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Large population-based cohort studies offer the chance to assess a broad number of diseases and intermediate phenotypes and to estimate their frequencies in the general population. Because of their large sample size new symptom clusters and interactions of genetic, environmental and clinical factors in the onset and course of disease can be described. The German National Cohort (GNC) is one of the mega cohorts with a study-specific concept for the assessment of different psychiatric diseases and a focus on affective disorders and on emotional and cognitive functions. Aim of this manuscript is to describe different design approaches for a priorisation in the assessment of phenotypes for psychiatric and/or neurological disorders in large cohorts and to introduce the concept of studying emotional and cognitive functions and related disorders in GNC. [ABSTRACT FROM AUTHOR]

Background Age-of-onset (AO) is increasingly used in molecular genetics of bipolar I disorder (BP-I) as a phenotypic specifier with the goal of reducing genetic heterogeneity. However, questions regarding the cut-off age for defining early onset (EO), as well as the number of onset groups characterizing BP-I have emerged over the last decade with no definite conclusion. The aims of this paper are: 1) to see whether a mixture of three distributions better describes the AO of BP-I than a mixture of two distributions in different independent samples; 2) to compare the morbid risk (MR) for BP-I and for major affective disorders and schizophrenia in first degree relatives of BP-I probands by proband onset group derived from commingling analysis, since the MR to relatives is a trait with strong genetic background. Methods We applied commingling (admixture) analysis to the AO of three BP-I samples from Romania (n=621), Germany (n=882), and Poland (n=354). Subsequently, the morbid risk (MR) for BP-I and for major psychoses (BP-I, BP-II, Mdd-UP, schizoaffective disorders, schizophrenia) was estimated in first degree relatives by proband AO-group derived from admixture analysis in the Romanian sample. Results In the three independent samples and in the combined sample two- and three-AO-group distributions fitted the empirical data equally well. The upper EO limit varied between 21 and 25 years from sample to sample. The MR for both BP-I and for all major psychoses was similar in first degree relatives of EO probands (AO?21) and in relatives of intermediate-onset probands (AO=22-34). Significant MR differences appeared only when comparing the EO group to the late-onset (LO) group (AO>34). Similar to Mdd-UP and schizophrenia, a significant MR decrease in proband first degree relatives was visible after proband AO of 34 years. Under the three-AO-group classification the MR for both BP-I and all major psychoses in first degree relatives did not differ by relative sex in any proband AO-group. Under the two-AO-group classification female relatives of LO probands (AO>24) had a significantly higher MR for all major psychoses than male relatives, while there was no sex difference for the relatives of EO probands. Limitations MR was not computed in the German and Polish samples because family data were not available and 34% of the relatives of the Romanian probands were not available for direct interview. Conclusion Similar to other clinical traits, the MR for major psychoses to relatives failed to support a three-AO-group classification in BP-I suggesting that this is not more useful for the molecular analysis than a two-AO-group classification. [ABSTRACT FROM AUTHOR]

Major Depression and Bipolar Disorder Type I (BIP-I) and Type II (BIP-II), are characterized by depressed, manic, and hypomanic episodes in which specific changes of physical activity, circadian rhythm, and sleep are observed. It is known that genetic factors contribute to variation in mood disorders and biological rhythms, but unclear to what extent there is an overlap between their underlying genetics. In the present study, data from genome-wide association studies were used to examine the genetic relationship between mood disorders and biological rhythms. We tested the genetic correlation of depression, BIP-I, and BIP-II with physical activity (overall physical activity, moderate activity, sedentary behaviour), circadian rhythm (relative amplitude), and sleep features (sleep duration, daytime sleepiness). Genetic correlations of depression, BIP-I, and BIP-II with biological rhythms were compared to discover commonalities and differences. A gene-based analysis tested for associations of single genes and common circadian genes with mood disorders. Depression was negatively correlated with overall physical activity and positively with sedentary behaviour, while BIP-I showed associations in the opposite direction. Depression and BIP-II had negative correlations with relative amplitude. All mood disorders were positively correlated with daytime sleepiness. Overall, we observed both genetic commonalities and differences across mood disorders in their relationships with biological rhythms: depression and BIP-I differed the most, while BIP-II was in an intermediate position. Gene-based analysis suggested potential targets for further investigation. The present results suggest shared genetic underpinnings for the clinically observed associations between mood disorders and biological rhythms. Research considering possible joint mechanisms may offer avenues for improving disease detection and treatment. [ABSTRACT FROM AUTHOR]

