distributions of -log(p) values for the SNP-disease associations or SNP-expression associations in this region were consistent throughout eight independent samples. Furthermore, imputing across the NKAIN1-SERINC2 region, we found that among all 795 SNPs in the discovery sample, 471 SNPs were nominally associated with alcohol dependence (1.7×10(-7)≤p≤0.047); 53 survived region- and cohort-wide correction for multiple testing; 92 SNPs were replicated in the replication sample (0.002≤p≤0.050). This region was neither significantly associated with alcohol dependence in African-Americans, nor with other non-alcoholism diseases. Finally, transcript expression of genes in NKAIN1-SERINC2 was significantly (p3.4×10(-7)) associated with expression of numerous genes in the neurotransmitter systems or metabolic pathways previously associated with alcohol dependence.NKAIN1-SERINC2 may harbor a causal variant(s) for alcohol dependence. It may contribute to the disease risk by way of neurotransmitter systems or metabolic pathways.

Excessive reactive oxygen species are thought to produce oxidative damage that underlies neurodegeneration and cognitive impairment in several disorders including schizophrenia. The functional Ala-9Val polymorphism of the mitochondrial enzyme manganese superoxide dismutase (MnSOD), which detoxifies superoxide radicals to hydrogen peroxide, has been associated with schizophrenia. However, no study has reported its role in cognitive deficits of schizophrenia as mediated through MnSOD activity. We recruited 923 schizophrenic inpatients and 566 healthy controls and compared them on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), plasma MnSOD activity, and the MnSOD Ala-9Val polymorphism. We assessed patient psychopathology using the Positive and Negative Syndrome Scale. We showed that the MnSOD Ala-9Val polymorphism may not contribute directly to the susceptibility to schizophrenia. The Ala variant was associated with worse attention performance among chronic schizophrenic patients but not among normal controls. Plasma MnSOD activity was significantly decreased in patients compared with that in normal controls. Moreover, MnSOD activity among the schizophrenic Ala allele carriers was correlated with the degree of cognitive impairments, especially attention and RBANS total score. We demonstrated an association between the MnSOD Ala-9Val variant and poor attention in schizophrenia. The association between higher MnSOD activity and cognitive impairment in schizophrenia is dependent on the MnSOD Ala-9Val polymorphism.

Humans express at least seven alcohol dehydrogenase (ADH) isoforms that are encoded by ADH gene cluster (ADH7–ADH1C–ADH1B–ADH1A–ADH6–ADH4–ADH5) at chromosome 4. ADHs are key catabolic enzymes for retinol and ethanol. The functional ADH variants (mostly rare) have been implicated in alcoholism risk. In addition to catalyzing the oxidation of retinol and ethanol, ADHs may be involved in the metabolic pathways of several neurotransmitters that are implicated in the neurobiology of neuropsychiatric disorders. In the present study, we comprehensively examined the associations between common ADH variants [minor allele frequency (MAF) >0.05] and 11 neuropsychiatric and neurological disorders. A total of 50,063 subjects in 25 independent cohorts were analyzed. The entire ADH gene cluster was imputed across these 25 cohorts using the same reference panels. Association analyses were conducted, adjusting for multiple comparisons. We found 28 and 15 single nucleotide polymorphisms (SNPs), respectively, that were significantly associated with schizophrenia in African-Americans and autism in European-Americans after correction by false discovery rate (FDR) (q

Introduction 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. Methods 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. Results 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). Discussion Depressive symptom severity was associated with HRQoL in patients with MDD. HRQoL may vary with severity of depression and/or anxiety-somatization at baseline.

Background: Alcohol and nicotine codependence can be considered as a more severe subtype of alcohol dependence. A portion of its risk may be attributable to genetic factors. Methods: We searched for significant risk genomic regions specific for this disorder using a genomewide association study. A total of 8,847 subjects underwent gene–disease association analysis, including (i) a discovery cohort of 818 European American cases with alcohol and nicotine codependence and 1,396 European American controls, (ii) a replication cohort of 5,704 Australian family subjects with 907 affected offspring, and (iii) a replication cohort of 449 African American cases and 480 African American controls. Additionally, a total of 38,714 subjects of European or African descent in 18 independent cohorts with 10 other nonalcoholism neuropsychiatric disorders were analyzed as contrast. Furthermore, 90 unrelated HapMap CEU individuals, 93 European brain tissue samples, and 80 European peripheral blood mononuclear cell samples underwent cis-acting expression quantitative locus (cis-eQTL) analysis. Results: We identified a significant risk region for alcohol and nicotine codependence between IPO11 and HTR1A on chromosome 5q that was reported to be suggestively associated with alcohol dependence previously. In the European American discovery cohort, 381 single nucleotide polymorphisms (SNPs) in this region were nominally associated with alcohol and nicotine codependence (p < 0.05); 57 associations of them survived region- and cohort-wide correction (a = 3.6 9 10 6 ); and the top SNP (rs7445832) was significantly associated with alcohol and nicotine codependence at the genome-wide significance level (p = 6.2 9 10 9 ). Furthermore, associations for 34 and 11 SNPs were replicated in the Australian and African American replication cohorts, respectively. Among these replicable associations, 4 reached genome-wide significance level in the meta-analysis of European Americans and European Australians: rs7445832 (p = 9.6 9 10 10 ), rs13361996 (p = 8.2 9 10 9 ), rs62380518 (p = 2.3 9 10 8 ), and rs7714850 (p = 3.4 9 10 8 ). Cis-eQTL analysis showed that many risk SNPs in this region had nominally significant cis-acting regulatory effects on HTR1A or IPO11 mRNA expression. Finally, no markers were significantly associated with any other neuropsychiatric disorder examined. Conclusions: We speculate that this IPO11-HTR1A region might harbor a causal variant for alcohol and nicotine codependence.

It has been hypothesized that the nicotinic acetylcholine receptors (nAChRs) play important roles in nicotine dependence (ND) and influence the number of cigarettes smoked per day (CPD) in smokers. We compiled the associations between nicotinic cholinergic receptor genes (CHRNs) and ND/CPD that were replicated across different studies, reviewed the expression of these risk genes in human/mouse brains, and verified their expression using independent samples of both human and mouse brains. The potential functions of the replicated risk variants were examined using cis-eQTL analysis or predicted using a series of bioinformatics analyses. We found replicated and significant associations for ND/CPD at 19 SNPs in six genes in three genomic regions (CHRNB3-A6, CHRNA5-A3-B4 and CHRNA4). These six risk genes are expressed in at least 18 distinct areas of the human/mouse brain, with verification in our independent human and mouse brain samples. The risk variants might influence the transcription, expression and splicing of the risk genes, alter RNA secondary or protein structure. We conclude that the replicated associations between CHRNB3-A6, CHRNA5-A3-B4, CHRNA4 and ND/CPD are very robust. More research is needed to examine how these genetic variants contribute to the risk for ND/CPD.

