The protocadherin 17 gene affects cognition, personality, amygdala structure and function, synapse development and risk of major mood disorders.

Major mood disorders, which primarily include bipolar disorder and major depressive disorder, are the leading cause of disability worldwide and pose a major challenge in identifying robust risk genes. Here, we present data from independent large-scale clinical data sets (including 29 557 cases and 32 056 controls) revealing brain expressed protocadherin 17 (PCDH17) as a susceptibility gene for major mood disorders. Single-nucleotide polymorphisms (SNPs) spanning the PCDH17 region are significantly associated with major mood disorders; subjects carrying the risk allele showed impaired cognitive abilities, increased vulnerable personality features, decreased amygdala volume and altered amygdala function as compared with non-carriers. The risk allele predicted higher transcriptional levels of PCDH17 mRNA in postmortem brain samples, which is consistent with increased gene expression in patients with bipolar disorder compared with healthy subjects. Further, overexpression of PCDH17 in primary cortical neurons revealed significantly decreased spine density and abnormal dendritic morphology compared with control groups, which again is consistent with the clinical observations of reduced numbers of dendritic spines in the brains of patients with major mood disorders. Given that synaptic spines are dynamic structures which regulate neuronal plasticity and have crucial roles in myriad brain functions, this study reveals a potential underlying biological mechanism of a novel risk gene for major mood disorders involved in synaptic function and related intermediate phenotypes.

The cAMP responsive element-binding (CREB)-1 gene increases risk of major psychiatric disorders.

Bipolar disorder (BPD), schizophrenia (SCZ) and unipolar major depressive disorder (MDD) are primary psychiatric disorders sharing substantial genetic risk factors. We previously reported that two single-nucleotide polymorphisms (SNPs) rs2709370 and rs6785 in the cAMP responsive element-binding (CREB)-1 gene (CREB1) were associated with the risk of BPD and abnormal hippocampal function in populations of European ancestry. In the present study, we further expanded our analyses of rs2709370 and rs6785 in multiple BPD, SCZ and MDD data sets, including the published Psychiatric Genomics Consortium (PGC) genome-wide association study, the samples used in our previous CREB1 study, and six additional cohorts (three new BPD samples, two new SCZ samples and one new MDD sample). Although the associations of both CREB1 SNPs with each illness were not replicated in the new cohorts (BPD analysis in 871 cases and 1089 controls (rs2709370, P=0.0611; rs6785, P=0.0544); SCZ analysis in 1273 cases and 1072 controls (rs2709370, P=0.230; rs6785, P=0.661); and MDD analysis in 129 cases and 100 controls (rs2709370, P=0.114; rs6785, P=0.188)), an overall meta-analysis of all included samples suggested that both SNPs were significantly associated with increased risk of BPD (11 105 cases and 51 331 controls; rs2709370, P=2.33 × 10-4; rs6785, P=6.33 × 10-5), SCZ (34 913 cases and 44 528 controls; rs2709370, P=3.96 × 10-5; rs6785, P=2.44 × 10-5) and MDD (9369 cases and 9619 controls; rs2709370, P=0.0144; rs6785, P=0.0314), with the same direction of allelic effects across diagnostic categories. We then examined the impact of diagnostic status on CREB1 mRNA expression using data obtained from independent brain tissue samples, and observed that the mRNA expression of CREB1 was significantly downregulated in psychiatric patients compared with healthy controls. The protein-protein interaction analyses showed that the protein encoded by CREB1 directly interacted with several risk genes of psychiatric disorders identified by GWAS. In conclusion, the current study suggests that CREB1 might be a common risk gene for major psychiatric disorders, and further investigations are necessary.

Replication of functional serotonin receptor type 3A and B variants in bipolar affective disorder: a European multicenter study.