Abstract Schizophrenia is a genetically influenced disease with a broad and heterogeneous phenotype transmitted in families. Of particular interest is the familial-genetic relationship between schizophrenia and affective disorders. Taking advantage of refined epidemiological methods, the dichotomy between both groups of disorders is not less consistently found than expected. Recently, linkage studies identified multiple candidate regions for susceptibility genes for each of both disorders. [ABSTRACT FROM AUTHOR]

Objective: Preliminary data suggested that there are three subgroups of bipolar affective disorder based on age at onset. The authors sought to replicate those findings and determine the cut-off age of each subgroup. Method: Admixture analysis was used to determine the bestfitting model for the observed ages at onset of 368 consecutively admitted patients. The results obtained were compared with those of the previously described model. The authors also investigated whether affected siblings are more likely to belong to the same theoretical age-at-onset subgroup as identified by admixture analysis. Results: The existence of three subgroups defined by age at onset was confirmed. The mean ages estimated in this model were 17.4 years (SD = 2.3), 25.1 years (SD = 6.2), and 40.4 years (SD = 11.3). Affected siblings were more likely to belong to the same theoretical subgroup. Conclusions: There are three age-at-onset subgroups of bipolar patients, and specific familial vulnerability factors might underlie each subgroup. [ABSTRACT FROM AUTHOR]

Overall Abstract Single gene and GWAS analyses of pharmacological treatment response in depression and bipolar disorder have had varying success in identifying functionally relevant genes associated with pharmacological treatment response such as response to SSRI in depression and lithium in bipolar disorder. Hence, the need to better understand the complex genetic underpinnings of pharmacoresponse may include methodologies such as RNA-seq and microarray analyses. Such approaches contribute to a more in in-depth functional characterization of risk loci related to treatment response and to characterize the genetic underpinnings of both adverse events (e.g. induction of mania by antidepressants) and of medical comorbidity contributing to poor treatment response. In addition, gene expression profile and eQTLs can assist an improved understanding of the functional genomics of mood disorders. Specifically, recent large-scale GWAS meta-analyses (ConLiGen) have implicated multiple novel loci, two of which met the threshold for genome-wide significance: GADL1 (Chen et al., 2014) and an intergenic locus on chromosome 21 (Hou et al., 2016). The functional implications of the related genes remain to be described. In a first presentation, results will be presented from whole blood RNA-seq-data in a subsample of ConLiGen to validate and characterize these associations with clinical lithium treatment response and how these loci impact gene function and lithium response (David Stacey). Addressing the need to investigate the genetic underpinning of a broader range of treatment outcomes and adverse events, the genetic contribution of a potential induction of mania by antidepressants will be discussed in a second presentation, that shows results from a GWAS of antidepressant-induced mania (Joanna Biernacka). Among other factors, the co-morbidity of depression with other psychiatric and cardiometabolic disorders may negatively influence antidepressants treatment outcome. Moreover, response to antidepressants is a complex trait with substantial contribution from a large number of common genetic variants of small effect. Hence, use of polygenic scores (PGS) could be a better alternative to estimate the overall effect of genetic factors on treatment response and assess the importance of co-morbidities and related phenotypes. To investigate this further, we evaluated whether PGS derived from 25 recognized comorbid cardiometabolic and psychiatric disorders, personality traits and educational attainment predict treatment outcome to SSRIs in major depressive disorder using the ISPC data (Bernhard Baune). Previous studies aiming to identify the transcriptome signature of depression are inconsistent with low replicability at the single gene level in both brain and peripheral tissues. In a fourth presentation, results from analyses of whole blood transcriptomes of 521 elderly people from the general population (The Sydney Memory and Age Study, MAS, Sydney) are shown to describe molecular networks involved in geriatric depression. Functional characterisation of two out of 29 modules of the co-expression network indicated that abnormalities in structural constituents of ribosome may be involved in the pathophysiology of geriatric depression. In addition, results of pathway analyses using Ingenuity Pathway Analysis software will be shown (Liliana Ciobanu). [ABSTRACT FROM AUTHOR]

