Level of suicidal intent predicts overall mortality and suicide after attempted suicide: a 12-year follow-up study

BACKGROUND: The aim of this study was to comprehensively examine clinical risk factors, including suicide intent and hopelessness, for suicide and risk of death from all causes after attempted suicide over a 12-year follow-up period. METHODS: A systematic sample of 224 patients from consecutive cases of attempted suicide referred to health care in four Finnish cities between 1 January and 31 July 1990 was interviewed. RESULTS: After 12 years of follow-up 22% of these patients had died, 8% by committing suicide. The only statistically significant risk factor for eventual suicide was high scores on Beck's Suicidal Intention Scale. Male gender, older age, physical illness or disability and high scores on Beck's Suicidal Intention Scale predicted death overall. CONCLUSIONS: Following attempted suicide, high intention to kill oneself is a significant risk factor for both death from all causes and suicide

Contribution of astrocytes to familial risk and clinical manifestation of schizophrenia

Previous studies have implicated several brain cell types in schizophrenia (SCZ), but the genetic impact of astrocytes is unknown. Considering their high complexity in humans, astrocytes are likely key determinants of neurodevelopmental diseases, such as SCZ. Human induced pluripotent stem cell (hiPSC)-derived astrocytes differentiated from five monozygotic twin pairs discordant for SCZ and five healthy subjects were studied for alterations related to high genetic risk and clinical manifestation of SCZ in astrocyte transcriptomics, neuron-astrocyte co-cultures, and in humanized mice. We found gene expression and signaling pathway alterations related to synaptic dysfunction, inflammation, and extracellular matrix components in SCZ astrocytes, and demyelination in SCZ astrocyte transplanted mice. While Ingenuity Pathway Analysis identified SCZ disease and synaptic transmission pathway changes in SCZ astrocytes, the most consistent findings were related to collagen and cell adhesion associated pathways. Neuronal responses to glutamate and GABA differed between astrocytes from control persons, affected twins, and their unaffected co-twins and were normalized by clozapine treatment. SCZ astrocyte cell transplantation to the mouse forebrain caused gene expression changes in synaptic dysfunction and inflammation pathways of mouse brain cells and resulted in behavioral changes in cognitive and olfactory functions. Differentially expressed transcriptomes and signaling pathways related to synaptic functions, inflammation, and especially collagen and glycoprotein 6 pathways indicate abnormal extracellular matrix composition in the brain as one of the key characteristics in the etiology of SCZ.Peer reviewe

Psychosis among "healthy" siblings of schizophrenia patients

BACKGROUND: Schizophrenia aggregates in families and accurate diagnoses are essential for genetic studies of schizophrenia. In this study, we investigated whether siblings of patients with schizophrenia can be identified as free of any psychotic disorder using only register information. We also analyzed the emergence of psychotic disorders among siblings of patients with schizophrenia during seven to eleven years of follow-up. METHODS: A genetically homogenous population isolate in north-eastern Finland having 365 families with 446 patients with a diagnosis of schizophrenia was initially identified in 1991 using four nationwide registers. Between 1998 and 2002, 124 patients and 183 siblings in 110 families were contacted and interviewed using SCID-I, SCID-II and SANS. We also compared the frequency of mental disorders between siblings and a random population comparison group sample. RESULTS: Thirty (16%) siblings received a diagnosis of psychotic disorder in the interview. 14 siblings had had psychotic symptoms already before 1991, while 16 developed psychotic symptoms during the follow-up. Over half of the siblings (n = 99, 54%) had a lifetime diagnosis of any mental disorder in the interview. CONCLUSION: Register information cannot be used to exclude psychotic disorders among siblings of patients with schizophrenia. The high rate of emergence of new psychotic disorders among initially healthy siblings should be taken into account in genetic analysis

Validation of the Finnish version of the SCOFF questionnaire among young adults aged 20 to 35 years

