Minna Torniainen-Holm

Truncating mutations in RBM12 are associated with psychosis

Thus far, a handful of highly penetrant mutations conferring risk of psychosis have been discovered. Here we used whole-genome sequencing and long-range phasing to investigate an Icelandic kindred containing ten individuals with psychosis (schizophrenia, schizoaffective disorder or psychotic bipolar disorder). We found that all affected individuals carry RBM12 (RNA-binding-motif protein 12) c.2377G>T (P = 2.2 × 10−4), a nonsense mutation that results in the production of a truncated protein lacking a predicted RNA-recognition motif. We replicated the association in a Finnish family in which a second RBM12 truncating mutation (c.2532delT) segregates with psychosis (P = 0.020). c.2377G>T is not fully penetrant for psychosis; however, we found that carriers unaffected by psychosis resemble patients with schizophrenia in their non-psychotic psychiatric disorder and neuropsychological test profile (P = 0.0043) as well as in their life outcomes (including an increased chance of receiving disability benefits, P = 0.011). As RBM12 has not previously been linked to psychosis, this work provides new insight into psychiatric disease.

Toxoplasma gondii infection and common mental disorders in the Finnish general population

OBJECTIVE We investigated whether T. gondii seropositivity is associated with 12-month depressive, anxiety and alcohol use disorders and current depressive symptoms and whether inflammation, measured by C-reactive protein (CRP) level, explains these associations. METHOD Health 2000 study (BRIF8901), conducted in years 2000-2001, is based on a nationally representative sample of Finns aged 30 and above, with 7112 participants and 88.6% response rate. DSM-IV depressive, anxiety and alcohol use disorders were assessed with the Composite International Diagnostic Interview and depressive symptoms with the Beck Depressive Inventory (BDI-21). We used logistic regression to investigate the association of T. gondii seropositivity with mental disorders and linear regression with BDI-21 scores. RESULTS T. gondii seroprevalence was significantly associated with 12-month generalized anxiety disorder but not with other anxiety, depressive or alcohol use disorders. T. gondii seropositivity was associated with higher BDI-21 scores (beta 0.56, 95% CI 0.12-1.00, P = 0.013) and with having a comorbid depressive and anxiety disorder (OR 1.86, 95% CI 1.16-2.97, P = 0.010). Higher CRP levels were associated with these outcomes and with T. gondii seropositivity, but adjusting for CRP did not change the effect of T. gondii seropositivity. LIMITATIONS Cross-sectional study design with no information on the timing of T. gondii infection. CONCLUSION T. gondii seropositivity is associated with generalized anxiety disorder, depressive symptoms and comorbid depressive and anxiety disorders, which is not mediated by inflammation.

Association of cytomegalovirus and Epstein-Barr virus with cognitive functioning and risk of dementia in the general population: 11-year follow-up study

BACKGROUND Earlier studies have documented an association between cytomegalovirus and cognitive impairment, but results have been inconsistent. Few studies have investigated the association of cytomegalovirus and Epstein-Barr virus with cognitive decline longitudinally. Our aim was to examine whether cytomegalovirus and Epstein-Barr virus are associated with cognitive decline in adults. METHOD The study sample is from the Finnish Health 2000 Survey (BRIF8901, n = 7112), which is representative of the Finnish adult population. The sample was followed up after 11 years in the Health 2011 Survey. In addition, persons with dementia were identified from healthcare registers. RESULTS In the Finnish population aged 30 and over, the seroprevalence of cytomegalovirus was estimated to be 84% and the seroprevalence of Epstein-Barr virus 98%. Seropositivity of the viruses and antibody levels were mostly not associated with cognitive performance. In the middle-aged adult group, cytomegalovirus serointensity was associated with impaired performance in verbal learning. However, the association disappeared when corrected for multiple testing. No interactions between infection and time or between the two infections were significant when corrected for multiple testing. Seropositivity did not predict dementia diagnosis. CONCLUSIONS The results suggest that adult levels of antibodies to cytomegalovirus and Epstein-Barr virus may not be associated with a significant decline in cognitive function or with dementia at population level.