Background Defining the molecular genomic basis of the likelihood of developing depressive disorder is a considerable challenge. We previously associated rare, exonic deletion copy number variants (CNV) with recurrent depressive disorder (RDD). Sex chromosome abnormalities also have been observed to co-occur with RDD. Methods In this reanalysis of our RDD dataset ( N = 3106 cases; 459 screened control samples and 2699 population control samples), we further investigated the role of larger CNVs and chromosomal abnormalities in RDD and performed association analyses with clinical data derived from this dataset. Results We found an enrichment of Turner’s syndrome among cases of depression compared with the frequency observed in a large population sample ( N = 34,910) of live-born infants collected in Denmark (two-sided p = .023, odds ratio = 7.76 [95% confidence interval = 1.79–33.6]), a case of diploid/triploid mosaicism, and several cases of uniparental isodisomy. In contrast to our previous analysis, large deletion CNVs were no more frequent in cases than control samples, although deletion CNVs in cases contained more genes than control samples (two-sided p = .0002). Conclusions After statistical correction for multiple comparisons, our data do not support a substantial role for CNVs in RDD, although (as has been observed in similar samples) occasional cases may harbor large variants with etiological significance. Genetic pleiotropy and sample heterogeneity suggest that very large sample sizes are required to study conclusively the role of genetic variation in mood disorders. [ABSTRACT FROM AUTHOR]

Patients suffering from bipolar affective disorder show deficits in working memory functions. In a previous functional magnetic resonance imaging study, we observed an abnormal hyperactivity of the amygdala in bipolar patients during articulatory rehearsal in verbal working memory. In the present study, we investigated the dynamic neurofunctional interactions between the right amygdala and the brain systems that underlie verbal working memory in both bipolar patients and healthy controls. In total, 18 euthymic bipolar patients and 18 healthy controls performed a modified version of the Sternberg item-recognition (working memory) task. We used the psychophysiological interaction approach in order to assess functional connectivity between the right amygdala and the brain regions involved in verbal working memory. In healthy subjects, we found significant negative functional interactions between the right amygdala and multiple cortical brain areas involved in verbal working memory. In comparison with the healthy control subjects, bipolar patients exhibited significantly reduced functional interactions of the right amygdala particularly with the right-hemispheric, i.e., ipsilateral, cortical regions supporting verbal working memory. Together with our previous finding of amygdala hyperactivity in bipolar patients during verbal rehearsal, the present results suggest that a disturbed right-hemispheric 'cognitive-emotional' interaction between the amygdala and cortical brain regions underlying working memory may be responsible for amygdala hyperactivation and affects verbal working memory (deficits) in bipolar patients. [ABSTRACT FROM AUTHOR]

