Bipolar multiplex families have an increased burden of common risk variants for psychiatric disorders.

Multiplex families with a high prevalence of a psychiatric disorder are often examined to identify rare genetic variants with large effect sizes. In the present study, we analysed whether the risk for bipolar disorder (BD) in BD multiplex families is influenced by common genetic variants. Furthermore, we investigated whether this risk is conferred mainly by BD-specific risk variants or by variants also associated with the susceptibility to schizophrenia or major depression. In total, 395 individuals from 33 Andalusian BD multiplex families (166 BD, 78 major depressive disorder, 151 unaffected) as well as 438 subjects from an independent, BD case/control cohort (161 unrelated BD, 277 unrelated controls) were analysed. Polygenic risk scores (PRS) for BD, schizophrenia (SCZ), and major depression were calculated and compared between the cohorts. Both the familial BD cases and unaffected family members had higher PRS for all three psychiatric disorders than the independent controls, with BD and SCZ being significant after correction for multiple testing, suggesting a high baseline risk for several psychiatric disorders in the families. Moreover, familial BD cases showed significantly higher BD PRS than unaffected family members and unrelated BD cases. A plausible hypothesis is that, in multiplex families with a general increase in risk for psychiatric disease, BD development is attributable to a high burden of common variants that confer a specific risk for BD. The present analyses demonstrated that common genetic risk variants for psychiatric disorders are likely to contribute to the high incidence of affective psychiatric disorders in the multiplex families. However, the PRS explained only part of the observed phenotypic variance, and rare variants might have also contributed to disease development.

"The Heidelberg Five" personality dimensions: Genome-wide associations, polygenic risk for neuroticism, and psychopathology 20 years after assessment.

HeiDE is a longitudinal population-based study that started in the 1990s and, at baseline, assessed an array of health-related personality questionnaires in 5133 individuals. Five latent personality dimensions (The Heidelberg Five) were identified and interpreted as Emotional Lability (ELAB), Lack of Behavioral Control (LBCN), Type A Behavior (TYAB), Locus of Control over Disease (LOCC), and Psychoticism (PSYC). At follow-up, 3268 HeiDE participants (post-QC) were genotyped on single nucleotide polymorphism (SNP) arrays. To further characterize The Heidelberg Five, we analyzed genomic underpinnings, their relations to the genetic basis of the Big Five trait Neuroticism, and longitudinal associations with psychiatric symptoms at follow-up. SNP-based heritability was significant for ELAB (34%) and LBCN (29%). A genome-wide association study for each personality dimension was conducted; only the phenotype PSYC yielded a genome-wide significant finding (p < 5 × 10-8 , top SNP rs138223660). Gene-based analyses identified significant findings for ELAB, TYAB, and PSYC. Polygenic risk scores for Neuroticism were only associated with ELAB. Each of The Heidelberg Five was related to depressive symptoms at follow-up. ELAB, LBCN, and PSYC were also associated with lifetime anxiety symptoms. These results highlight the clinical importance of health-related personality traits and identify LBCN as a heritable "executive function" personality trait.

Investigating polygenic burden in age at disease onset in bipolar disorder: Findings from an international multicentric study.

OBJECTIVES: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients. METHODS: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models. RESULTS: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. CONCLUSIONS: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype.

No Reliable Association between Runs of Homozygosity and Schizophrenia in a Well-Powered Replication Study.

