Common variant at 16p11.2 conferring risk of psychosis.

Epidemiological and genetic data support the notion that schizophrenia and bipolar disorder share genetic risk factors. In our previous genome-wide association study, meta-analysis and follow-up (totaling as many as 18 206 cases and 42 536 controls), we identified four loci showing genome-wide significant association with schizophrenia. Here we consider a mixed schizophrenia and bipolar disorder (psychosis) phenotype (addition of 7469 bipolar disorder cases, 1535 schizophrenia cases, 333 other psychosis cases, 808 unaffected family members and 46 160 controls). Combined analysis reveals a novel variant at 16p11.2 showing genome-wide significant association (rs4583255[T]; odds ratio=1.08; P=6.6 × 10(-11)). The new variant is located within a 593-kb region that substantially increases risk of psychosis when duplicated. In line with the association of the duplication with reduced body mass index (BMI), rs4583255[T] is also associated with lower BMI (P=0.0039 in the public GIANT consortium data set; P=0.00047 in 22 651 additional Icelanders).

Both low birthweight and high birthweight are associated with cognitive impairment in persons with schizophrenia and their first-degree relatives.

BACKGROUND: Both low birthweight and high birthweight have been associated with an increased risk for schizophrenia and cognitive impairments in the general population. We assessed the association between birthweight and cognitive performance in persons with schizophrenia and their unaffected first-degree relatives. METHOD: We investigated a population-based family sample comprising persons with schizophrenia (n = 142) and their unaffected first-degree relatives (n = 277). Both patients and relatives were interviewed with the Structured Clinical Interview for DSM-IV Axis I Disorders, Clinician Version (SCID-CV) and a comprehensive neuropsychological test battery was administered. Information on birthweight was obtained from obstetric records. We used generalized estimating equation (GEE) models to investigate the effect of birthweight, as a continuous variable, on cognitive functioning, adjusting for within-family correlation and relevant covariates. RESULTS: Both low birthweight and high birthweight were associated with lower performance in visuospatial reasoning, processing speed, set-shifting and verbal and visual working memory among persons with schizophrenia and their unaffected first-degree relatives compared to individuals with birthweight in the intermediate range. The group × birthweight interactions were non-significant. CONCLUSIONS: Both low birthweight and high birthweight are associated with deficits in cognition later in life. Schizophrenia does not seem to modify the relationship between birthweight and cognition in families with schizophrenia.

Copy number variations of chromosome 16p13.1 region associated with schizophrenia.

Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35,079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia.

Expanding the range of ZNF804A variants conferring risk of psychosis.

A trio of genome-wide association studies recently reported sequence variants at three loci to be significantly associated with schizophrenia. No sequence polymorphism had been unequivocally (P<5 × 10(-8)) associated with schizophrenia earlier. However, one variant, rs1344706[T], had come very close. This polymorphism, located in an intron of ZNF804A, was reported to associate with schizophrenia with a P-value of 1.6 × 10(-7), and with psychosis (schizophrenia plus bipolar disorder) with a P-value of 1.0 × 10(-8). In this study, using 5164 schizophrenia cases and 20,709 controls, we replicated the association with schizophrenia (odds ratio OR = 1.08, P = 0.0029) and, by adding bipolar disorder patients, we also confirmed the association with psychosis (added N = 609, OR = 1.09, P = 0.00065). Furthermore, as it has been proposed that variants such as rs1344706[T]-common and with low relative risk-may also serve to identify regions harboring less common, higher-risk susceptibility alleles, we searched ZNF804A for large copy number variants (CNVs) in 4235 psychosis patients, 1173 patients with other psychiatric disorders and 39,481 controls. We identified two CNVs including at least part of ZNF804A in psychosis patients and no ZNF804A CNVs in controls (P = 0.013 for association with psychosis). In addition, we found a ZNF804A CNV in an anxiety patient (P = 0.0016 for association with the larger set of psychiatric disorders).

Proton MRS in twin pairs discordant for schizophrenia.