Objectives Copy number variants ( CNVs) have been shown to affect susceptibility for neuropsychiatric disorders. To date, studies implicating the serotonergic system in complex conditions have just focused on single nucleotide polymorphisms ( SNPs). We therefore sought to identify novel common genetic copy number polymorphisms affecting genes of the serotonergic system, and to assess their putative role in bipolar affective disorder ( BPAD) and major depressive disorder ( MDD). Methods A selection of 41 genes of the serotonergic system encoding receptors, the serotonin transporter, metabolic enzymes and chaperones were investigated using a paired-end mapping ( PEM) approach on next-generation sequencing data from the pilot project of the 1000 Genomes Project. For association testing, 593 patients with MDD, 1,145 patients with BPAD, and 1,738 healthy controls were included in the study. Results PEM led to the identification of a microdeletion in the gene encoding tryptophan hydroxylase 2 ( TPH2), affecting an amygdala- and hippocampus-specific isoform. It was not associated with BPAD or MDD using a case-control association approach. Conclusions We did not find evidence for a role of the TPH2 microdeletion in the pathoetiology of affective disorders. Further studies examining its putative role in behavioral traits regulated by the limbic system are warranted. [ABSTRACT FROM AUTHOR]

Background: Disruption of the circadian rhythm is a key feature of bipolar disorder. Variation in genes encoding components of the molecular circadian clock has been associated with increased risk of the disorder in clinical populations. Similarly in animal models, disruption of the circadian clock can result in altered mood and anxiety which resemble features of human mania; including hyperactivity, reduced anxiety and reduced depression-like behaviour. One such mutant, after hours (Afh), an ENU-derived mutant with a mutation in a recently identified circadian clock gene Fbxl3, results in a disturbed (long) circadian rhythm of approximately 27 hours. Methodology: Anxiety, exploratory and depression-like behaviours were evaluated in Afh mice using the open-field, elevated plus maze, light-dark box, holeboard and forced swim test. To further validate findings for human mania, polymorphisms in the human homologue of FBXL3, genotyped by three genome wide case control studies, were tested for association with bipolar disorder. Principal Findings: Afh mice showed reduced anxiety- and depression-like behaviour in all of the behavioural tests employed, and some evidence of increased locomotor activity in some tests. An analysis of three separate human data sets revealed a gene wide association between variation in FBXL3 and bipolar disorder (P = 0.009). Conclusions: Our results are consistent with previous studies of mutants with extended circadian periods and suggest that disruption of FBXL3 is associated with mania-like behaviours in both mice and humans. [ABSTRACT FROM AUTHOR]

Abstract: The G72/G30 gene is one of the common loci shared both by schizophrenia and bipolar disorder. Studies accumulating since the discovery of this gene complex produced controversial results in both disorders in different populations. Objective: We investigated the association between the G72/G30 gene and bipolar I disorder (BPI) in the Romanian population paying special attention to the association of G72/G30 with lifetime psychosis and in particular with persecutory delusions in BPI patients. Method: Fourteen G72/G30-SNPs were genotyped in a Romanian sample of 198 BPI patients and 180 controls screened for psychiatric disorders. Statistical analysis was performed with FAMHAP and HAPLOVIEW-v3.32. The significance level of the results was corrected through permutations in 100,000 simulations. Results: None of the fourteen SNPs was associated with the global diagnosis of BPI in our total patient sample or with the psychotic BPI subtype. When confining the psychotic phenotype to persecutory delusions, we observed trends to association for SNPs previously associated with schizophrenia and persecutory delusions in BPI [M21 (P =0.080); M22 (P =0.092; P =0.042 under dominant transmission model); M24 (P =0.092)]. Four SNPs reached nominal significance in the non-psychotic BPI subgroup [rs3916965 (M12) (P =0.044), rs1935057 (P =0.037), rs3916967 (M14) (P =0.043), and rs2391191 (M15, non-synonymous) (P =0.043)]. After correction through permutations, the haploblock GA including M14 and M15 showed a trend to association with BPI (P =0.0524; OR=1.82) in the non-psychotic BPI subgroup. Conclusion: We report a potential association of different G72/G30-SNPs with non-psychotic mood episodes and with persecutory delusions in BPI Romanian patients. The results represent a first partial replication of two studies: Williams et al. (2006) and Schulze et al. (2005). The results have just a suggestive value since the Bonferroni correction for multiple testing was not applied. [Copyright &y& Elsevier]