It is well known that inbreeding increases the risk of recessive monogenic diseases, but it is less certain whether it contributes to the etiology of complex diseases such as schizophrenia. One way to estimate the effects of inbreeding is to examine the association between disease diagnosis and genome-wide autozygosity estimated using runs of homozygosity (ROH) in genome-wide single nucleotide polymorphism arrays. Using data for schizophrenia from the Psychiatric Genomics Consortium (n = 21,868), Keller et al. (2012) estimated that the odds of developing schizophrenia increased by approximately 17% for every additional percent of the genome that is autozygous (ß = 16.1, CI(ß) = [6.93, 25.7], Z = 3.44, p = 0.0006). Here we describe replication results from 22 independent schizophrenia case-control datasets from the Psychiatric Genomics Consortium (n = 39,830). Using the same ROH calling thresholds and procedures as Keller et al. (2012), we were unable to replicate the significant association between ROH burden and schizophrenia in the independent PGC phase II data, although the effect was in the predicted direction, and the combined (original + replication) dataset yielded an attenuated but significant relationship between Froh and schizophrenia (ß = 4.86,CI(ß) = [0.90,8.83],Z = 2.40,p = 0.02). Since Keller et al. (2012), several studies reported inconsistent association of ROH burden with complex traits, particularly in case-control data. These conflicting results might suggest that the effects of autozygosity are confounded by various factors, such as socioeconomic status, education, urbanicity, and religiosity, which may be associated with both real inbreeding and the outcome measures of interest.

Attitudes toward the right to autonomous decision-making in psychiatric genetic testing: Controversial and context-dependent.

Recent breakthroughs in psychiatric genetics have identified genetic risk factors of yet unknown clinical value. A main ethical principal in the context of psychiatric research as well as future clinical genetic testing is the respect for a person's autonomy to decide whether to undergo genetic testing, and whom to grant access to genetic data. However, experience within the psychiatric genetic research setting has indicated controversies surrounding attitudes toward this ethical principal. This study aimed to explore attitudes concerning the right of individuals to self-determine testing and disclosure of results, and to determine whether these attitudes are context-dependent, that is, not directly related to the test result but rather to specific circumstances. N = 160 individuals with major depression or bipolar disorder and n = 29 relatives of individuals with either illness completed an online-questionnaire assessing attitudes toward genetic testing, genetic research, disclosure of results, incidental findings, and access to psychiatric genetic test results. Generally, the right of the person's autonomy was considered very important, but attitudes varied. For example, half of those who considered that children should have the right to refuse psychiatric genetic testing even against their parents' will, also state that they should be tested upon their parents' wishes. Also, the majority of respondents considered the physician entitled to disregard their stated wishes concerning the disclosure of incidental findings in case of good treatment options. Thus, researchers and clinicians must be aware that attitudes toward psychiatric genetic testing are often mutable and should discuss these prior to testing.

Impact on birth weight of maternal smoking throughout pregnancy mediated by DNA methylation.

BACKGROUND: Cigarette smoking has severe adverse health consequences in adults and in the offspring of mothers who smoke during pregnancy. One of the most widely reported effects of smoking during pregnancy is reduced birth weight which is in turn associated with chronic disease in adulthood. Epigenome-wide association studies have revealed that smokers show a characteristic "smoking methylation pattern", and recent authors have proposed that DNA methylation mediates the impact of maternal smoking on birth weight. The aims of the present study were to replicate previous reports that methylation mediates the effect of maternal smoking on birth weight, and for the first time to investigate whether the observed mediation effects are sex-specific in order to account for known sex-specific differences in methylation levels. METHODS: Methylation levels in the cord blood of 313 newborns were determined using the Illumina HumanMethylation450K Beadchip. A total of 5,527 CpG sites selected on the basis of evidence from the literature were tested. To determine whether the observed association between maternal smoking and birth weight was attributable to methylation, mediation analyses were performed for significant CpG sites. Separate analyses were then performed in males and females. RESULTS: Following quality control, 282 newborns eventually remained in the analysis. A total of 25 mothers had smoked consistently throughout the pregnancy. The birthweigt of newborns whose mothers had smoked throughout pregnancy was reduced by >200g. After correction for multiple testing, 30 CpGs showed differential methylation in the maternal smoking subgroup including top "smoking methylation pattern" genes AHRR, MYO1G, GFI1, CYP1A1, and CNTNAP2. The effect of maternal smoking on birth weight was partly mediated by the methylation of cg25325512 (PIM1); cg25949550 (CNTNAP2); and cg08699196 (ITGB7). Sex-specific analyses revealed a mediating effect for cg25949550 (CNTNAP2) in male newborns. CONCLUSION: The present data replicate previous findings that methylation can mediate the effect of maternal smoking on birth weight. The analysis of sex-dependent mediation effects suggests that the sex of the newborn may have an influence. Larger studies are warranted to investigate the role of both the identified differentially methylated loci and the sex of the newborn in mediating the association between maternal smoking during pregnancy and birth weight.