Introduction Numerous studies have characterized impaired cerebral functioning in nicotine-addicted individuals. Whereas nicotine interacts with multiple neurotransmitters in cortical and subcortical circuits, it directly targets the cholinergic system, sourced primarily from the basal nucleus of Meynert (BNM). However, no studies have examined how this cholinergic system is influenced by cigarette smoking. Here, we addressed this gap of research. Methods Using a dataset from the Functional Connectome Projects, we investigated this issue by contrasting seed-based BNM connectivity of 40 current smokers and 170 age- and gender-matched nonsmokers. We followed our data analytic routines in recent work and examined differences between smokers and nonsmokers in men and women combined as well as separately. Results Compared to nonsmokers, female but not male smokers demonstrated greater positive BNM connectivity to the supplementary motor area, bilateral anterior insula, and right superior temporal/supramarginal gyri as well as greater negative connectivity to the posterior cingulate cortex and precuneus. Further, BNM connectivity to the supplementary motor area is negatively correlated to the Fagerstrom Test for Nicotine Dependence score in male but not female smokers. Conclusions Along with a previous report of upregulated nicotinic acetylcholine receptor in male but not female smokers, these new findings highlight functional changes of the cholinergic systems in cigarette smokers. The results suggest sex-specific differences in cholinergic dysregulation and a need for multiple imaging modalities to capture the neural markers of nicotine addiction. Implications Nicotine influences cognition via cholinergic projections of the basal forebrain to the cerebral cortex. This study examined changes in resting-state whole-brain functional connectivity of the BNM in cigarette smokers. The new findings elucidate for the first time sex differences in BNM-cerebral connectivity in cigarette smoking.

Domestic physical violence (DPV) is common in China due to its long history of slavery and feudalism. This study aimed to examine the effects of exposure to DPV on children's behavior in a Chinese community. Ninety-three 12- to 16-year-old adolescents exposed to DPV were compared to 54 adolescents with no exposure to DPV. We found that DPV exposure was associated with adverse behaviors in children, especially among boys. Children witnessing DPV alone had similar behavioral scores as the abused children. We recommend that both abused and DPV witness-only adolescents in Chinese communities need treatment to mitigate the effects on maladjusted behaviors. The intervention programs for children who witness domestic violence are also important.

// Tao Huang 1, 2, * , Yan Ji 2, * , Dan Hu 1, * , Baozheng Chen 1 , Hejun Zhang 1 , Chao Li 1 , Gang Chen 1 , Xingguang Luo 3 , Xiong-wei Zheng 1, 4 , Xiandong Lin 1, 4 1 Department of Pathology, Fujian Provincial Cancer Hospital and Fujian Medical University Cancer Hospital, Fuzhou, Fujian, China 2 Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine, Shanghai, China 3 Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA 4 Fujian Provincial Key Laboratory of Translational Cancer Medicine, Fuzhou, Fujian, China * Co-first authors Correspondence to: Xiong-wei Zheng, email: agu1960@126.com Xiandong Lin, email: linxdong1970@yeah.net Keywords: gastric cancer, epstein–barr virus, long non-coding RNA, biomarker, SNHG8 Received: July 10, 2016 Accepted: October 31, 2016 Published: November 07, 2016 ABSTRACT The Epstein–Barr virus (EBV) is associated with a variety of cancers, including gastric cancer, which has one of the highest mortality rates of all human cancers. Long non-coding RNAs (lncRNAs) have been suggested to have important causal roles in gastric cancer. However, the interaction between lncRNAs and EBV has not yet been studied. To this end, we sequenced 11,311 lncRNAs and 144,826 protein-coding transcripts from four types of tissue: one non-EBV-infected gastric carcinoma (EBVnGC) and its adjacent normal tissue, and one EBV-associated gastric carcinoma (EBVaGC) and its adjacent normal tissue. Five lncRNAs showed EBVaGC-specific expression; of those, one (SNHG8) was validated using real-time PCR in an independent cohort with 88 paired gastric cancer and adjacent tissue samples. To explore the functions of SNHG8, we identified its mRNA targets on the lncRNA–mRNA co-expression network of the Illumina Body Map, which contains the RNA sequencing data of mRNAs and lncRNAs from 16 normal human tissues. SNHG8 lncRNA was found to affect several gastric cancer-specific pathways and target genes of EBV. Our results reveal the intertwined tumorigenesis mechanisms of lncRNA and EBV and identify SNHG8 as a highly possible candidate biomarker and drug target of gastric cancer.

Recent evidence suggests that a dopamine beta-hydroxylase (DBH) polymorphism may play a role in determining an individual's predisposition to developing nicotine dependence. The mechanism for such an association may reflect nicotine's mediation of drug reward in the brain through actions on dopamine, a key mediator of drug reward. Because schizophrenia patients have usually high rates of nicotine use, they are a model group to study such an association. In this study, we hypothesized that the functional polymorphism of DBH (D beta H5'-Ins/Del) was associated with smoking in patients with schizophrenia. This polymorphism was genotyped in 636 chronic male schizophrenia (smoker/nonsmoker=490/146) and 396 male controls (smoker/nonsmoker=231/165) using a case-control design. The cigarettes smoked per day (CPD) and smoking behaviors were evaluated by clinician-administered questionnaires and the Fagerstrom Test for Nicotine Dependence (FTND). The results showed no significant differences in DBH 5'-Ins/Del genotype and allele distributions between the patients and healthy controls or between smokers and nonsmokers in either patients or healthy controls alone. However, schizophrenic smokers with the Del allele smoked fewer cigarettes each day and had lower FTND score than those with Ins/Ins genotype. These results suggest that the DBH 5'-Ins/Del polymorphism may influence smoking severity among schizophrenic smokers. (C) 2012 Elsevier B.V. All rights reserved.