The major mood disorders, which include bipolar disorder and major depressive disorder (MDD), are considered heritable traits, although previous genetic association studies have had limited success in robustly identifying risk loci. We performed a meta-analysis of five case-control cohorts for major mood disorder, including over 13,600 individuals genotyped on high-density SNP arrays. We identified SNPs at 3p21.1 associated with major mood disorders (rs2251219, P = 3.63 × 10−8; odds ratio = 0.87; 95% confidence interval, 0.83–0.92), with supportive evidence for association observed in two out of three independent replication cohorts. These results provide an example of a shared genetic susceptibility locus for bipolar disorder and MDD. [ABSTRACT FROM AUTHOR]

Objective: The majority of research into functional psychosis has proceeded under the assumption that schizophrenia and bipolar disorder are distinct entities with separate underlying disease processes and treatments. This view has been increasingly challenged in both clinical and genetic studies. Findings in recent association studies at two specific genes suggest that the occurrence of mood-incongruent psychotic features may indicate a relatively homogeneous subset of the bipolar phenotype. We examined this hypothesis. Methods: Caucasian affected individuals were ascertained from Europe (the United Kingdom, the Republic of Ireland, Germany, Italy and Andalusia). Consensus best-estimate diagnoses were assigned by two independent raters according to all available information. There was no cross-site evaluation of inter-rater reliability. Families multiply affected by bipolar spectrum mood disorder were selected, comprising 383 affected relative pairs. Individuals were considered to be affected if they were diagnosed with DSM-IV bipolar I disorder or schizoaffective disorder, bipolar type. Multipoint, affected relative pair covariate linkage analysis was performed. Results: Significant familiality of incongruent psychosis was observed [intra-class correlation coefficient (ICC) = 0.309; p = 0.001, one-tail]. Covariate linkage analysis provided three regions with genome-wide suggestive evidence for linkage on chromosomes 1q32.3 (LOD = 4.15, expected 0.12 times per genome scan), 7p13 (LOD = 3.32) and 20q13.31 (LOD = 2.98). No region in our analysis met criteria for genome-wide significance. Conclusion: Our results provide molecular support for the hypothesis that genes may exist for specific forms of bipolar illness, dependent on the presence or absence of incongruent psychosis. Our findings suggest that researchers should take account of mood-congruence/incongruence of psychotic features in studies of bipolar disorder. [ABSTRACT FROM AUTHOR]

Background: Blunting of prolactin response after serotonergic stimulation during a major depressive episode has been described by several investigators. In this study, the neuroendocrine responses to clomipramine were assessed in remitted patients suffering from hereditary depression. Methods: Twenty remitted patients from 11 large families with multigenerational, multiple cases of major affective disorder (bipolar disorder n=15, recurrent depression n=5, according DSM-IV) and 12 healthy relatives were investigated. After intravenous application of 12.5 mg of the serotonin re-uptake inhibitor clomipramine, serum prolactin and cortisol levels were analysed. Results: Patients and comparison group did not differ significantly with respect to age, baseline prolactin and cortisol concentrations. A gender effect was found in an exploratory analysis for prolactin but not for cortisol and therefore the data for prolactin were analysed seperately. After clomipramine infusion, the increase of cortisol was significantly lower in patients than in the comparison group (P=.046). For prolactin, this effect could be found in the male (P=.012) as well as in the female (P=.007) subsample. Conclusions: These results suggest that blunted prolactin and cortisol responses to serotonergic stimulation are characteristic for remitted depressive patients with previous episodes of major affective disorders. Depression and Anxiety, 2009. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: G72 is a vulnerability gene for schizophrenia and affective psychosis, disorders that are characterized by deficits in working memory. In the present study we investigated whether the G72 genotype influences verbal and spatial working memory functions in healthy individuals. Working memory was assessed at the behavioural level in 423 subjects using the spatial span of the Wechsler Memory Scale (spatial working memory) and the letter–number-span test (verbal working memory). In a sub-sample of 83 subjects, we assessed working memory functions also at the neural level using functional magnetic resonance imaging during a classical letter variant of the n-back task. Unexpectedly the high risk allele carriers performed better in the verbal working memory task than the other subjects. These behavioural differences were accompanied by brain activation differences in the right parahippocampus, a brain region that plays a major role in schizophrenia and affective disorders. The high risk variant of a vulnerability gene therefore does not necessarily have to negatively affect cognitive abilities per se, but may even have beneficial effects on cognitive functions in the non-affected population. [Copyright &y& Elsevier]