Proton magnetic resonance spectroscopy ((1)H MRS) neurometabolite abnormalities have been detected widely in subjects with and at risk for schizophrenia. We hypothesized that such abnormalities would be present both in patients with schizophrenia and in their unaffected twin siblings. We acquired magnetic resonance spectra (TR/TE=3000/30 ms) at voxels in the mesial prefrontal gray matter, left prefrontal white matter and left hippocampus in 14 twin pairs discordant for schizophrenia (2 monozygotic, 12 dizygotic), 13 healthy twin pairs (4 monozygotic, 9 dizygotic) and 1 additional unaffected co-twin of a schizophrenia proband. In the mesial prefrontal gray matter voxel, N-acetylaspartate (NAA), creatine+phosphocreatine (Cr), glycerophosphocholine+phosphocholine (Cho) and myo-inositol (mI) did not differ significantly between patients with schizophrenia, their unaffected co-twins or healthy controls. However, glutamate (Glu) was significantly lower in patients with schizophrenia (31%, percent difference) and unaffected co-twins (21%) than in healthy controls (collapsed across twin pairs). In the left hippocampus voxel, levels of NAA (23%), Cr (22%) and Cho (36%) were higher in schizophrenia patients compared with controls. Hippocampal NAA (25%), Cr (22%) and Cho (37%) were also significantly higher in patients than in their unaffected co-twins. Region-to-region differences in metabolite levels were also notable within all three diagnosis groups. These findings suggest that (1)H MRS neurometabolite abnormalities are present not only in patients with schizophrenia, but also in their unaffected co-twins. Thus, reduced mesial prefrontal cortical Glu and elevated hippocampal NAA, Cr and Cho may represent trait markers of schizophrenia risk and, when exacerbated, state markers of schizophrenia itself.

The effect of psychiatric co-morbidity on cognitive functioning in a population-based sample of depressed young adults.

BACKGROUND: Psychiatric co-morbidity is often inadequately controlled for in studies on cognitive functioning in depression. Our recent study established no major deficits in cognition among young adults with a history of pure unipolar depression. The present study extends our previous work by examining the effects of psychiatric co-morbidity and other disorder characteristics on depression-related cognitive functioning. METHOD: Performance in verbal and visual short-term memory, verbal long-term memory and learning, attention, processing speed, and executive functioning was compared between a population-based sample aged 21-35 years with a lifetime history of unipolar depressive disorders (n=126) and a random sample of healthy controls derived from the same population (n=71). Cognitive functioning was also compared between the subgroups of pure (n=69) and co-morbid (n=57) depression. RESULTS: The subgroups of pure and co-morbid depression did not differ in any of the cognitive measures assessed. Only mildly compromised verbal learning was found among depressed young adults in total, but no other cognitive deficits occurred. Received treatment was associated with more impaired verbal memory and executive functioning, and younger age at first disorder onset with more impaired executive functioning. CONCLUSIONS: Psychiatric co-morbidity may not aggravate cognitive functioning among depressed young adults. Regardless of co-morbidity, treatment seeking is associated with cognitive deficits, suggesting that these deficits relate to more distress.

DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder.

Disrupted in schizophrenia 1 (DISC1) has been associated with risk of schizophrenia, schizoaffective disorder, bipolar disorder, major depression, autism and Asperger syndrome, but apart from in the original translocation family, true causal variants have yet to be confirmed. Here we report a harmonized association study for DISC1 in European cohorts of schizophrenia and bipolar disorder. We identify regions of significant association, demonstrate allele frequency heterogeneity and provide preliminary evidence for modifying interplay between variants. Whereas no associations survived permutation analysis in the combined data set, significant corrected associations were observed for bipolar disorder at rs1538979 in the Finnish cohorts (uncorrected P=0.00020; corrected P=0.016; odds ratio=2.73+/-95% confidence interval (CI) 1.42-5.27) and at rs821577 in the London cohort (uncorrected P=0.00070; corrected P=0.040; odds ratio=1.64+/-95% CI 1.23-2.19). The rs821577 single nucleotide polymorphism (SNP) showed evidence for increased risk within the combined European cohorts (odds ratio=1.27+/-95% CI 1.07-1.51), even though significant corrected association was not detected (uncorrected P=0.0058; corrected P=0.28). After conditioning the European data set on the two risk alleles, reanalysis revealed a third significant SNP association (uncorrected P=0.00050; corrected P=0.025). This SNP showed evidence for interplay, either increasing or decreasing risk, dependent upon the presence or absence of rs1538979 or rs821577. These findings provide further support for the role of DISC1 in psychiatric illness and demonstrate the presence of locus heterogeneity, with the effect that clinically relevant genetic variants may go undetected by standard analysis of combined cohorts.