The present study searched for replicable risk genomic regions for alcohol and nicotine co-dependence using a genome-wide association strategy. The data contained a total of 3,143 subjects including 818 European-American (EA) cases with alcohol and nicotine co-dependence, 1,396 EA controls, 449 African-American (AA) cases, and 480 AA controls. We performed separate genome-wide association analyses in EAs and AAs and a meta-analysis to derive combined P-values, and calculated the genome-wide false discovery rate (FDR) for each SNP. Regions with P

In the present study, we aimed to report the individual sex-different genetic markers across autosomes in European- and African-origin populations. A total of 8,400 females and 8,081 males in 19 independent cohorts were genotyped across genomes using Illumina or Affymetrix arrays. The allele frequencies were compared between females and males in 9 non-clean cohorts (with some human disease traits) using genome-wide logistic regression and then the nominally significant associations were replicated across 10 clean cohorts (without disease traits). Meta-analysis was performed to derive the combined p values across all cohorts. We found 13 markers that were genome-wide significant (p≤5×10-8) between females and males in the meta-analysis of all cohorts of European descent, including rs7740449 at SYNE1, rs7531151 at PLD5, rs697455 at PPP1R12B, rs6745746 at LOC100128413, rs17000079 at PARM1, rs11948070 at PDE4D, rs7801825 at INSIG1, rs9551642 at MTUS2, rs2932174 at TPTE2, rs1961597 at SALL3, rs4117529 at METTL4, rs6021473 at SALL4 and rs6092466 at RAE1, and one marker, i.e., rs10145208 at PCNX, that was genome-wide significant in the meta-analysis of all cohorts of African descent. The most robust finding was rs7740449 at SYNE1, next to ESR1. We conclude that there are many sex-different markers on autosomes. These markers may be informative in differentiating females and males.

Previous studies using SAGE (the Study of Addiction: Genetics and Environment) and COGA (the Collaborative Study on the Genetics of Alcoholism) genome-wide association study (GWAS) data sets reported several risk loci for alcohol dependence (AD), which have not yet been well replicated independently or confirmed by functional studies. We combined these two data sets, now publicly available, to increase the study power, in order to identify replicable, functional, and significant risk regions for AD. A total of 4116 subjects (1409 European-American (EA) cases with AD, 1518 EA controls, 681 African-American (AA) cases, and 508 AA controls) underwent association analysis. An additional 443 subjects underwent expression quantitative trait locus (eQTL) analysis. Genome-wide association analysis was performed in EAs to identify significant risk genes. All available markers in the genome-wide significant risk genes were tested in AAs for associations with AD, and in six HapMap populations and two European samples for associations with gene expression levels. We identified a unique genome-wide significant gene--KIAA0040--that was enriched with many replicable risk SNPs for AD, all of which had significant cis-acting regulatory effects. The distributions of -log(p) values for SNP-disease and SNP-expression associations for all markers in the TNN-KIAA0040 region were consistent across EAs, AAs, and five HapMap populations (0.369 ≤ r ≤ 0.824; 2.8 × 10⁻⁹ ≤ p ≤ 0.032). The most significant SNPs in these populations were in high LD, concentrating in KIAA0040. Finally, expression of KIAA0040 was significantly (1.2 × 10⁻¹¹ ≤ p ≤1 .5 × 10⁻⁶) associated with the expression of numerous genes in the neurotransmitter systems or metabolic pathways previously associated with AD. We concluded that KIAA0040 might harbor a causal variant for AD and thus might directly contribute to risk for this disorder. KIAA0040 might also contribute to the risk of AD via neurotransmitter systems or metabolic pathways that have previously been implicated in the pathophysiology of AD. Alternatively, KIAA0040 might regulate the risk via some interactions with flanking genes TNN and TNR. TNN is involved in neurite outgrowth and cell migration in hippocampal explants, and TNR is an extracellular matrix protein expressed primarily in the central nervous system.

Background A genetic contribution to smoking behavior is well-established. To identify loci that increase the risk for smoking behavior, many genome-wide linkage scans have been performed with various smoking behavior assessments. Numerous putative susceptibility loci have been identified, but only a few of these were replicated in independent studies. Methods We used genome search meta-analysis (GSMA) to identify risk loci by pooling all available independent genome scan results on smoking behavior. Additionally, to minimize locus heterogeneity, subgroup analyses of the smoking behavior assessed by the Fagerstrom Test for Nicotine Dependence (FTND) and maximum number of cigarettes smoked in a 24-hour period (MaxCigs24) were carried out. Samples of European ancestry were also analyzed separately. Results A total number of 15 genome scan results were available for analysis, including 3404 families with 10,253 subjects. Overall, the primary GSMA across all smoking behavior identified a genome-wide suggestive linkage in chromosome 17q24.3-q25.3 ( p SR = .001). A secondary analysis of FTND in European-ancestry samples (625 families with 1878 subjects) detected a genome-wide suggestive linkage in 5q33.1–5q35.2 ( p SR = .0076). Subgroup analysis of MaxCigs24 (966 families with 3273 subjects) identified a genome-wide significant linkage in 20q13.12-q13.32 ( p SR = .00041, p OR = .048), where a strongly supported nicotine dependence candidate gene, CHRNA4 , is located. Conclusions The regions identified in the current study deserve close attention and will be helpful for candidate gene identification or target re-sequencing studies in the future.

Background Straub et al. (2002b) located a susceptibility region for schizophrenia at the DTNBP1 locus. At least 40 studies (including one study in US populations) attempted to replicate this original finding, but the reported findings are highly diverse and at least five pathways by which dysbindin protein might be involved in schizophrenia have been proposed. This study aimed to test the association in two common US populations by using powerful analytic methods. Methods Six markers at DTNBP1 were genotyped by mass spectroscopy (‘MassARRAY’ technique) in a sample of 663 individuals, including 346 healthy individuals European--Americans (EAs) and 48 African--Americans (AAs), and 317 individuals with schizophrenia (235 EAs and 82 AAs). Thirty-eight ancestry-informative markers were genotyped in this sample to infer the ancestry proportions. Diplotype, haplotype, genotype, and allele frequency distributions were compared between the cases and controls, controlling for possible population stratification, admixture, and sex-specific effects, and taking interaction effects into account, using a logistic regression analysis (an extended structured association method). Results Conventional case-control comparisons showed that genotypes of the markers P1578 (rs1018381) and P1583 (rs909706) were nominally associated with schizophrenia in EAs and in AAs, respectively. These associations became less or nonsignificant after controlling for population stratification and admixture effects (using structured association or regression analysis), and became nonsignificant after correction for multiple testing. However, regression analysis showed that the common diplotypes (ACCCTT/GCCGCC or GCCGCC/GCCGCC) and the interaction effects of haplotypes GCCGCC×GCCGCC significantly affected risk for schizophrenia in EAs, effects that were modified by sex. Fine-mapping using δ or J statistics located the specific markers (δ: P1328; J: P1333) closest to the putative risk sites in EAs. Conclusion This study shows that DTNBP1 is a risk gene for schizophrenia in EAs. Variation at DTNBP1 may modify risk for schizophrenia in this population.