Background: Previous genetic studies investigating a possible involvement of variations at the brain derived neurotrophic factor (BDNF) gene locus in major depressive disorder (MDD), bipolar affective disorder (BPAD), and schizophrenia have provided inconsistent results. Methods: We performed single-marker and haplotype analyses using three BDNF polymorphisms in 2,376 individuals (465 MDD, 281 BPAD, 533 schizophrenia, and 1,097 control subjects). Results: Single-marker analysis did not provide strong evidence for association. Haplotype analysis of marker combination rs988748-(GT)n-rs6265 produced nominally significant associations for all investigated phenotypes (global p values: MDD p = .00006, BPAD p = .0057, schizophrenia p = .016). Association with MDD was the most robust finding and could be replicated in a second German sample of MDD patients and control subjects (p = .0092, uncorrected). Stratification of our schizophrenia sample according to the presence or absence of a lifetime history of depressive symptoms showed that our finding in schizophrenia might be attributable mainly to the presence of depressive symptoms. Conclusions: Association studies of genetic variants of the BDNF gene with various psychiatric disorders have been published with reports of associations and nonreplications. Our findings suggest that BDNF may be a susceptibility gene for MDD and schizophrenia—in particular, in a subgroup of patients with schizophrenia with a lifetime history of depressive symptoms. [Copyright &y& Elsevier]

Schizophrenia and affective disorder have been considered to be nosologically and etiologically distinct disorders. This postulate is challenged by progress in new biological research. Both disorders are strongly influenced by genetic factors; thus genetic research is a main contributor to this discussion. We review current evidence of the genetic relationship between schizophrenia and affective disorders, mainly bipolar disorder (the various genetic research methods have been particularly applied to bipolar disorder). Recent family and twin studies reveal a growing consistency in demonstrating cosegregation between both disorders which is difficult to detect with certainty given the low base rates. Systematic molecular genetic search for specific genes impacting on either disorder has now identified one gene which is apparently involved in both disorders (G72/G30); other candidate genes reveal some evidence to present as susceptibility genes with very modest effects for each of both disorders, although not consistently so (e. g., COMT, BDNF). There is room for speculation about other common susceptibility genes, given the overlap between candidate regions for schizophrenia and those for bipolar disorder emerging from linkage studies. [ABSTRACT FROM AUTHOR]

Summary: The stress response is mediated by a negative feedback effect of glucocorticoids on corticosteroid receptors. Here, we examine the potential contribution of these receptors and their response to a glucocorticoid challenge to dysfunctions of the hypothalamic–pituitary–adrenal axis reported for patients with affective disorders. In a pilot-study, we established B-lymphoblastoid cell lines from patients suffering from affective disorders and healthy subjects and measured the quantity of glucocorticoid receptors at steady state conditions after 12-weeks cell culture. After short-term incubation with 0.1μM hydrocortisone for 48h, the decrease of glucocorticoid receptors was also investigated. After 12-weeks cell culture, we found a significantly higher number of cytosolic glucocorticoid receptors in B-lymphoblastoids from patients (B max=804.9±342.5fmol/mg protein) compared to those from healthy subjects (B max=576.9±190.3fmol/mg protein: p=0.045; t-test). The increase of the glucocorticoid receptor level in the group of patients could be attributed largely to the higher number of these receptors measured in B-lymphoblastoids of patients suffering from major depressive disorder. The in vitro regulation of glucocorticoid receptors in response to 0.1μM hydrocortisone for 48h resulted in a significantly larger decrease in cultures of B-lymphoblastoids derived from patients (to 32.9±7.5%) than in those from healthy subjects (to 45.8±8.2%). The stronger decrease of glucocorticoid receptors in the group of patients (p=0.0001; t-test) was independent of the duration of illness and medication, suggesting a trait-like characteristic of the response. [Copyright &y& Elsevier]