The NDE1 genomic locus can affect treatment of psychiatric illness through gene expression changes related to microRNA-484

Genetic studies of familial schizophrenia in Finland have observed significant associations with a group of biologically related genes, DISC1, NDE1, NDEL1, PDE4B and PDE4D, the ‘DISC1 network’. Here, we use gene expression and psychoactive medication use data to study their biological consequences and potential treatment implications. Gene expression levels were determined in 64 individuals from 18 families, while prescription medication information has been collected over a 10-year period for 931 affected individuals. We demonstrate that the NDE1 SNP rs2242549 associates with significant changes in gene expression for 2908 probes (2542 genes), of which 794 probes (719 genes) were replicable. A significant number of the genes altered were predicted targets of microRNA-484 (p = 3.0 × 10−8), located on a non-coding exon of NDE1. Variants within the NDE1 locus also displayed significant genotype by gender interaction to early cessation of psychoactive medications metabolized by CYP2C19. Furthermore, we demonstrate that miR-484 can affect the expression of CYP2C19 in a cell culture system. Thus, variation at the NDE1 locus may alter risk of mental illness, in part through modification of miR-484, and such modification alters treatment response to specific psychoactive medications, leading to the potential for use of this locus in targeting treatment.

The effectiveness of email-based exercises in promoting psychological wellbeing and healthy lifestyle: a two-year follow-up study

BackgroundWeb-based interventions provide a possibility to enhance well-being in large groups of people. Only a few studies have studied the effectiveness of the interventions and there is no information on the sustainability of the effects. Study aims were to investigate both the short (2-month) and long-term (2-year) effects of email-based training for mental health and lifestyle.MethodsPersons who completed an ‘Electronic Health Check’, as advertised in a TV program, were offered a chance to participate in email-based interventions. The baseline questionnaire was completed by 73 054 people, with 42 761 starting interventions, and 16 499 people participating in at least one of the follow-ups. Persons who did not choose to start the interventions served as controls.ResultsAt baseline, the intervention group had a higher level of stress and lower gratitude and confidence in the future than the control group. Both groups showed improvement in the level of stress, but improvement was more marked in the intervention group (P < .001 for both time points). In confidence in the future and gratitude, people who chose interpersonal interventions showed significant improvements at both time points (P < .001), whereas those choosing lifestyle interventions showed improvement only at the 2-month follow-up. Participants who had done the exercises according to instructions had the most sustained improvements in measures of psychological health at the 2-year follow-up. As for lifestyle, people who had started lifestyle interventions increased their exercise (P < .001 at both time points).ConclusionsInternet-based interventions are feasible for mental health promotion and should be available for people interested in improving their psychological well-being and lifestyle.

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

Abstract 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. HighlightsWhole blood gene expression changes are associated with cognitive performance.Associated genes enriched for inflammatory processes.Inflammatory processes a therapeutical interest towards cognitive impairments.

Variants in regulatory elements of PDE4D associate with Major Mental Illness in the Finnish population

We have previously reported a replicable association between variants at the PDE4D gene and familial schizophrenia in a Finnish cohort. In order to identify the potential functional mutations alluded to by these previous findings, we sequenced 945kb of the PDE4D genomic locus in 96 individuals, followed by two stages of genotyping across 6,668 individuals from multiple Finnish cohorts for major mental illnesses. We identified 4,570 SNPs across the PDE4D gene, with 380 associated to schizophrenia (p≤0.05). Importantly, two of these variants, rs35278 and rs165940, are located at transcription factor binding sites, and displayed replicable association in the two-stage enlargement of the familial schizophrenia cohort, (combined statistics for rs35278 p=0.0012; OR=1.18, 95% CI 1.06-1.32; and rs165940 p=0.0016; OR=1.27, 95% CI 1.13-1.41). Further analysis using additional cohorts and endophenotypes revealed that rs165940 principally associates within the psychosis (p=0.025, OR=1.18, 95% CI 1.07-1.30) and cognitive domains of major mental illnesses. Specifically, the cognitive domain was a factor score for quantitative neuropsychological endophenotypes related to verbal learning and memory (p=0.0078, β=-0.19). Moreover, expression data from the GTEx database demonstrated that rs165940 significantly correlates with the mRNA expression levels of PDE4D in the cerebellum (p-value=0.04; post-prob=0.9; m-value=1.4), demonstrating a potential functional consequence for this variant. Thus, rs165940 represents the most likely functional variant for major mental illness at the PDE4D locus in the Finnish population, increasing risk broadly to psychotic disorders.