The prototypical atypical antipsychotic agent, clozapine, is more efficacious for refractory schizophrenia than the 'typical' antipsychotics, but the mechanism underlying this enhanced efficacy is still under investigation. Since 2002, at least 22 association studies have shown that the DTNBP1 can be associated with the risk for schizophrenia. We hypothesized that DTNBP1 might also influence the response to antipsychotic treatments. This study aimed to investigate the relationship between the DTNBP1 and the effects of clozapine and haloperidol on refractory schizophrenia.Patients with refractory schizophrenia were assigned to clozapine (n=85) or haloperidol (n=96) and followed for 3 months. Symptom improvement was evaluated by Positive and Negative Syndrome Scale score. Six markers at DTNBP1 and 38 ancestry-informative markers were genotyped in all participants. The relationships between the effects of antipsychotics and the diplotypes, haplotypes, genotypes, and alleles of DTNBP1 were tested by analysis of covariance, analysis of variance, and t-test.Patients with diplotype ACCCTC/GTTGCC, genotypes T/T+T/C, or allele T of marker rs742105 (P1333) have better response to clozapine (0.005or =Por =0.049), and patients with diplotype ACCCTC/GCCGCC, genotype A/G, or allele A of marker rs909706 (P1583) have better response to haloperidol (0.007or =Por =0.080) in European-Americans, African-Americans, and/or the combined sample; European-American patients with diplotype ACCCTC/GCCGCC have worse response to clozapine on positive symptoms (P=0.011).This study shows that the DTNBP1 gene modulates the effects of both the atypical antipsychotic clozapine and the typical antipsychotic haloperidol. Participants with different DTNBP1 diplotypes, haplotypes, genotypes, or alleles might have different responses to these antipsychotics.

We recently reported that, in a European-American (EA) sample, the interaction between two cannabinoid receptor 1 gene (CNR1) variants significantly increased risk for drug dependence (DD), including cocaine dependence (CD). This study aimed to investigate directly the association between CNR1 and CD in four independent samples. Eight markers across the 45 kb CNR1 region and four large samples, ie, family-based European-American (EA) sample (n=734), case-control EA sample (n=862), family-based African-American (AA) sample (n=834) and case-control AA sample (n=619) were examined in the present study. We investigated the association of these markers with CD and cocaine-induced paranoia (CIP) in the EA family sample first, and then replicated positive results in the other three samples. The interaction between two independent CNR1 variants, ie, the G allele-containing genotypes of rs6454674 (SNP3(G+)), and the T/T genotype of rs806368 (SNP8(T)/T), significantly increased risk for CD in the EA family (P(GEE)=0.015) and EA case-control (P(regression)=0.003) samples. EA subjects with SNP3(G+) and SNP8(T)/T had higher risk to develop CD than those EA subjects with the other genotypes for these two SNPs (LR+ =1.4). The SNP3(G)-SNP8(T)haplotype also showed significant association (P=0.018) with CD in the EA case-control sample. SNP8-containing haplotypes showed significant association with both CD (P(global)=0.007) and CIP (P(global)=0.003) in the EA family sample. In the AA family sample, SNP8(T)/T significantly conferred higher risk for CD (P=0.019). We conclude that two independent CNR1 variants have significant interaction effects on risk for CD in EAs; they may also have effects on risk for CD in AAs.

Personality traits are among the most complex quantitative traits. Certain personality traits are associated with substance dependence (SD); genetic factors may influence both. Associations between opioid receptor (OPR) genes and SD have been reported. This study investigated the relationship between OPR genes and personality traits in a case-control sample. We assessed dimensions of the five-factor model of personality in 556 subjects: 250 with SD [181 European-Americans (EAs) and 69 African-Americans (AAs)] and 306 healthy subjects (266 EAs and 40 AAs). We genotyped 20 OPRM1 markers, 8 OPRD1 markers, and 7 OPRK1 markers, and 38 unlinked ancestry-informative markers in these subjects. The relationships between OPR genes and personality traits were examined using MANCOVA, controlling for gene-gene interaction effects and potential confounders. Associations were decomposed by Roy-Bargmann Stepdown ANCOVA. We found that personality traits were associated as main or interaction effects with the haplotypes, diplotypes, alleles and genotypes at the three OPR genes (0.002P0.046 from MANCOVA; 0.0004P0.049 from ANCOVA). Diplotype TTAGGA/TTCAGA at OPRM1 had main effects on Extraversion (P = 0.008), and diplotypes OPRM1(insertion mark)TTCAGA/TTCAGA and OPRD1(insertion mark)CAC/TAC had interaction effects on Openness (P = 0.010) after conservative correction for multiple testing. The present study demonstrates that the genes encoding the mu-, delta-, and kappa-opioid receptors may contribute to variation in personality traits. Further, the three OPR genes have significant interaction effects on personality traits. This work provides additional evidence that personality traits and SD have a partially overlapping genetic basis.

Human personality traits have been closely linked to substance dependence (SD), and are partially genetically determined. Recently, associations between alcohol dehydrogenase 7 (ADH7) and SD have been reported, which led us to investigate the relationship between ADH7 variation and personality traits. We assessed dimensions of the five-factor model of personality and genotyped 4 ADH7 markers and 38 unlinked ancestry-informative markers in 244 subjects with SD [178 European-Americans (EAs) and 66 African-Americans (AAs)] and 293 healthy subjects (253 EAs and 40 AAs). The relationships between ADH7 markers and personality traits were comprehensively examined using multivariate analysis of covariance (MANCOVA), and then decomposed by Roy Bargmann Stepdown analysis of covariance (ANCOVA). Generally, older individuals, AAs, and males had significantly lower personality scores (4.7 x 10(-5) < or = P < or = 0.032), as reported previously. In SD subjects, Extraversion was most significantly associated with ADH7 haplotypes (3.7 x 10(-4) < or = P < or = 0.001), diplotypes (0.007 < or = P < or = 0.012), and genotypes (P = 0.001), followed by Conscientiousness (0.005 < or = P < or = 0.033). The contributory haplotype and diplotypes contained the alleles and genotypes of rs284786 (SNP1) and rs1154470 (SNP4). In healthy subjects, other personality factors (except Extraversion) were associated with ADH7 diplotypes (0.005 < or = P < or = 0.016) and genotypes (0.002 < or = P < or = 0.052). Some of the gene effects on personality factors were modified by sex. The present study demonstrated that the ADH7 variation may contribute to the genetic component of variation in personality traits, with the risk for SD and personality traits being partially shared.