Preliminary Evidence for an Association Between Variants of the Catechol-O-Methyltransferase (COMT) Gene and Premature Ejaculation.

BACKGROUND: Studies have suggested that dopamine plays a role in the neurobiological mechanism that triggers ejaculation, leading scientists to hypothesize that dopamine-related genetic polymorphisms could contribute to symptoms of premature ejaculation (PE). AIM: To investigate associations between dopamine receptor and catechol-O-methyltransferase (COMT; an enzyme involved in the catabolism of dopamine) gene-linked polymorphisms and PE. METHODS: PE status in patient groups was determined by clinical diagnosis performed by a physician specializing in sexual medicine. Self-reported PE symptoms from a validated questionnaire also were reported. Saliva samples were collected from 149 patients with PE and 1,022 controls from a population-based sample. In total, we tested associations between PE and 11 single-nucleotide polymorphisms in the dopamine receptor D1, D2, and D3 genes and in the COMT gene. OUTCOMES: We found no associations between dopamine receptor gene polymorphisms and PE, but 2 COMT-linked loci (rs4680 and rs4818) had significant associations after correction for multiple testing. RESULTS: 1 COMT gene-linked locus that was associated with PE symptoms in the present study, rs4680, is a well-documented functional polymorphism that causes a valine-to-methionine substitution. The other polymorphism, rs4818, is in high linkage disequilibrium with the rs4680 locus, indicating that they capture the same effect. Surprisingly, the rs4680 variant that was statistically significantly more prevalent in the PE group (ie, the valine-encoding allele) has been associated with higher enzymatic activity and therefore lower synaptic dopamine levels. CLINICAL TRANSLATION: Drugs targeting the dopaminergic system could affect PE symptoms. STRENGTHS AND LIMITATIONS: No replication sample was available for the present study; thus, our findings should be interpreted with caution. Moreover, a limitation of our study is the small sample in the context of genetic association studies (although it should be mentioned that genetically informative samples with phenotypic information about PE symptoms are scarce, and most previous genetic association studies of PE have used samples of similar or smaller size). However, our results are plausible: we report an association between one of the most extensively studied and understood genetic polymorphisms in psychiatric research and PE, and our results are in line with the long-standing hypothesis that dopamine influences human ejaculatory function. CONCLUSIONS: We report an association between 2 COMT gene-linked loci and PE symptoms, but our results should be treated with caution until independently replicated. Jern P, Johansson A, Strohmaier J, et al. Preliminary Evidence for an Association Between Variants of the Catechol-O-Methyltransferase (COMT) Gene and Premature Ejaculation. J Sex Med 2017;14:1558-1565.

Integrated pathway-based approach identifies association between genomic regions at CTCF and CACNB2 and schizophrenia.

In the present study, an integrated hierarchical approach was applied to: (1) identify pathways associated with susceptibility to schizophrenia; (2) detect genes that may be potentially affected in these pathways since they contain an associated polymorphism; and (3) annotate the functional consequences of such single-nucleotide polymorphisms (SNPs) in the affected genes or their regulatory regions. The Global Test was applied to detect schizophrenia-associated pathways using discovery and replication datasets comprising 5,040 and 5,082 individuals of European ancestry, respectively. Information concerning functional gene-sets was retrieved from the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and the Molecular Signatures Database. Fourteen of the gene-sets or pathways identified in the discovery dataset were confirmed in the replication dataset. These include functional processes involved in transcriptional regulation and gene expression, synapse organization, cell adhesion, and apoptosis. For two genes, i.e. CTCF and CACNB2, evidence for association with schizophrenia was available (at the gene-level) in both the discovery study and published data from the Psychiatric Genomics Consortium schizophrenia study. Furthermore, these genes mapped to four of the 14 presently identified pathways. Several of the SNPs assigned to CTCF and CACNB2 have potential functional consequences, and a gene in close proximity to CACNB2, i.e. ARL5B, was identified as a potential gene of interest. Application of the present hierarchical approach thus allowed: (1) identification of novel biological gene-sets or pathways with potential involvement in the etiology of schizophrenia, as well as replication of these findings in an independent cohort; (2) detection of genes of interest for future follow-up studies; and (3) the highlighting of novel genes in previously reported candidate regions for schizophrenia.