Background: Several lines of evidence indicate that abnormalities in the functioning of the central serotonergic system are involved in the pathogenesis of affective illness. A 44-base-pair insertion/deletion polymorphism in the 5′ regulatory region of the serotonin transporter gene (5-HTTLPR), which influences expression of the serotonin transporter, has been the focus of intensive research since an initial report on an association between 5-HTTLPR and depression-related personality traits. Consistently replicated evidence for an involvement of this polymorphism in the etiology of mood disorders, particularly in major depressive disorder (MDD), remains scant. Methods: We assessed a potential association between 5-HTTLPR and MDD, using the largest reported sample to date (466 patients, 836 control subjects). Individuals were all of German descent. Patients were systematically recruited from consecutive inpatient admissions. Control subjects were drawn from random lists of the local Census Bureau and screened for psychiatric disorders. Results: The short allele of 5-HTTLPR was significantly more frequent in patients than in control subjects (45.5% vs. 39.9%; p = .006; odds ratio = 1.26). Conclusions: These results support an involvement of 5-HTTLPR in the etiology of MDD. They also demonstrate that the detection of small genetic effects requires very large and homogenous samples. [Copyright &y& Elsevier]

Abstract: Demographical and clinical characteristics have been reported to modulate the risk for suicide. This study analysed demographical and clinical characteristics with respect to lifetime suicide attempts in 500 individuals affected with schizophrenic or affective disorders. Suicide attempts were associated with poor premorbid social adjustment, low age at onset, low scores on the “Global Assessment Scale” and childlessness in females. [Copyright &y& Elsevier]

We previously reported an association of DRD4 exon 3 long alleles with delusional symptomatology, independently from psychiatric diagnoses [Am. J. Med. Genet. 105 (2001) 283; Psychiatry Res. 80 (1998) 129]. The aim of this investigation was to replicate these results in an independent sample from Germany. We studied 394 subjects, affected by bipolar disorder (n = 32), schizoaffective disorder (n = 45), and schizophrenia (n = 317). All affected subjects were evaluated using the Operational Criteria for Psychotic Illness (OPCRIT) checklist. DRD4 variants were not associated with symptomatology of major psychosis. Our present results, obtained in an independent German sample, did not confirm the association between DRD4 variants and delusional symptomatology. However it should be considered that the original sample included a much higher rate of mood disorders and this could partially explain the discrepancy. [Copyright &y& Elsevier]

The available data from preclinical and pharmacological studies on the role of the serotonin transporter (5-HTT) support the hypothesis that a dysfunction in brain serotonergic system activity contributes to the vulnerability to affective disorders (AD). 5-HTT is the major site of serotonin reuptake into the presynaptic neuron, and it has been shown that the polymorphic repeat polymorphism in the 5-HTT promotor region (5-HTTLPR) may affect gene-transcription activity. 5-HTT maps to chromosome 17 at position 17q11.17-q12, and the 5-HTTLPR polymorphisms have been extensively investigated in AD with conflicting results. The present study tested the genetic contribution of the 5-HTTLPR polymorphism in a large European multicenter case-control sample, including 539 unipolar (UPAD), 572 bipolar patients (BPAD), and 821 controls (C). Our European collaboration has led to efforts to optimize a methodology that attenuates some of the major limitations of the case-control association approach. No association was found with primary psychiatric diagnosis (UPAD and BPAD) and with phenotypic traits (family history of AD, suicidal attempt, and presence of psychotic features). Our negative findings are not attributable to the lack of statistical power, and may contribute to clarify the role of 5-HTTLPR polymorphism in AD.European Journal of Human Genetics (2004) 12, 377-382. doi:10.1038/sj.ejhg.5201149 Published online 21 January 2004 [ABSTRACT FROM AUTHOR]