Background Human cannabinoid receptor 1 (CB1), which is encoded by the CNR1 gene, may play a role in the development of substance dependence (SD). Following initial reports of association of CNR1 with SD, we studied multiple markers at this locus in a large case–control sample. Methods Ten CNR1 markers and 38 ancestry-informative markers were genotyped in 451 healthy control subjects and 550 SD (AD and/or DD) patients (including European Americans [EAs] and African Americans [AAs]). Common confounding effects on association analysis of population stratification and admixture, age, and sex were controlled for using regression analysis. Disease risk and protective alleles were fine-mapped using a linkage disequilibrium measure (δ). Results In EAs, risk for each SD subtype significantly increased with the number of "G" alleles at rs6454674 (single nucleotide polymorphisms [SNP]3). SNP3^G + (the genotypes containing a G allele) and SNP8^T/T genotypes had significant interaction effects (p = .0003 for comorbid DD and AD, .0002 for DD, and .007 for AD). SNP3 and SNP8 together exerted stronger genetic effects on SD than either did individually. The peak δ values among all the markers were seen for SNP3 and SNP8 (rs806368). Conclusions We demonstrate that CNR1 variation and interactive effects play important roles in risk for both DD and AD.

There have been many conflicting reports concerning the association of the DRD2 locus with alcohol dependence (AD). To investigate whether these findings could be reconciled by considering the genomic region of DRD2 in greater detail, we conducted two separate association studies of AD in 1220 European-American subjects using family-based (488 subjects) and case-control (318 cases and 414 controls) designs, and 43 single nucleotide polymorphisms mapped to the gene cluster of NCAM1, TTC12, ANKK1 and DRD2. 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. Haplotype associations centered on TTC12 exon 3 [rs1893699-rs723077; optimal individual haplotype simulated P-value (P(oihs)) = 0.00021] in both independent samples (family and case-control). Additional AD-associated haplotypes centered around NCAM1 exon 12 in the family sample (P(oihs) = 0.0032), and at exons 2 and 5 of ANKK1 in the case-control sample (P(oihs) = 0.00058). LD contrasts between cases and controls support selection at TTC12 exon 3 and ANKK1 exon 2. The armadillo repeat domains encoded by TTC12 and dopamine interact in the Wnt pathway and may have effects on dopamine cell development in the ventral midbrain. We conclude that risk for AD is attributable in part to variants in four regions within this cluster: exon 3 of TTC12, exon 12/intron13 of NCAM1 and exons 2 and 5 of ANKK1. The complexity of these relationships, many of which replicate between our independent samples, may explain prior inconsistent results.

Personality traits are among the most complex quantitative traits. Certain personality traits have been postulated to be part of the inherited component of substance dependence (SD) risk. Association between the M2 cholinergic receptor gene (CHRM2) and SD has recently been reported and replicated (Wang et al. Hum. Mol. Genet. (2004);13:1903-1911; Luo et al. Hum. Mol. Genet. 2005;14:2421-2434). In this study, we investigated the relationship between CHRM2 variation and personality traits in two American populations. We assessed dimensions of the five-factor model of personality, and genotyped six CHRM2 markers and 38 unlinked ancestry-informative markers in 239 subjects with SD [173 European-Americans (EAs) and 66 African-Americans (AAs)] and 275 healthy subjects (237 EAs and 38 AAs). The relationships between CHRM2 markers and personality traits were examined using multivariate analysis of covariance, controlling for marker-marker interaction effects and potential confounders. Associations were decomposed by Roy Bargmann stepdown analysis of covariance. Generally, substance-dependent patients, older individuals, males, and AAs scored higher on Neuroticism and lower on other personality factors. Diplotype CTCAAA/ CTCGTT (P = 0.005) and the interaction between its two haplotypes (CTCAAA x CTCGTT) (P = 0.003) were associated with lower Conscientiousness scores. Haplotype CTCGAT (P = 0.006) and its interaction with haplotype TCAAAT (P = 0.002) were associated with higher Agreeableness scores. The trait-influencing variant site in CHRM2 for Agreeableness was close to marker rs1824024 (SNP3) (P = 0.002). CHRM2 variation may contribute to the genetic component of variation in personality traits. Personality traits might substantially underlie the heritable component of SD.

Synaptic actions of gamma-amino butyric acid (GABA) have been implicated in many facets of ethanol's effects and risk for alcoholism. We examined whether variation in glutamate decarboxylase-2 (GAD2), a gene encoding for a major enzyme in the synthesis of GABA, contributes to risk of alcohol dependence (AD). We screened GAD2 for sequence variants using dHPLC in a population of 96 individuals. Several single nucleotide polymorphisms (SNPs), including four rare non-synonymous polymorphisms, were identified. Thirteen SNPs located in the GAD2 gene were genotyped in a sample of 113 Russian males with AD and 100 Russian male controls. These analyses revealed a modest association between the functional GAD2 -243 A > G SNP (rs2236418) and AD (allele P = 0.038, genotype P = 0.008). An additional sample of 138 Russian males with AD were genotyped for the GAD2 -243 A > G. These analyses supported an association of this polymorphism with AD (combined sample allele P = 0.038, genotype P = 0.0009). We extended these findings to additional populations: a sample of 538 college students assessed using the AUDIT and a sample of European-American (EA) AD subjects (n = 235) and controls (n = 310). Analyses in these populations did not support a role for GAD2 in alcoholism. In summary, the results of an extensive search for an association of GAD2 with AD suggest that variation in GAD2 is not a major risk factor for AD in EAs. The functional promoter GAD2 -243 A > G variant may influence risk for AD in some populations, or its role may be limited to susceptibility to severe AD.