Replication of linkage on chromosome 7q22 and association of the regional Reelin gene with working memory in schizophrenia families.

Schizophrenia is a common and complex mental disorder. Hereditary factors are important for its etiology, but despite linkage signals reported to several chromosomal regions in different populations, final identification of predisposing genes has remained a challenge. Utilizing a large family-based schizophrenia study sample from Finland, we have identified several linked loci: 1q32.2-q42, 2q, 4q31, 5q and 7q22. In this study, an independent sample of 352 nuclear schizophrenia families (n=1626) allowed replication of linkage on 7q21-32. In a sample of 245 nuclear families (n=1074) originating from the same geographical region as the families revealing the linkage, SNP and microsatellite association analyses of the four regional candidate genes, GRM3, RELN, SEMA3A and VGF, revealed no significant association to the clinical diagnosis of schizophrenia. Instead, quantifiable trait component analyses with neuropsychological endophenotypes available from 186 nuclear families (n=861) of the sample showed significant association to RELN variants for traits related to verbal (P=0.000003) and visual working memory (P=0.002), memory (P=0.002) and executive functioning (P=0.002). Trait-associated allele-positive subjects scored lower in the tests measuring working memory (P=0.0004-0.0000000004), memory (P=0.02-0.0001) and executive functioning (P=0.001). Our findings suggest that allelic variants of RELN contribute to the endophenotypes of schizophrenia.

Occupational burnout as a predictor of disability pension: a population-based cohort study.

OBJECTIVES: The aim of this study was to investigate whether burnout predicts new disability pension at population level during a follow-up of approximately 4 years. The diagnosis for which the disability pension was granted was also examined in relation to the level of burnout. METHODS: We used a population-based cohort sample (n = 3125) of 30-60-year-old employees from an epidemiological health study, the Health 2000 Study, gathered during 2000-2001 in Finland. The data collection comprised an interview, a clinical health examination including a standardised mental health interview, and a questionnaire including the Maslach Burnout Inventory-General Survey. Disability pensions and their causes until December 2004 were extracted from national pension records. The association between burnout and new disability pension was analysed with logistic regression models adjusted for sociodemographic factors and health at baseline. RESULTS: Altogether 113 persons were granted a new disability pension during the follow-up: 22% of those with severe burnout, 6% of those with mild burnout, and 2% of those with no burnout at baseline. After sociodemographic factors and health were adjusted for, each one-point increase in the overall burnout sum score was related to 49% increase in the odds for a future disability pension. A disability pension was most often granted on the basis of mental and behavioural disorders and diseases of the musculoskeletal system among those with burnout. After adjustments, exhaustion dimension among men and cynicism dimension among a combined group of men and women predicted new disability pensions. CONCLUSION: Burnout predicts permanent work disability and could therefore be used as a risk marker of chronic health-related work stress. To prevent early exit from work life, working conditions and employee burnout should be regularly assessed with the help of occupational health services.

The association between team climate at work and mental health in the Finnish Health 2000 Study.

OBJECTIVES: Depression, anxiety and alcohol use disorders are common mental health problems in the working population. However, the team climate at work related to these disorders has not been studied using standardised interview methods and it is not known whether poor team climate predicts antidepressant use. This study investigated whether team climate at work was associated with DSM-IV depressive, anxiety and alcohol use disorders and subsequent antidepressant medication in a random sample of Finnish employees. METHODS: The nationally representative sample comprised 3347 employees aged 30-64 years. Team climate was measured with a self-assessment scale. Diagnoses of depressive, anxiety and alcohol use disorders were based on the Composite International Diagnostic Interview. Data on the purchase of antidepressant medication in a 3-year follow-up period were collected from a nationwide pharmaceutical register of the Social Insurance Institution. RESULTS: In the risk factor adjusted models, poor team climate at work was significantly associated with depressive disorders (OR 1.61, 95% CI 1.10 to 2.36) but not with alcohol use disorders. The significance of the association between team climate and anxiety disorders disappeared when the model was adjusted for job control and job demands. Poor team climate also predicted antidepressant medication (OR 1.53, 95% CI 1.02 to 2.30). CONCLUSION: A poor team climate at work is associated with depressive disorders and subsequent antidepressant use.