Parents' Attitudes toward Clinical Genetic Testing for Autism Spectrum Disorder-Data from a Norwegian Sample.

Clinical genetic testing (CGT) of children with autism spectrum disorder (ASD) may have positive and negative effects. Knowledge about parents' attitudes is needed to ensure good involvement of caregivers, which is crucial for accurate diagnosis and effective clinical management. This study aimed to assess parents' attitudes toward CGT for ASD. Parent members of the Norwegian Autism Society were given a previously untested questionnaire and 1455 answered. Linear regression analyses were conducted to evaluate contribution of parent and child characteristics to attitude statements. Provided it could contribute to a casual explanation of their child's ASD, 76% would undergo CGT. If it would improve the possibilities for early interventions, 74% were positive to CGT. Between 49-67% agreed that CGT could have a negative impact on health insurance, increase their concern for the child's future and cause family conflicts. Parents against CGT (9%) were less optimistic regarding positive effects, but not more concerned with negative impacts. The severity of the children's ASD diagnosis had a weak positive association with parent's positive attitudes to CGT (p-values range from <0.001 to 0.975). Parents prefer that CGT is offered to those having a child with ASD (65%), when the child's development deviates from normal (48%), or before pregnancy (36%). A majority of the parents of children with ASD are positive to CGT due to possibilities for an etiological explanation.

Investigation of SHANK3 in schizophrenia.

The postsynaptic scaffolding protein SHANK3 is essential for the normal function of glutamatergic synapses in the brain. Emerging evidence suggests that impaired plasticity of glutamatergic synapses contributes to the pathology of schizophrenia (SCZ). To investigate whether variants in the SHANK3 gene contribute to the etiology of SCZ, we sequenced SHANK3 in 500 affected individuals (cohort C1). In total, we identified 48 variants and compared them to European controls from the 1000 Genomes Project and the Exome Variant Server. Five variants showed significant differences in frequencies between patients and controls. We were able to follow three of them up in an independent cohort (C2) comprising 993 SCZ patients and 932 German controls. We could not confirm an association for three of these variants (rs140201628, rs1557620, and rs61729471). Two rare variants with predicted functional relevance were identified in further SCZ individuals of cohort C1: c.3032G>T (p.G1011V) and c.*27C>T. The latter variant was found in one additional SCZ individual and the p.G1011V variant was identified in two additional SCZ individuals from cohort C2. The p.G1011V variant was the most interesting variant in our study; together with previous studies this variant has been identified in 4 out of 1,524 SCZ patients and in 4 out of 2,147 individuals with autism spectrum disorder (ASD), but not in 2468 European Sanger-sequenced controls. Therefore, we consider this variant a promising candidate variant for follow-up studies in larger samples and functional investigations. © 2017 Wiley Periodicals, Inc.

Sexual Function Is Correlated With Body Image and Partnership Quality in Female University Students.