The paper reports the first controlled family study investigating not only 1st but also 2nd and 3rd degree relatives of patients with schizophrenia by direct diagnostic interviews. Regardless of their degree of relationship, all biological relatives of the patients were found to be at an elevated risk of schizophrenia (5.0% in 1st, 3.1% in 2nd, 1.5% in 3rd degree relatives compared to 0.8% among controls). Schizoaffective and affective disorders have also been found to be more common in the three groups of relatives but without a monotone decline of prevalence rates across the groups. Other psychiatric disorders were not found to be at an elevated risk in relatives of patients compared to controls. Thus, our findings support the hypothesis that psychotic, as well as affective disorders, aggregate in families of individuals with schizophrenia.However, in our study, the risk of schizophrenia and the risk of affective disorders correlated. Particularly, the magnitude of the risk of schizophrenia among relatives of probands with schizophrenia varied with the occurrence of affective disorders in relatives. In relatives, the risk of schizophrenia was maximal in absence of a family history of affective disorder. This constellation holds true even if only families of index cases without any affective syndrome during lifetime are considered. [Copyright &y& Elsevier]

Highlights from the article: Longitudinal studies with phenotypes beyond mere diagnoses might help to biologically and clinically stratify patients. At the time of abstract submission, the sample consisted of 1,047 adult patients with a DSM-IV lifetime diagnosis of schizophrenia (SZ), schizophreniform disorder (SZF), brief psychotic disorder (BPD), schizoaffective disorder (SZA), bipolar disorder (BD), or recurrent major depression (rMDD), as well as 288 control participants. 54% of the clinical participants have a lifetime diagnosis of a predominantly psychotic disorder; 46 % have a lifetime diagnosis of a predominantly affective disorder.

A response to a letter to the editor about an article on the replication of Association of 3p21.1 with Susceptibility to Bipolar Disorder but not Major Depression" in the previous is presented.

Objective: Family and twin studies suggest that liability for suicide attempts is heritable and distinct from mood disorder susceptibility. The authors therefore examined the association between common genomewide variation and lifetime suicide attempts. Method: The authors analyzed data on lifetime suicide attempts from genomewide association studies of bipolar I and II disorder as well as major depressive disorder. Bipolar disorder subjects were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder cohort, the Wellcome Trust Case Control Consortium bipolar cohort, and the University College London cohort. Replication was pursued in the NIMH Genetic Association Information Network bipolar disorder project and a German clinical cohort. Depression subjects were drawn from the Sequential Treatment Alternatives to Relieve Depression cohort, with replication in the Netherlands Study of Depression and Anxiety/Netherlands Twin Register depression cohort. Results: Strongest evidence of association for suicide attempt in bipolar disorder was observed in a region without identified genes (rs1466846); five loci also showed suggestive evidence of association. In major depression, strongest evidence of association was observed for a single nucleotide polymorphism in ABI3BP, with six loci also showing suggestive association. Replication cohorts did not provide further support for these loci. However, meta-analysis incorporating approximately 8,700 mood disorder subjects identified four additional regions that met the threshold for suggestive association, including the locus containing the gene coding for protein kinase C-epsilon, previously implicated in models of mood and anxiety. Conclusions: The results suggest that inherited risk for suicide among mood disorder patients is unlikely to be the result of individual common variants of large effect. They nonetheless provide suggestive evidence for multiple loci, which merit further investigation. [ABSTRACT FROM AUTHOR]