Gene expression changes related to immune processes associate with cognitive endophenotypes of schizophrenia.

Schizophrenia is a heterogeneous disorder characterized by a spectrum of symptoms and many different underlying causes. Thus, instead of using the broad diagnosis, intermediate phenotypes can be used to possibly decrease the underlying complexity of the disorder. Alongside the classical symptoms of delusions and hallucinations, cognitive deficits are a core feature of schizophrenia. To increase our understanding of the biological processes related to these cognitive deficits, we performed a genome-wide gene expression analysis. A battery of 14 neuropsychological tests was administered to 844 individuals from a Finnish familial schizophrenia cohort. We grouped the applied neuropsychological tests into five factors for further analysis. Cognitive endophenotypes, whole blood mRNA, genotype, and medication use data were studied from 47 individuals. Expression level of several RNA probes were significantly associated with cognitive performance. The factor representing Verbal Working Memory was associated with altered expression levels of 11 probes, of which one probe was also associated with a specific sub-measure of this factor (WMS-R Digit span backward). While, the factor Processing speed was related to one probe, which additionally associated among 55 probes with a specific sub-measure of this factor (WAIS-R Digit symbol). Two probes were associated with the measure recognition memory performance. Enrichment analysis of these differentially expressed probes highlighted immunological processes. Our findings are in line with genome-wide genetic discoveries made in schizophrenia, suggesting that immunological processes may be of biological interest for future drug design towards schizophrenia and the cognitive dysfunctions that underlie it.

The factorial structure of the Suicide Intent Scale: a comparative study in clinical samples from 11 European regions.

Although the Suicide Intent Scale (SIS) is a widely used instrument in research on suicidal behavior, comparative research on the latent structure of the SIS has been neglected. To determine whether a general factor model of the SIS is supported, alternative factor models of the SIS were evaluated comparatively in 11 clinical samples. The SIS was applied as part of a structured clinical interview to patients after an episode of non-fatal suicidal behavior. The samples were drawn from 11 study centers within the frame of the WHO/EURO multicenter study on suicidal behavior. Three different two-factor and two three-factor models of the SIS were examined in each sample using principal component analysis with orthogonal Procrustes rotation. The factorial structure of the 'subjective part' of the SIS (items 9-14) was strongly supported, whereas an acceptable model fit for the 'objective part' was not found. Possible future revisions of 'objective' SIS items may be worth consideration. As a limitation, the results of the study might not generalize to other samples that use different definitions of non-fatal suicidal behavior.

Cognitive functioning in a population-based sample of young adults with a history of non-psychotic unipolar depressive disorders without psychiatric comorbidity.

BACKGROUND: There is evidence for cognitive dysfunction in unipolar depression among middle-aged and elderly patients, but cognitive functioning among depressed young adults has scarcely been systematically investigated. The aims of the present study were to examine cognitive functioning among depressed young adults identified from the general population and to determine whether cognitive deficits vary as a function of different disorder characteristics, such as severity and age at onset. METHODS: Performance in verbal and visual short-term memory, verbal long-term memory and learning, attention, processing speed, and executive functioning was compared between a population-based sample of 21-35-year-olds with a lifetime history of non-psychotic unipolar depressive disorders without psychiatric comorbidity (n=68) and healthy controls derived from the same population (n=70). RESULTS: Depressed young adults were not found to be impaired in any of the assessed cognitive functions, except for some suggestion of mildly compromised verbal learning. Nevertheless, younger age at depression onset was associated with more impaired executive functioning. LIMITATIONS: The results may slightly underestimate of the true association between depression and cognitive impairments in the young adult population due to possible dropout of participants. Additionally, the problem of multiple testing was not entirely corrected. CONCLUSION: The findings from this study indicate that a lifetime history of non-psychotic unipolar depressive disorders among young adults without psychiatric comorbidity may be associated only with minimal cognitive deficits, even when some residual depressive symptoms are prevalent. However, early-onset depression may represent a more severe form of the disorder, associated with more cognitive dysfunction.