Contribution of rare and common variants to intellectual disability in a high-risk population sub-isolate of Northern Finland

The contribution of de novo and ultra-rare genetic variants in severe and moderate intellectual disability (ID) has been extensively studied whereas the genetic architecture of mild ID has been less well characterized. To elucidate the genetic background of milder ID we studied a regional cohort of 442 ID patients enriched for mild ID (>50%) from a population isolate of Finland. We analyzed rare variants using exome sequencing and CNV genotyping and common variants using common variant polygenic risk scores. As controls we used a Finnish collection of exome sequenced (n=11311) and GWAS chip genotyped (n=11699) individuals. We show that rare damaging variants in genes known to be associated with cognitive defects are observed more often in severe (27%) than in mild ID (13%) patients (p-value: 7.0e-4). We further observed a significant enrichment of protein truncating variants in loss-of-function intolerant genes, as well as damaging missense variants in genes not yet associated with cognitive defects (OR: 2.1, p-value: 3e-8). For the first time to our knowledge, we show that a common variant polygenic load significantly contributes to all severity forms of ID. The heritability explained was the highest for educational attainment (EDU) in mild ID explaining 2.2% of the heritability on liability scale. For more severe ID it was lower at 0.6%. Finally, we identified a homozygote variant in the CRADD gene to be a cause of a specific syndrome with ID and pachygyria. The frequency of this variant is 50x higher in the Finnish population than in non-Finnish Europeans, demonstrating the benefits of utilizing population isolates in rare variant analysis of diseases under negative selection.

F166. LOW-GRADE INFLAMMATION IN FIRST-EPISODE PSYCHOSIS IS DETERMINED BY WAIST CIRCUMFERENCE INCREASE

Abstract Background There is evidence of low-grade inflammation in psychosis, as measured by the high-sensitivity C-reactive protein (hs-CRP). Significant weight gain is common during the first months of antipsychotic treatment. In the general population, overweight and obesity often lead to systemic low-grade inflammation. Lifestyle factors, such as smoking, can contribute to the pro-inflammatory changes. The metabolic changes in people with first-episode psychosis (FEP) taking place after the onset of psychosis can be especially harmful as these individuals are typically young and without major somatic illnesses. We aimed to study how the low-grade inflammation, measured by hs-CRP, develops in FEP and to clarify the effect of waist circumference increase in the inflammation. Methods The Helsinki Early Psychosis Study recruited FEP patients (age 18 to 40 years) attaining their first treatment for psychosis from the catchment area of the Helsinki University Hospital. We recruited 95 FEP patients and 62 controls. The inclusion criterion for the study was receiving a score of at least 4 in Unusual thought content or Hallucinations in the Brief Psychiatric Rating Scale - Extended (BPRS-E). Diagnoses of psychotic disorders according to the DSM-IV criteria were later verified using the Structured Diagnostic Interview for DSM-IV and reviewing all medical records. Substance-induced psychotic disorders and psychotic disorders due to a general medical condition were excluded. We measured the changes in hs-CRP, weight, waist circumference, glucose metabolism and lipids at baseline and at follow-ups of 2 and 12 months. We used linear mixed effects models to analyze the relationship between hs-CRP and waist circumference. In the model, we included a random intercept for each patient and, as fixed effects, we entered sex, time (days from baseline measurement), waist circumference and antipsychotic use at each assessment point, and baseline cigarette smoking. Results At baseline, FEP patients (mean age 26.1 years) had higher insulin resistance, total and LDL cholesterol, apolipoprotein B and triglyceride levels than controls. However, baseline weight and waist circumference, hs-CRP, fasting glucose and HDL cholesterol were similar between patients and controls. A robust change in anthropometric measures and inflammation was evident among patients by 12 months. Hs-CRP was significantly higher in patients at 12-month follow up than at baseline (baseline hs-CRP 0.67 mg/l, IQR 0.33–2.54; 12-month 1.73 mg/l, IQR 0.49–4.21; Wilcoxon signed-rank p = 0.007). When at the baseline the prevalence of overweight or obesity was 30% (28/94) in patients with FEP, by 12 months the prevalence was 59% (35/59) (McNemar′s test p < 0.001). The proportion of patients gaining ≥ 7 % of baseline weight was 68 % (40/59). The median weight gain among patients was 9.6 kg (IQR 1.5–13.6 kg), and the waist circumference increase 6.0 cm (IQR 2.0–13.0 cm). In the mixed effects model waist circumference (p < 0.0001) and sex (p = 0.014) were significantly associated with hs-CRP level. Discussion We detected a significant elevation in hs-CRP in people with FEP during the first treatment year. The rise in hs-CRP was determined by waist circumference increase. Patients with FEP are in a marked risk of developing abdominal obesity and subsequent low-grade inflammation during the first year of treatment. Prevention of the early metabolic changes in first-episode psychosis is important, as abdominal obesity and inflammation are associated with increased risk of cardiovascular events and mortality.