Serotonin type 3 receptors (5-HT(3)) are involved in learning, cognition and emotion, and have been implicated in various psychiatric phenotypes. However, their contribution to the pathomechanism of these disorders remains elusive. Three single nucleotide polymorphisms (SNPs) in the HTR3A and HTR3B genes (rs1062613, rs1176744 and rs3831455) have been associated with bipolar affective disorder (BPAD) in pilot studies, and all of them are of functional relevance. We performed a European multicenter study to confirm previous results and provide further evidence for the relevance of these SNPs to the etiology of neuropsychiatric disorders. This involved analysis of the distribution of the three SNPs among 1804 BPAD cases and 2407 healthy controls. A meta-analysis revealed a pooled odds ratio of 0.881 (P = 0.009, 95% confidence intervals = 0.802-0.968) for the non-synonymous functional SNP HTR3B p.Y129S (rs1176744), thereby confirming previous findings. In line with this, the three genome-wide association study samples BOMA (Bonn-Mannheim)-BPAD, WTCCC (Wellcome Trust Case Control Consortium)-BPAD and GAIN (Genetic Association Information Network)-BPAD, including >3500 patients and 5200 controls in total, showed an overrepresentation of the p.Y129 in patients. Remarkably, the meta-analysis revealed a P-value of 0.048 (OR = 0.934, fixed effect model). We also performed expression analyses to gain further insights into the distribution of HTR3A and HTR3B mRNA in the human brain. HTR3A and HTR3B were detected in all investigated brain tissues with the exception of the cerebellum, and large differences in the A:B subunit ratio were observed. Interestingly, expression of the B subunit was most prominent in the brain stem, amygdalae and frontal cortex, regions of relevance to psychiatric disorders. In conclusion, the present study provides further evidence for the presence of impaired 5-HT(3) receptor function in BPAD.

Genome-wide survey implicates the influence of copy number variants (CNVs) in the development of early-onset bipolar disorder.

We used genome-wide single nucleotide polymorphism (SNP) data to search for the presence of copy number variants (CNVs) in 882 patients with bipolar disorder (BD) and 872 population-based controls. A total of 291 (33%) patients had an early age-at-onset < or =21 years (AO < or =21 years). We systematically filtered for CNVs that cover at least 30 consecutive SNPs and which directly affect at least one RefSeq gene. We tested whether (a) the genome-wide burden of these filtered CNVs differed between patients and controls and whether (b) the frequency of specific CNVs differed between patients and controls. Genome-wide burden analyses revealed that the frequency and size of CNVs did not differ substantially between the total samples of BD patients and controls. However, separate analysis of patients with AO < or =21 years and AO>21 years showed that the frequency of microduplications was significantly higher (P=0.0004) and the average size of singleton microdeletions was significantly larger (P=0.0056) in patients with AO < or =21 years compared with controls. A search for specific BD-associated CNVs identified two common CNVs: (a) a 160 kb microduplication on 10q11 was overrepresented in AO < or = 21 years patients (9.62%) compared with controls (3.67%, P=0.0005) and (b) a 248 kb microduplication on 6q27 was overrepresented in the AO< or = 21 years subgroup (5.84%) compared with controls (2.52%, P=0.0039). These data suggest that CNVs have an influence on the development of early-onset, but not later-onset BD. Our study provides further support for previous hypotheses of an etiological difference between early-onset and later-onset BD.

Different familial transmission patterns in bipolar I disorder with onset before and after age 25.

Gene identification in common disorders such as Alzheimer disease and breast cancer has greatly profited from the use of age of onset as criterion to delineate subgroups of disease characterized by different inheritance patterns. In bipolar affective disorder, where the majority of linkage studies have produced conflicting results, studies reporting clinical characteristics and familial occurrence of disease have suggested that age of onset might serve as an indicator for identifying more homogeneous subgroups of disease. Our study was the first to examine this hypothesis by the means of segregation analysis. We investigated a sample of 177 bipolar I probands recruited from consecutive admissions and their first- and second-degree relatives (2,407 subjects). Probands were subdivided into an early-onset (n = 107) and a late-onset group (n = 70) using an age of onset of 25 as a cut-off point. This age was chosen because the observed age of onset distribution was bimodal with a cut-off of 25 years. Morbid risks for affective disorder were found significantly higher (P = 0.01) in relatives of probands with an early onset than in probands with late onset of disease. The segregation analysis showed that the disease is transmitted differently in early- and late-onset groups. In the early-onset group, a non-Mendelian major gene with a polygenic component was favored while the data in the late-onset group were compatible with a multifactorial model. This result may have important implications for future molecular studies aiming at the identification of disease-associated genes.

A transcultural outcome study of adolescent eating disorders.