Costs of brain disorders in Finland.

OBJECTIVE: To calculate the costs of brain disorders on the national level. METHODS: Electronic data bases, national registers and internet data. RESULTS: Any brain disorder was estimated to affect a fifth of the Finnish population. The three most common disorders were migraine, anxiety disorder and affective disorder. The total costs of brain disorders constituted 3% of the national gross product, or 45% of all the health-care costs. However, this is likely a conservative estimate, because not all chronic brain disorders and not all costs were included. Of the total costs of brain disorders, 32% were for direct health care, 23% for indirect medical care and 45% for indirect costs. Dementia was the most costly individual brain disorder followed by addiction and affective disorders. Most costly per case were brain tumours and multiple sclerosis. CONCLUSION: Brain disorders constitute a costly part of the population's health costs. Directed preventive measures are needed to counteract the population morbidity and to control the increasing cost pressure in health care.

Contribution of non-work and work-related risk factors to the association between income and mental disorders in a working population: the Health 2000 Study.

OBJECTIVES: To examine the contribution of non-work and work factors to the association between income and DSM-IV depressive and anxiety disorders in a working population. METHODS: A representative sample of the Finnish working population aged 30-64 (1667 men, 1707 women) in 2000-2001 responded to a survey questionnaire on non-work factors (marital status, housing conditions, non-work social support, violence victimisation, smoking, physical symptoms), work factors (job demands, job control, social support at work, educational prospects, job insecurity) and household income. Somatic health was examined in a standard health examination. The 12-month prevalence of depressive and anxiety disorders was examined with the Composite International Diagnostic Interview. RESULTS: The risk of having a depressive or anxiety disorder was 2.8 times higher in the low-income group than in the high-income group among men and 2.0 times higher among women. For men, non-work and work factors explained 20% and 31% of this association, respectively. For women, the corresponding figures were 65% and 23%. CONCLUSIONS: Low income is associated with frequent mental disorders among a working population. In particular, work factors among men and non-work factors among women contribute to the income differences in mental health.

Genetic influences on brain structure.

Here we report on detailed three-dimensional maps revealing how brain structure is influenced by individual genetic differences. A genetic continuum was detected in which brain structure was increasingly similar in subjects with increasing genetic affinity. Genetic factors significantly influenced cortical structure in Broca's and Wernicke's language areas, as well as frontal brain regions (r2(MZ) > 0.8, p < 0.05). Preliminary correlations were performed suggesting that frontal gray matter differences may be linked to Spearman's g, which measures successful test performance across multiple cognitive domains (p < 0.05). These genetic brain maps reveal how genes determine individual differences, and may shed light on the heritability of cognitive and linguistic skills, as well as genetic liability for diseases that affect the human cortex.

Multiple deletions of mitochondrial DNA in several tissues of a patient with severe retarded depression and familial progressive external ophthalmoplegia.

Multiple deletions of mitochondrial DNA (mtDNA) have recently been reported in familial progressive external ophthalmoplegia (PEO), in a case of progressive encephalomyopathy, and in inherited recurrent myoglobinuria. The inheritance of familial PEO has been autosomal dominant, which indicates that a mutation in an unknown nuclear gene results in several mtDNA deletions of different sizes in these patients. We report a patient with autosomal dominant PEO, whose major clinical symptom, however, was severe retarded depression. The morphological analyses of the tissue samples derived from autopsy showed various abnormalities in the mitochondria in all the tissues studied. The activities of the respiratory chain enzymes encoded by mtDNA were remarkably reduced in the skeletal muscle. The mtDNA analyses confirmed that besides myopathy, this patient had a multisystem disorder with widespread distribution of multiple deletions of mtDNA. The highest percentage of mutated mtDNA was found in the brain, skeletal muscle and the heart, the relative quantity of mutated mtDNA correlating to the severity of the clinical symptoms.