Nicotine's rewarding effects are mediated through distinct subunits of nAChRs, encoded by different nicotinic cholinergic receptor (CHRN) genes and expressed in discrete regions in the brain. In the present study, we aimed to test the associations between rare variants at CHRN genes and nicotine dependence (ND), and alcohol dependence (AD). A total of 26,498 subjects with nine different neuropsychiatric disorders in 15 independent cohorts, which were genotyped on Illumina, Affymetrix, or PERLEGEN microarray platforms, were analyzed. Associations between rare variants (minor allele frequency (MAF)

Accumulating evidence has shown that brain-derived neurotrophic factor (BDNF) may be involved in the pathogenesis of schizophrenia. Moreover, BDNF genetic variants, especially the Val66Met polymorphism, may influence specific aspects of human cognition. This study aimed to investigate the potential association of BDNF gene polymorphisms with susceptibility to schizophrenia and cognitive impairments in patients with schizophrenia in a Han Chinese population.Four polymorphisms (rs6265, rs12273539, rs10835210, and rs2030324) of the BDNF gene were analyzed in a case-control study of 1,887 Han Chinese individuals (844 patients meeting DSM-IV diagnosis of schizophrenia and 1,043 healthy controls). Cognitive function was measured using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) in 598 patients and 434 controls. The current study was conducted from 2008 to 2011.Significant differences in the genotype and allele frequencies between patients and controls were observed only for rs10835210 (both P.05). Further, we found that the rs10835210 polymorphism had a significant effect on language performance only in schizophrenia (P.05). However, BDNF rs12273539 played a stronger role in cognitive performance among both patients and healthy controls, especially on attention (P.001) and the RBANS total score (P.01).These findings suggest the role of these BDNF gene variants in susceptibility to schizophrenia and in some aspects of cognitive function.

There is little understanding of how unipolar major depressive disorder (UMDD) symptoms evolve in response to antidepressant treatment. The present research examined the associations between symptom trajectories and clinical remission in Chinese patients with UMDD. A total of 165 outpatients with UMDD received treatment of fluoxetine (20mg/day) for six weeks and were assessed for symptom severity at week 1, 2, 4 and 6. We found that patients with UMDD show heterogeneity in treatment response to fluoxetine. Psychomotor retardation is a prominent symptom during the six weeks of assessment and its severity at baseline is negatively associated with clinical remission.

Alcohol addiction may increase the risk of obesity due to shared genetic components. The Copine V (CPNE5) gene is involved in Ca(2+) binding and may play an important role in the development of the central nervous system. This study tested the genetic associations of 77 single-nucleotide polymorphisms (SNPs) within the CPNE5 gene with alcohol dependence (AD) and obesity using a Caucasian sample - The Study of Addiction - Genetics and Environment (SAGE) sample (1066 AD cases and 1278 non-AD controls, 422 obese cases and 1395 non-obese controls). The Marshfield sample (1442 obese cases and 2122 non-obese controls) was used for replication of obesity. Multiple logistic regression analysis was performed using the PLINK software. In the SAGE sample, we identified 10 SNPs associated with AD and 17 SNPs associated with obesity (p < 0.05). Interestingly, 6 SNPs (rs9986517, rs9470387, rs3213534, rs10456444, rs3752482, and rs9470386) were associated with both AD (OR = 0.77, 0.77, 0.83, 0.84, 0.79 and 1.14, respectively; p = 9.72 × 10(-5), 1.1 × 10(-4), 4.09 × 10(-3), 5.26 × 10(-3), 1.59 × 10(-2), and 3.81 × 10(-2), respectively) and obesity (OR = 0.77, 0.77, 0.78, 0.77, 0.68 and 1.18, respectively; p = 2.74 × 10(-3), 2.69 × 10(-3), 2.45 × 10(-3), 1.01 × 10(-3), 5.18 × 10(-3) and 3.85 × 10(-2), respectively). In the Marshfield sample, rs3752480 was associated with obesity (p = 0.0379). In addition, four SNPs (rs9986517, rs10456444, rs7763347 and rs4714010) showed associations with obesity in the meta-analysis using both samples (p = 0.00493, 0.0274, 0.00346, and 0.0141, respectively). These findings provide the first evidence of common genetic variants in the CPNE5 gene influencing both the AD and obesity; and will serve as a resource for replication in other populations.

We comprehensively examined the rare variants in the IPO11-HTR1A region to explore their roles in neuropsychiatric disorders. Five hundred seventy-three to 1,181 rare SNPs in subjects of European descent and 1,234–2,529 SNPs in subjects of African descent (0

Glutamate carboxypeptidase II (GCPII) is a transmembrane zinc metallopeptidase found mainly in the nervous system, prostate and small intestine. In the nervous system, glia-bound GCPII mediates the hydrolysis of the neurotransmitter N-acetylaspartylglutamate (NAAG) into glutamate and N-acetylaspartate. Inhibition of GCPII has been shown to attenuate excitotoxicity associated with enhanced glutamate transmission under pathological conditions. However, different strains of mice lacking the GCPII gene are reported to exhibit striking phenotypic differences. In this study, a GCPII gene knockout (KO) strategy involved removing exons 3-5 of GCPII. This generated a new GCPII KO mice line with no overt differences in standard neurological behavior compared to their wild-type (WT) littermates. However, GCPII KO mice were significantly less susceptible to moderate traumatic brain injury (TBI). GCPII gene KO significantly lessened neuronal degeneration and astrocyte damage in the CA2 and CA3 regions of the hippocampus 24 h after moderate TBI. In addition, GCPII gene KO reduced TBI-induced deficits in long-term spatial learning/memory tested in the Morris water maze and motor balance tested via beam walking. Knockout of the GCPII gene is not embryonic lethal and affords histopathological protection with improved long-term behavioral outcomes after TBI, a result that further validates GCPII as a target for drug development consistent with results from studies using GCPII peptidase inhibitors.

Drug dependence (DD) is commonly co-morbid with alcohol dependence (AD). Many studies have also shown common genetic risk factors for these disorders. We previously reported associations of AD with seven alcohol dehydrogenase (ADH) genes. The present study examines the relationship between these genes and DD. We genotyped 16 markers within the ADH gene cluster and 38 unlinked ancestry-informative markers in a case-control sample of 718 individuals. All markers were consistent with Hardy-Weinberg equilibrium in controls, but some markers showed Hardy-Weinberg disequilibrium in cases (minimal P = 0.002). Genotypes of many markers were associated with DD, both before and after controlling for admixture effects (minimal P < 1.0 × 10 −6 ). Diplotype trend regression analysis showed that ADH5 and ADH6 genotypes, and diplotypes at ADH1A, ADH1B, ADH1C and ADH7 (minimal P = 0.002), were associated with DD in European-Americans and/or African-Americans. This first report of an allelic association of these loci with DD provides new insight into the mechanism of genetic risk for DD. These findings, obtained using a series of powerful and reliable analytic methods, may also help to explain the high rate of co-morbidity between AD and DD.