OBJECTIVE: The aim of the study was to assess the treatment and outcome of adolescent eating disorders in an international study including Western and Eastern European clinical and research centres. METHOD: A total of 138 patients with adolescent onset of an eating disorder (primarily anorexia nervosa) were followed-up after a mean interval of 5 years after first admission. RESULTS: On average, the patients had spent 25% of the total follow-up period in either in-patient or out-patient treatment. Half of them required a second hospitalization and a quarter required a third hospitalization for the eating disorder. At follow-up, 68% of the total sample did not have an eating disorder. The prediction of outcome revealed different patterns of risk variables depending on the type of criterion. CONCLUSION: The outcome of adolescent eating disorders is relatively similar across cultures, and better than in patients with later onset of the disorder.

Patterns of parental transmission and familial aggregation models in bipolar affective disorder.

Two recent studies [McMahon et al., 1995: Am J Hum Genet 56:1277-1286; Gershon et al., 1996: Am J Med Genet (Neuropsychiatr Genet) 67:202-207] reported an excess of maternal transmission in bipolar affective disorder in multiply affected families. In a sample of 130 families ascertained through a bipolar proband without regard to psychiatric family history we analysed the frequency of maternal (MAT) and paternal (PAT) transmissions, the morbid risk (MR) in relatives of transmitting mothers and fathers and the inheritance patterns in families with MAT vs. PAT transmission of the disease. In the total sample of 130 families we identified 39 families where the disease was transmitted from the paternal side (PAT families) and 35 families where the disease was transmitted from the maternal side (MAT families). Counting PAT and MAT transmissions in these unilineal families we found nearly equal numbers for both transmission types under a narrow (BP: bipolar disorder, schizoaffective-bipolar type disorder) and a broad definition (AFF: BP, recurrent unipolar depression) of the phenotype. The MRs for narrow and broad phenotypes were not significantly different in any type of PAT relative in PAT families vs. MAT relatives in MAT families. However, in PAT families there were two times more affected females than males with both disease models, while in MAT families there was no MR difference by relatives' sex. The transmission of BP was compatible with the Mendelian major gene model in PAT families and with the multifactorial model in MAT families. Extension of the relatives' phenotype led to borderline non-Mendelian major effects in PAT families and reproduced the multifactorial model in MAT families.

Genetic anticipation and imprinting in bipolar I illness.

BACKGROUND: The study focused on: (1) the existence of genetic anticipation in a randomly selected sample of bipolar I patients using broad and narrow definitions of the affection status in the parental generation; (2) the relationship between anticipation and the age at investigation in probands and in their relatives; (3) the relationship between anticipation and imprinting. METHOD: One hundred and fifteen bipolar I patients and their first- to third-degree relatives were diagnosed according to DSM-III-R criteria using the Diagnostic Interview for Genetic Studies and the Family Interview for Genetic Studies. RESULTS: Age at onset was found to be 6-10 years younger in probands with affected parents or uncles/aunts. Two-thirds of these families showed positive anticipation under both the broad and the narrow definitions of affection status in the parents' generation. The age at investigation was younger in probands showing positive anticipation. Anticipation was found only in probands inheriting the disorder from the paternal side. CONCLUSIONS: In spite of the inevitable association between young current age and young age at onset, which could result in spurious anticipation effects, our findings suggest that this phenomenon is not the sole cause of observed anticipation.

Clinical evidence for genomic imprinting in bipolar I disorder.

The phenotypic indicators of the genomic imprinting model were applied to clinical psychopathology data on 100 bipolar (BP) I probands and their families. The paternal transmission was associated with a significantly younger age of onset of the BP illness in probands and a higher rate of affective disorders in first- and second-degree relatives. The effect of the sex of the transmitting parent on age of onset in probands decreased but remained significant when controlling for the effect of the probands' age at investigation. Probands' sex had no significant influence on their age of onset. The severity of the BP illness in probands in terms of number of illness episodes and annual frequency was not influenced by the sex of the transmitting parent.

A trial to apply the concept of genomic imprinting to the manic-depressive illness.

The phenotypic indicators of genomic imprinting were applied to the familial psychopathology data collected through the family history method about 886 adult relatives of 65 manic-depressive probands directly investigated. The probands and their relatives were diagnosed according to DSM-III/DSM-III-R criteria. A first analysis of the age at onset of the BP illness by affective status of the probands' parents suggested that the BP disorder begins about 8 years earlier in the probands whose father was affectively ill (13.84% cases) than in the probands whose mother was affectively ill (24.6% cases) (t = -3.29, P < .004). When controlling this result for the effect of the probands' sex, its statistical significance decreased. The severity of the BP illness seemed also to be influenced by the affective status of the probands' father but only when assessing the probands' illness severity over a long time period and taking into account their psychosocial functioning; the number of manic and depressive hospitalized and non-hospitalized episodes as a single measure of the BP disorder severity as well as the morbidity risk in the first degree relatives of the probands did not significantly differentiate the patients whose disorder was transmitted by the father/paternal side as compared with the patients who inherited the BP disorder from the mother/maternal side.