INTRODUCTION: According to the World Health Organization definition, sexual health is more than mere physical sexual function; it also encompasses emotional, mental, and social well-being in relation to sexuality and is not merely the absence of dysfunction or disease. In line with this definition, various studies have reported that female sexual function is associated with partnership quality, body image, and body self-acceptance. AIM: To investigate whether female sexual function is influenced by (i) body self-acceptance and (ii) partnership quality, as important factors in psychosocial well-being, and (iii) whether the effects of body self-acceptance are moderated by partnership quality. METHODS: In total, 2,685 female medical students no older than 35 years from Germany, Austria, and Switzerland completed an anonymous online questionnaire comprising the Female Sexual Function Index (FSFI) and the Self-Acceptance of the Body Scale. Respondents were asked to state whether they had been in a steady partnership in the preceding 6 months. When present, the quality of the partnership status was rated (enamoredness, love, friendship, or conflicted). To determine correlations, group differences, and moderating effects among body self-acceptance, partnership quality, and sexual function, the data were analyzed using Spearman correlations, Kruskal-Wallis tests, and analyses of variance. MAIN OUTCOME MEASURES: Female sexual function (FSFI total score). RESULTS: (i) In sexually active women, higher FSFI scores were significantly associated with greater body self-acceptance and a steady partnership during the preceding 6 months. (ii) Total FSFI scores were highest in women who described their partnership as enamored (29.45) or loving (28.55). Lower scores were observed in single women (26.71) and in women who described their partnerships as friendship (25.76) or as emotionally conflicted (23.41). (iii) Total FSFI score was affected by an interaction between body self-acceptance and partnership quality. Body self- acceptance was positively associated with FSFI total scores, particularly in single women and women in emotionally conflicted partnerships. CONCLUSION: Our findings suggest that in young women, body self-acceptance and partnership quality are positively associated with better sexual function, and that high body self-acceptance might buffer the negative impact on sexual function of partnership quality. The present data suggest that psychological interventions to improve the body image of younger women can positively affect sexual function and thereby improve sexual health.

Low Birth Weight in MZ Twins Discordant for Birth Weight is Associated with Shorter Telomere Length and lower IQ, but not Anxiety/Depression in Later Life.

Shorter telomere length (TL) has found to be associated with lower birth weight and with lower cognitive ability and psychiatric disorders. However, the direction of causation of these associations and the extent to which they are genetically or environmentally mediated are unclear. Within-pair comparisons of monozygotic (MZ) and dizygotic (DZ) twins can throw light on these questions. We investigated correlations of within pair differences in telomere length, IQ, and anxiety/depression in an initial sample from Brisbane (242 MZ pairs, 245 DZ same sex (DZSS) pairs) and in replication samples from Amsterdam (514 MZ pairs, 233 DZSS pairs) and Melbourne (19 pairs selected for extreme high or low birth weight difference). Intra-pair differences of birth weight and telomere length were significantly correlated in MZ twins, but not in DZSS twins. Greater intra-pair differences of telomere length were observed in the 10% of MZ twins with the greatest difference in birth weight compared to the bottom 90% in both samples and also in the Melbourne sample. Intra-pair differences of telomere length and IQ, but not of TL and anxiety/depression, were correlated in MZ twins, and to a smaller extent in DZSS twins. Our findings suggest that the same prenatal effects that reduce birth weight also influence telomere length in MZ twins. The association between telomere length and IQ is partly driven by the same prenatal effects that decrease birth weight.

Investigation of the role of TCF4 rare sequence variants in schizophrenia.

Transcription factor 4 (TCF4) is one of the most robust of all reported schizophrenia risk loci and is supported by several genetic and functional lines of evidence. While numerous studies have implicated common genetic variation at TCF4 in schizophrenia risk, the role of rare, small-sized variants at this locus-such as single nucleotide variants and short indels which are below the resolution of chip-based arrays requires further exploration. The aim of the present study was to investigate the association between rare TCF4 sequence variants and schizophrenia. Exon-targeted resequencing was performed in 190 German schizophrenia patients. Six rare variants at the coding exons and flanking sequences of the TCF4 gene were identified, including two missense variants and one splice site variant. These six variants were then pooled with nine additional rare variants identified in 379 European participants of the 1000 Genomes Project, and all 15 variants were genotyped in an independent German sample (n = 1,808 patients; n = 2,261 controls). These data were then analyzed using six statistical methods developed for the association analysis of rare variants. No significant association (P < 0.05) was found. However, the results from our association and power analyses suggest that further research into the possible involvement of rare TCF4 sequence variants in schizophrenia risk is warranted by the assessment of larger cohorts with higher statistical power to identify rare variant associations.

Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder.

We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 × 10(-8); odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 × 10(-4); odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 10(-9) (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD. NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies.

Perceived stress has genetic influences distinct from neuroticism and depression.