Calcyon is a brain-specific D1 dopamine receptor-interacting protein, with a potential role in D1-mediated physiological processes, including motor control, reward mechanisms, and cognitive processes. Our objective was to investigate the relationship between polymorphism of the CALCYON gene and (1) schizophrenia and (2) cocaine dependence in African-American (AA) and European-American (EA) subjects. Two single nucleotide polymorphisms (SNPs) at the CALCYON locus were genotyped in 70 AA and 206 EA individuals with schizophrenia and 90 AA and 118 EA individuals with cocaine dependence. The control group was comprised of 46 AA and 207 EA subjects screened to exclude those with psychiatric or substance use disorders. The specific polymorphisms studied were markers +295214G/A and +297151T/G. Comparisons of allele and haplotype frequencies between cases and controls were performed with the Fisher's Exact Test. Linkage disequilibrium (LD) between these two SNPs was calculated with the 3LOCUS program. No alleles or haplotypes were found to be associated with schizophrenia or cocaine dependence either in AA or EA subjects. The markers +295214G/A and +297151T/G are in the same haplotype block in all subgroups. Allele and haplotype frequencies differed significantly between EA and AA subjects. These results suggest that these two genetic variants in the CALCYON gene do not play a major role in predisposition to either schizophrenia or cocaine dependence in AA or EA subjects. Furthermore, these findings begin to establish a haplotype map for this gene in the AA and EA populations.

Background The goal of this study was to investigate the relationship between the NOTCH4 gene and schizophrenia in African American (AA) and European American (EA) subjects. Methods Two single nucleotide polymorphisms (SNPs) at the NOTCH4 locus were genotyped in 123 AA schizophrenia patients, 223 EA schizophrenia patients, 85 AA healthy control subjects, and 211 EA healthy control subjects. The specific markers studied were -1725T/G and -25T/C. Comparisons of allele and haplotype frequencies between patients and control subjects were performed with the chi-square test, the Fisher's Exact Test, and CLUMP software. Linkage disequilibrium (LD) between these two SNPs was calculated with the 3LOCUS program. Results The haplotype -1725G/-25T associates to schizophrenia in AA subjects ( p = .0008), but not in EA subjects. Alleles -1725G and allele -25T are in positive LD both in AAs and EAs. Allele and haplotype frequencies differ significantly between AAs and EAs. Conclusions The haplotype -1725G/-25T at the NOTCH4 locus, which results from SNPs of NOTCH4 that are in LD, may increase susceptibility to schizophrenia in AAs. Any effect of this locus on risk for schizophrenia is population-specific.

This study examined whether a reportedly functional polymorphism in the gene encoding the μ-opioid receptor protein (A118G, which causes an Asn40Asp substitution in the receptor's extracellular domain), modifies the cortisol response to the opioid antagonist naloxone. The polymorphism occurs commonly in European Americans and some other population groups, underscoring its potential phenotypic significance. Methods: Using a balanced, within-subject design involving two test sessions over a period of 3–7 days, we examined ACTH and cortisol responses to intravenous naloxone (125 μg/kg) or placebo in 30 healthy subjects (21 males, mean age = 24.4 years). Plasma ACTH and cortisol concentrations were measured over 120 min post infusion. DNA isolated from whole blood was PCR amplified and genotyped via restriction enzyme digestion, with genotypes assigned based on agarose gel size fractionation. Results: Subjects with one or more Asp40 alleles (n = 6; 5 heterozygotes and 1 homozygote) had significantly higher cortisol concentrations at baseline and at 15, 60, and 90 min after naloxone infusion than subjects homozygous for the Asn40 allele (n = 24). Subjects with the Asp40 allele also had a greater peak cortisol response and a greater area under the cortisol time curve than those homozygous for the Asn40 allele. There were no effects of the Asn40Asp polymorphism on plasma ACTH concentration or on self-reported anxiety or distress. Conclusions: These findings are consistent with recent reports showing an enhanced cortisol response to naloxone and a reduced agonist effect of morphine-6-glucuronide among subjects with the Asp40 variant. Given evidence of its pharmacological significance, the clinical relevance of this polymorphism warrants further investigation. © 2003 Wiley-Liss, Inc.

Objective: To develop effective methods for GWAS in admixed populations such as African Americans. Methods: We show that, when testing the null hypothesis that the test SNP is not in background linkage disequilibrium with the causal variants, several existing methods cannot control well the family-wise error rate (FWER) in the strong sense in GWAS. These existing methods include association tests adjusting for global ancestry and joint association tests that combine statistics from admixture mapping tests and association tests that correct for local ancestry. Furthermore, we describe a generalized sequential Bonferroni (smooth-GSB) procedure for GWAS that incorporates smoothed weights calculated from admixture mapping tests into association tests that correct for local ancestry. We have applied the smooth-GSB procedure to analyses of GWAS data on American Africans from the Atherosclerosis Risk in Communities (ARIC) Study. Results: Our simulation studies indicate that the smooth-GSB procedure not only control the FWER, but also improves statistical power compared with association tests correcting for local ancestry. Conclusion: The smooth-GSB procedure can result in a better performance than several existing methods for GWAS in admixed populations.

Alcohol dependence is more common among men than among women. Potential explanations for this include the role of genes in sex chromosomes (X and Y). In the present study, we scanned the entire Y chromosome and its homologs on the X chromosome in men to identify male-specific risk genes for alcohol dependence.Two thousand nine hundred and twenty-seven individuals in two independent cohorts were analyzed. The European-American male cohort (883 cases with alcohol dependence and 445 controls) served as the discovery cohort and the European-American female cohort (526 cases and 1073 controls) served as a contrast group. All individuals were genotyped on the Illumina Human 1M beadchip. Two thousand two hundred and twenty-four single nucleotide polymorphisms (SNPs) on the Y chromosome or in the homologs on the X chromosome were analyzed. The allele frequencies were compared between cases and controls within each cohort using logistic regression analysis.We found that, after experiment-wide correction, two SNPs on the X chromosome were associated significantly with alcohol dependence in European-American men (P = 1.0 × 10 for rs5916144 and P = 5.5 × 10 for rs5961794 at 3' UTR of NLGN4X), but not in the women. A total of 26 SNPs at 3'UTR of or within NLGN4X were nominally associated with alcohol dependence in men (5.5 × 10 ≤ P ≤ 0.05), all of which were not statistically significant in women.We conclude that NLGN4X was a significant male-specific risk gene for alcohol dependence in European-Americans. NLGN4X might harbor a causal variant(s) for alcohol dependence. A defect of synaptogenesis in neuronal circuitry caused by NLGN4X mutations is believed to play a role in alcohol dependence.