<p>Abstract</p> <p>Background</p> <p>We tested the validity of the SCOFF, a five-question screening instrument for eating disorders, in a general population sample.</p> <p>Methods</p> <p>A random sample of 1863 Finnish young adults was approached with a questionnaire that contained several screens for mental health interview, including the SCOFF. The questionnaire was returned by 1316 persons. All screen positives and a random sample of screen negatives were invited to SCID interview. Altogether 541 subjects participated in the SCID interview and had filled in the SCOFF questionnaire. We investigated the validity of the SCOFF in detecting current eating disorders by calculating sensitivity, specificity, and positive and negative predictive values (PPV and NPV) for different cut-off scores. We also performed a ROC analysis based on these 541 persons, of whom nine had current eating disorder.</p> <p>Results</p> <p>The threshold of two positive answers presented the best ability to detect eating disorders, with a sensitivity of 77.8%, a specificity of 87.6%, a PPV of 9.7%, and a NPV of 99.6%. None of the subjects with current eating disorder scored zero points in the SCOFF.</p> <p>Conclusion</p> <p>Due to its low PPV, there are limitations in using the SCOFF as a screening instrument in unselected population samples. However, it might be used for ruling out the possibility of eating disorders.</p

Seasonal Changes in Mood and Behavior Are Linked to Metabolic Syndrome

BACKGROUND: Obesity is a major public health problem worldwide. Metabolic syndrome is a risk factor to the cardiovascular diseases. It has been reported that disruptions of the circadian clockwork are associated with and may predispose to metabolic syndrome. METHODOLOGY AND PRINCIPAL FINDINGS: 8028 individuals attended a nationwide health examination survey in Finland. Data were collected with a face-to-face interview at home and during an individual health status examination. The waist circumference, height, weight and blood pressure were measured and samples were taken for laboratory tests. Participants were assessed using the ATP-III criteria for metabolic syndrome and with the Seasonal Pattern Assessment Questionnaire for their seasonal changes in mood and behavior. Seasonal changes in weight in particular were a risk factor of metabolic syndrome, after controlling for a number of known risk and potential confounding factors. CONCLUSIONS AND SIGNIFICANCE: Metabolic syndrome is associated with high global scores on the seasonal changes in mood and behavior, and with those in weight in particular. Assessment of these changes may serve as a useful indicator of metabolic syndrome, because of easy assessment. Abnormalities in the circadian clockwork which links seasonal fluctuations to metabolic cycles may predispose to seasonal changes in weight and to metabolic syndrome

Deletion of TOP3β, a component of FMRP-containing mRNPs, contributes to neurodevelopmental disorders

Implicating particular genes in the generation of complex brain and behavior phenotypes requires multiple lines of evidence. The rarity of most high impact genetic variants typically precludes the possibility of accruing statistical evidence that they are associated with a given trait. We show here that the enrichment of a rare Chromosome 22q11.22 deletion in a recently expanded Northern Finnish sub-isolate enables the detection of association between TOP3β and both schizophrenia and cognitive impairment. Biochemical analysis of TOP3β revealed that this topoisomerase is a component of cytosolic messenger ribonucleoproteins (mRNPs) and is catalytically active on RNA. The recruitment of TOP3β to mRNPs was independent of RNA cis-elements and was coupled to the co-recruitment of FMRP, the disease gene product in fragile X mental retardation syndrome (FXS). Thus, we uncover a novel role for TOP3β in mRNA metabolism and provide several lines of evidence implicating it in neurodevelopmental disorders

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (OR=1.11, P=5.7×10−15), which persisted after excluding loci implicated in previous studies (OR=1.07, P=1.7 ×10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 ×10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P= 7.3 ×10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by non-allelic homologous recombination

Age at first birth in women is genetically associated with increased risk of schizophrenia

Prof. Paunio on PGC:n jäsenPrevious studies have shown an increased risk for mental health problems in children born to both younger and older parents compared to children of average-aged parents. We previously used a novel design to reveal a latent mechanism of genetic association between schizophrenia and age at first birth in women (AFB). Here, we use independent data from the UK Biobank (N = 38,892) to replicate the finding of an association between predicted genetic risk of schizophrenia and AFB in women, and to estimate the genetic correlation between schizophrenia and AFB in women stratified into younger and older groups. We find evidence for an association between predicted genetic risk of schizophrenia and AFB in women (P-value = 1.12E-05), and we show genetic heterogeneity between younger and older AFB groups (P-value = 3.45E-03). The genetic correlation between schizophrenia and AFB in the younger AFB group is -0.16 (SE = 0.04) while that between schizophrenia and AFB in the older AFB group is 0.14 (SE = 0.08). Our results suggest that early, and perhaps also late, age at first birth in women is associated with increased genetic risk for schizophrenia in the UK Biobank sample. These findings contribute new insights into factors contributing to the complex bio-social risk architecture underpinning the association between parental age and offspring mental health.Peer reviewe

Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants

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 (β = 16.1, CI(β) = [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 (β = 4.86,CI(β) = [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