The present study investigated whether the genetic determinants of neuroticism and depressive symptoms differ from those underlying perceived psychological stress. Multivariate structural equation models, which included age and sex as modifiers, were fitted to the total sample of 798 adolescents and young adults (female, n = 459; mean age 15.5 years). The sample included 139 monozygotic and 241 dizygotic twin pairs. Stress was measured using item response theory (IRT) scores, as derived from the Perceived Stress Scale and/or the Daily Life and Stressors Scale. Neuroticism was measured using the Neo-Five Factor Inventory or the Junior Eysenck Personality Questionnaire, depending on the age of the participant. Depressive symptoms were assessed using the IRT-scores of the Somatic and Psychological Health Report. The results suggest that the genetic effects underlying perceived psychological stress are largely shared with those that influence neuroticism and liability to depressive symptoms. However, separate genetic effects for perceived psychological stress that are not shared with neuroticism and depressive symptoms were also identified. The source of the identified trait specific effects requires further investigation.

Epigenetic alteration of the dopamine transporter gene in alcohol-dependent patients is associated with age.

Chronic alcohol abuse and dependence are associated with dysfunctional dopaminergic neurotransmission in mesocorticolimbic circuits. Genetic and environmental factors have been shown to modulate susceptibility to alcohol dependence, and both may act through epigenetic mechanisms that can modulate gene expression, e.g. DNA methylation at CpG sites. Recent studies have suggested that DNA methylation patterns may change over time. However, few data are available concerning the rate of these changes in specific genes. A recent study found that hypermethylation of the promoter of the dopamine transporter (DAT) gene was positively correlated with alcohol dependence and negatively correlated with alcohol craving. The aim of the present study was to replicate these findings in a larger sample of alcohol-dependent patients and population-based controls matched for age and sex. No difference in methylation level was observed between patients and controls, and no difference in methylation level was observed before and after alcohol withdrawal in patients. However, patients with more severe craving showed a trend towards lower DAT methylation levels (P = 0.07), which is consistent with previous findings. Furthermore, in our overall sample, DAT methylation levels increased with age. Interestingly, a separate analysis of patients suggested that this finding was mainly driven by the patient group. Although the present data do not clarify whether chronic alcohol abuse is responsible for this phenomenon or merely enhances an ageing-specific process, our findings suggest that hypermethylation in alcohol-dependent patients is a consequence, rather than a cause, of the disorder.

Neuregulin 3 is associated with attention deficits in schizophrenia and bipolar disorder.

Linkage and fine mapping studies have established that the neuregulin 3 gene (NRG3) is a susceptibility locus for schizophrenia. Association studies of this disorder have implicated NRG3 variants in both psychotic symptoms and attention performance. Psychotic symptoms and cognitive deficits are also frequent features of bipolar disorder. The aims of the present study were to extend analysis of the association between NRG3 and psychotic symptoms and attention in schizophrenia and to determine whether these associations also apply to bipolar disorder. A total of 358 patients with schizophrenia and 111 patients with bipolar disorder were included. Psychotic symptoms were evaluated using the Operational Criteria Checklist for Psychotic Illness (OPCRIT) and attention performance was assessed using the Trail Making Test (TMT). Symptoms and performance scores were then tested for association with the NRG3 variant rs6584400. A significant association was found between the number of rs6584400 minor alleles and the total OPCRIT score for psychotic symptoms in patients with schizophrenia. Moreover, in both schizophrenia and bipolar disorder patients, minor allele carriers of rs6584400 outperformed homozygous major allele carriers in the TMT. The results suggest that rs6584400 is associated with psychotic symptoms and attention performance in schizophrenia. The finding of a significant association between rs6584400 and attention performance in bipolar disorder supports the hypothesis that this NRG3 variant confers genetic susceptibility to cognitive deficits in both schizophrenia and bipolar disorder.

Impulsivity, decision-making, and risk behavior in bipolar disorder and major depression from bipolar multiplex families.