The Neuregulin 3 (NRG3) gene at 10q22–q24 has been implicated in multiple psychiatric traits such as cognitive impairment. We therefore hypothesized that NRG3 gene polymorphisms may play a role in Alzheimer disease (AD). This present study explored the association of NRG3 with the age at onset (AAO) of AD and the risk of developing AD. Secondary data analysis of 257 single-nucleotide polymorphisms (SNPs) in NRG3 gene was performed in 806 Alzheimer’s disease patients and 782 controls using logistic regression and linear regression analyses. Eight SNPs were associated with the risk of AD (p

Maximum number of drinks (MaxDrinks) defined as "Maximum number of alcoholic drinks consumed in a 24-h period" is an intermediate phenotype that is closely related to alcohol dependence (AD). Family, twin and adoption studies have shown that the heritability of MaxDrinks is approximately 0.5. We conducted the first genome-wide association (GWA) study and meta-analysis of MaxDrinks as a continuous phenotype. 1059 individuals were from the Collaborative Study on the Genetics of Alcoholism (COGA) sample and 1628 individuals were from the Study of Addiction - Genetics and Environment (SAGE) sample. Family sample with 3137 individuals was from the Australian twin-family study of alcohol use disorder (OZALC). Two population-based Caucasian samples (COGA and SAGE) with 1 million single-nucleotide polymorphisms (SNPs) were used for gene discovery and one family-based Caucasian sample was used for replication. Through meta-analysis we identified 162 SNPs associated with MaxDirnks (p < 10(-4)). The most significant association with MaxDrinks was observed with SNP rs11128951 (p = 4.27 × 10(-8)) near SGOL1 gene at 3p24.3. Furthermore, several SNPs (rs17144687 near DTWD2, rs12108602 near NDST4, and rs2128158 in KCNB2) showed significant associations with MaxDrinks (p < 5 × 10(-7)) in the meta-analysis. Especially, 8 SNPs in DDC gene showed significant associations with MaxDrinks (p < 5 × 10(-7)) in the SAGE sample. Several flanking SNPs in above genes/regions were confirmed in the OZALC family sample. In conclusions, we identified several genes/regions associated with MaxDrinks. These findings can improve the understanding about the pathogenesis of alcohol consumption phenotypes and alcohol-related disorders.

Variants (such as rs9939609) in the fat mass- and obesity-associated (FTO) gene have been associated with obesity, type 2 diabetes, some cancers, and alcohol consumption. This study tested the associations of 167 single-nucleotide polymorphisms (SNPs) within FTO gene with alcohol dependence (AD) using two Caucasian samples: the Collaborative Study on the Genetics of Alcoholism (COGA) sample (660 AD cases and 400 controls) and the Study of Addiction: Genetics and Environment (SAGE) sample (623 cases and 1,016 controls). Logistic regression analysis of AD as a binary trait was performed using the PLINK software. For the SAGE sample, the top three SNPs showing associations with AD were rs8062891, rs1108086, and rs1420318 (p = 0.00088, 0.00086 and 0.00086, respectively). Two SNPs (rs12597786 and rs7204609) associated with AD in the SAGE sample (p = 0.017 and 0.034, respectively) were replicated in the COGA sample (p = 0.017 and 0.014, respectively). Through meta-analysis of two samples using PLINK, the top three SNPs associated with AD were rs8062891, rs12597786, and rs7204609 (p = 0.00064, 0.00076 and 0.0011, respectively). Haplotype analysis in the SAGE sample further supported the associations with AD in single-marker analysis. In addition, we found association of rs17817449 (which has a strong linkage disequilibrium with rs9939609) with AD in the SAGE sample (p = 0.00339). The findings provide evidence of joint intervention and prevention of AD and obesity.

Objectives The spontaneous low frequency fluctuations (LFF) of blood oxygenation level-dependent (BOLD) signal in resting state have been identified as a biological measure of baseline spontaneous activity in the brain. Increasingly, studies of spontaneous resting state functional connectivity have demonstrated neural network abnormalities in bipolar disorder (BD). This study used the amplitude of low frequency fluctuations (ALFF) to explore the regional functional changes in BD during resting state. Methods Twenty-nine BD participants and 29 matched healthy controls (HC) were recruited to undergo resting-state functional magnetic resonance imaging scan on a 3.0 T magnetic resonance imaging system. The ALFF of BOLD signal in gray matter for each participant was calculated, and then was compared between BD and HC using ALFF maps. Results Compared to the HC group, the BD group showed increased ALFF in ventral prefrontal cortex, dorsal lateral prefrontal cortex, frontal eye field, insula, and putamen with extension into the ventral striatum, as well as decreased ALFF in the lingual gyrus ( p Limitations Although we observed differences in ALFF between BD and HC, we cannot conclusively state that these differences are caused by the pathophysiology of BD since most of BD participants were being treated with medications at the time of scanning. Conclusions Our results revealed altered regional brain activity in BD during resting state. The affected regions have been associated with BD pathophysiology. This suggests that methods using ALFF method may potentially be useful in further studies of this disorder.

We previously reported a risk genomic region (ie, PTP4A1-PHF3-EYS) for alcohol dependence in a genome-wide association study (GWAS). We also reported a rare variant constellation across this region that was significantly associated with alcohol dependence. In the present study, we significantly increased the marker density within this region and examined the specificity of the associations of common variants for alcohol dependence.One African-American discovery sample (681 cases with alcohol dependence and 508 controls), one European-American replication sample (1,409 alcohol dependent cases and 1,518 controls), and one European-Australian replication sample (a total of 6,438 family subjects with 1,645 alcohol dependent probands) underwent association analysis. A total of 38,714 subjects from 18 other cohorts with 10 different neuropsychiatric disorders served as contrast groups.We found 289 SNPs that were nominally associated with alcohol dependence in the discovery sample (p.05). Fifty-six associations of them were significant after correction (1.9 × 10(-6) ≤ p ≤ 1.6 × 10(-5)). No markers were significantly associated with other neuropsychiatric disorders after experiment-wide correction.We confirmed with our previous findings that PTP4A1-PHF3-EYS variants were significantly associated with alcohol dependence, which were replicable across multiple independent populations and were specific for alcohol dependence. These findings suggested that this region might harbor a causal variant(s) for alcohol dependence.

In a recent genome-wide association study (GWAS), we identified a unique novel, functional and replicable risk genomic region for alcohol dependence. This region (Chr6: 64,066,604-64,831,120) included the protein tyrosine phosphatase type IVA 1 gene (PTP4A1), the plant homeodomain finger protein 3 gene (PHF3) and part of the eyes shut homolog gene (EYS). It was enriched with numerous replicable common risk variants (minor allele frequency (MAF) >0.05) for alcohol dependence across African–Americans, European–Americans and European–Australians. Within 90 Mb range surrounding this region in the discovery sample, all variants with P