S66. THEORY OF MIND IN A FIRST-EPISODE PSYCHOSIS POPULATION USING THE HINTING TASK

Abstract Background Impaired social functioning is one of the most apparent features of psychotic disorders. Deficits in social cognition may explain impaired functioning even more than the other cognitive deficits related to psychosis. Of the areas of social cognition, especially relevant to psychosis appear to be deficiencies in theory of mind (ToM), the ability to perceive and interpret the mental states of others, or “mentalizing”. Currently, it is unclear to what extent general cognitive deficits explain impairment in ToM. We wanted to explore 1) the possible difference in ToM between first-episode psychosis (FEP) patients and controls, 2) whether diagnosis group (schizophrenia vs. other psychotic disorders) and level of functioning are associated with ToM, and 3) to what extent these differences are explained by general cognitive performance. Methods This study examined ToM in young adults with FEP (n=66). Of those, 25 had schizophrenia and the rest were diagnosed with other psychotic disorders. Age- and gender-matched controls were identified from the Population Information System (n=62). The participants were administered a broad neuropsychological assessment, part of which was the Hinting Task assessing ToM. With 10 short discussions in everyday situations, the Hinting Task assesses the ability to conclude, from indirect speech, what another person really means. A factor score of the Hinting Task was formed, taking into account the varying difficulty level and relevance of the 10 items. To investigate the association between ToM and general cognitive functions, we summarized non-social cognitive performance constructing a “g factor”, which was used as an overall index of general cognitive performance. Results The internal consistency of the Hinting Task calculated from the dichotomized data was modest, with McDonald’s categorical omega estimated at .57 (95 % CI .36, .71). In the single dimensional factor solution, items 8 and 9 had the weakest loadings and item 10 the strongest. Items 9 and 10 of the Hinting Task were the easiest, and items 1 and 8 were the most difficult. Participants with FEP (mean score 16.0) performed worse than controls (mean score 17.4) on the Hinting Task (Cohen’s d=0.50 calculated from factor scores). However, the difference between FEP and control groups was no longer significant when general cognition was controlled for. 75 % of the variance between the groups was explained by general cognitive deficits, especially impaired processing speed (WAIS-III Digit Symbol) and episodic memory (WMS-III Logical Memory). When the FEP group was divided according to diagnosis, those with schizophrenia scored lower on the Hinting Task than the other psychosis patients. The ToM difference between individuals with schizophrenia and controls (Cohen’s d=1.1) remained significant even when general cognitive performance was controlled for. In contrast, those with other psychotic disorders than schizophrenia did not differ from controls. ToM performance of the best functioning patient group (20 patients who had a GAF score ≥50, Hinting Task mean score 17.8) did not differ from that of the control group. Discussion Based on this study, and supporting previous findings (Bora & Pantelis, Schizophr. Res. 2013), deficits in ToM were already present in early psychosis. They were largely overlapping with deficits in general cognitive processes. However, and in line with previous meta-analytical findings (Sprong et al., Br. J. Psychiatry 2007), in a subgroup of the FEP patients with schizophrenia, impairments in ToM remained after controlling for overall cognitive functioning. In conclusion, specific deficits in ToM could be found in schizophrenia, independent from general cognitive deficits.