OBJECTIVES: Bipolar disorder (BD) and major depressive disorder (MDD) are characterized by specific alterations of mood. In both disorders, alterations in cognitive domains such as impulsivity, decision-making, and risk-taking have been reported. Identification of similarities and differences of these domains in BD and MDD could give further insight into their etiology. The present study assessed impulsivity, decision-making, and risk-taking behavior in BD and MDD patients from bipolar multiplex families. METHODS: Eighty-two participants (BD type I, n = 25; MDD, n = 26; healthy relatives (HR), n = 17; and healthy controls (HC), n = 14) underwent diagnostic interviews and selected tests of a cognitive battery assessing neurocognitive performance across multiple subdomains including impulsivity (response inhibition and delay aversion), decision-making, and risk behavior. Generalized estimating equations (GEEs) were used to analyze whether the groups differed in the respective cognitive domains. RESULTS: Participants with BD and MDD showed higher impulsivity levels compared to HC; this difference was more pronounced in BD participants. BD participants also showed lower inhibitory control than MDD participants. Overall, suboptimal decision-making was associated with both mood disorders (BD and MDD). In risk-taking behavior, no significant impairment was found in any group. LIMITATIONS: As sample size was limited, it is possible that differences between BD and MDD may have escaped detection due to lack of statistical power. CONCLUSIONS: Our findings show that alterations of cognitive domains-while present in both disorders-are differently associated with BD and MDD. This underscores the importance of assessing such domains in addition to mere diagnosis of mood disorders.

Association between copy number variants in 16p11.2 and major depressive disorder in a German case-control sample.

The majority of genetic risk factors for major depressive disorder (MDD) still await identification. Since copy number variants (CNVs) have been implicated in various neuropsychiatric disorders, the question arises as to whether CNVs also play a role in MDD. We performed a genome-wide CNV study using Illumina's SNP array data from 604 MDD patients and 1,643 controls. Putative CNVs were detected with the CNV algorithms QuantiSNP and PennCNV. CNVs with ≥30 consecutive SNPs and a log Bayes Factor/confidence value of ≥30 were statistically analyzed using PLINK. Further analyses and technical verification were only performed in the case of regions for which CNV calls from both programs showed nominal significance. Set-based tests were used to test whether common variants in the CNV regions showed association in two GWAS datasets of MDD. CNVs from four chromosomal regions were associated with MDD. The following were more frequent in patients than controls: microdeletions in 7p21.3 (P = 0.033) and 18p11.32 (P = 0.030); microduplications in 15q26.3 (P = 0.033); and the combination of microdeletion/duplications in 16p11.2 (P ≤ 0.018). SNPs in CNV region 16p11.2 showed significant association in a set-based test (P = 0.026). Microdeletions/duplications in 16p11.2 are the most promising CNVs, since these affect genes and CNVs in this region have been implicated in other neuropsychiatric disorders. The association finding for common SNPs provides further support for the hypothesis that this region is involved in the development of MDD. © 2012 Wiley Periodicals, Inc.

Genetic variation in G72 correlates with brain activation in the right middle temporal gyrus in a verbal fluency task in healthy individuals.

The D-amino acid oxidase activator gene (G72) has been found associated with several psychiatric disorders such as schizophrenia, major depression, and bipolar disorder. Impaired performance in verbal fluency tasks is an often replicated finding in the mentioned disorders. In functional neuroimaging studies, this dysfunction has been linked to signal changes in prefrontal and lateral temporal areas and could possibly constitute an endophenotype. Therefore, it is of interest whether genes associated with the disorders, such as G72, modulate verbal fluency performance and its neural correlates. Ninety-six healthy individuals performed a semantic verbal fluency task while brain activation was measured with functional MRI. All subjects were genotyped for two single nucleotide polymorphisms (SNP) in the G72 gene, M23 (rs3918342) and M24 (rs1421292), that have previously shown association with the above-mentioned disorders. The effect of genotype on brain activation was assessed with fMRI during a semantic verbal fluency task. Although there were no differences in performance, brain activation in the right middle temporal gyrus (BA 39) and the right precuneus (BA 7) was positively correlated with the number of M24 risk alleles in the G72 gene. G72 genotype does modulate brain activation during language production on a semantic level in key language areas. These findings are in line with structural and functional imaging studies in schizophrenia, which showed alterations in the right middle temporal gyrus.