Adolescent offspring of endogenous unipolar depressive parents and of normal parents.

Ninety-six children aged 10-17 of unipolar endogenous depressive proband parents and 96 matched control children of well parents were investigated using DSM-IIIR diagnostic criteria. Both sets of parents were also studied. Although the rate of psychopathology was significantly higher in proband than in control children, adaptive functioning as a measure of the severity of the psychopathology did not differentiate the two groups of children. Among factors related to the mental status of the children were: severity and onset under 30 years of age of the parental depression and lifelong association of parental anxiety with depression. Personality measurements performed in children showed different personality structures in proband offspring. Data on adolescent psychopathology and personality showed little evidence of a homotypic relationship with the adult affective disorders.

Depressive disorders and depressive personality traits in offspring aged 10-17 of bipolar and of normal parents.

Sixty proband children (P) of bipolar I parents and 60 control children of normal parents (C), in the age range 10-17, were investigated clinically by K-SADS-E interview and psychologically by personality inventories. In the global psychopathology rate of 63% in P children and 25% in C children, depressive disorders reached 8% in P children and 0% in C children, while depressive personality traits reached 22% in P children and 15% in C children. Cluster analysis evidenced a variety of personality structures, but 3 clusters were striking: a cluster characterized by high anxiety and depressive reactivity (17% P and 5% C children), a cluster characterized by high depressive reactivity and emotional instability (5% P children), and a hyperthymic cluster (5 % P children). Sixty-seven percent of P children and 36% of C children showed deviant personality traits (p<.01).

Children aged 10-17 of endogenous unipolar depressive parents and of normal parents. I. Psychopathology rate and relationship of the severity of the psychopathology to familial and environmental variables.

Seventy two children aged 10-17 of 42 endogenous unipolar depressive parents (proband children) and 72 children aged 10-17 of 66 normal parental couples (control children) were studied. Overall rate of psychopathology (disorders present at the time of investigation and one year before) reached 51% in proband children and 29% in control children. Depressive disorder rate reached 10% in proband children and 4% in control children. The sex of the depressive parent did not influence the psychopathology rate in offspring, while the early age of onset of the illness (under 30 years) in parent increased the psychopathology risk in children. The severity of the psychopathology in children defined as functional impairment was significantly dependent on the severity of the depressive illness in proband parent, the presence of psychopathology in the spouse of the depressive parent, the presence of psychopathology in the relatives of both parents, the socio-cultural level of the family and the violence expressed in the familial atmosphere.

A rating scale for the severity of psychopathology in children.

The Scale for Assessing Severity of the Psychopathology in Children (SSPC) is intended to measure the overall psychosocial impairment caused to children and adolescents by psychic disorders. The scale contains 3 items (number of impaired areas of psychosocial functioning and duration of the modifications of child's behaviour; decrease of school performances below the expected level according to IQ; subjective distress caused by the psychic disorder either to the child or to the family leading to call for medical help) defining a single dimension. Each item is scaled on four degrees of impairment and described behaviourally in a detailed way. The total score summed over the 3 items corresponds to four levels of severity of the psychopathology. Interrater reliability, sensitivity to change and concurrent validity of the SSPC are examined over three studies.

Psychopathology in children aged 10-17 of bipolar parents: psychopathology rate and correlates of the severity of the psychopathology.

Seventy-two proband children aged 10-17 of bipolar parents, matched with 72 control children of normal parents, were investigated using DSM-III diagnostic criteria and multiple sources of information. The psychopathology rate in children (61% in probands versus 25% in controls) was related to the impact of psychic disorders on the children's adaptive functioning. The effect of several variables describing the psychiatric status of both parents and familial environment on the severity of psychopathology in children was analysed. Disordered and non-disordered probands were compared with respect to illness characteristics of their parents, familial environment, personality traits, and IQ by means of canonical discriminant analysis.