[Show abstract][Hide abstract] ABSTRACT: Objective
Research suggests autoimmune processes to be involved in psychiatric disorders. We aimed to address the prevalence and incidence of autoimmune diseases in a large Finnish patient cohort with anorexia nervosa, bulimia nervosa, and binge eating disorder.
Patients (N = 2342) treated at the Eating Disorder Unit of Helsinki University Central Hospital between 1995 and 2010 were compared with general population controls (N = 9368) matched for age, sex, and place of residence. Data of 30 autoimmune diseases from the Hospital Discharge Register from 1969 to 2010 were analyzed using conditional and Poisson regression models.
Of patients, 8.9% vs. 5.4% of control individuals had been diagnosed with one or more autoimmune disease (OR 1.7, 95% CI 1.5–2.0, P<0.001). The increase in endocrinological diseases (OR 2.4, 95% CI 1.8–3.2, P<0.001) was explained by type 1 diabetes, whereas Crohn's disease contributed most to the risk of gastroenterological diseases (OR 1.8, 95% CI 1.4–2.5, P<0.001). Higher prevalence of autoimmune diseases among patients with eating disorders was not exclusively due to endocrinological and gastroenterological diseases; when the two categories were excluded, the increase in prevalence was seen in the patients both before the onset of the eating disorder treatment (OR 1.5, 95% CI 1.1–2.1, P = 0.02) and at the end of the follow-up (OR 1.4, 95% CI 1.1–1.8, P = 0.01).
We observed an association between eating disorders and several autoimmune diseases with different genetic backgrounds. Our findings support the link between immune-mediated mechanisms and development of eating disorders. Future studies are needed to further explore the risk of autoimmune diseases and immunological mechanisms in individuals with eating disorders and their family members.
PLoS ONE 08/2014; 9(8):e104845. DOI:10.1371/journal.pone.0104845 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain, providing biological plausibility for the findings. Many findings have the potential to provide entirely new insights into aetiology, but associations at DRD2 and several genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that have important roles in immunity, providing support for the speculated link between the immune system and schizophrenia.
[Show abstract][Hide abstract] ABSTRACT: The Prodromal Questionnaire (PQ) identifies psychiatric help-seekers in need of clinical interviews to diagnose psychosis risk. However, some providers use the PQ alone to identify risk. Therefore, we tested its predictive utility among 731 adolescent psychiatric help-seekers, with a 3-9-year register-based follow-up. Nine latent factors corresponded well with postulated subscales. Depersonalization predicted later hospitalization with a psychosis diagnosis (HR 1.6 per SD increase), and Role Functioning predicted any psychiatric hospitalization (HR 1.3). Published cut-off scores were poor predictors of psychosis; endorsement rates were very high for most symptoms. Therefore, we do not recommend using the PQ without second-stage clinical interviews.
Schizophrenia Research 07/2014; 158(1-3). DOI:10.1016/j.schres.2014.06.031 · 4.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: IMPORTANCE We investigated the variation in neuropsychological function explained by risk alleles at the psychosis susceptibility gene ZNF804A and its interacting partners using single nucleotide polymorphisms (SNPs), polygenic scores, and epistatic analyses. Of particular importance was the relative contribution of the polygenic score vs epistasis in variation explained. OBJECTIVES To (1) assess the association between SNPs in ZNF804A and the ZNF804A polygenic score with measures of cognition in cases with psychosis and (2) assess whether epistasis within the ZNF804A pathway could explain additional variation above and beyond that explained by the polygenic score. DESIGN, SETTING, AND PARTICIPANTS Patients with psychosis (n = 424) were assessed in areas of cognitive ability impaired in schizophrenia including IQ, memory, attention, and social cognition. We used the Psychiatric GWAS Consortium 1 schizophrenia genome-wide association study to calculate a polygenic score based on identified risk variants within this genetic pathway. Cognitive measures significantly associated with the polygenic score were tested for an epistatic component using a training set (n = 170), which was used to develop linear regression models containing the polygenic score and 2-SNP interactions. The best-fitting models were tested for replication in 2 independent test sets of cases: (1) 170 individuals with schizophrenia or schizoaffective disorder and (2) 84 patients with broad psychosis (including bipolar disorder, major depressive disorder, and other psychosis). MAIN OUTCOMES AND MEASURES Participants completed a neuropsychological assessment battery designed to target the cognitive deficits of schizophrenia including general cognitive function, episodic memory, working memory, attentional control, and social cognition. RESULTS Higher polygenic scores were associated with poorer performance among patients on IQ, memory, and social cognition, explaining 1% to 3% of variation on these scores (range, P = .01 to .03). Using a narrow psychosis training set and independent test sets of narrow phenotype psychosis (schizophrenia and schizoaffective disorder), broad psychosis, and control participants (n = 89), the addition of 2 interaction terms containing 2 SNPs each increased the R2 for spatial working memory strategy in the independent psychosis test sets from 1.2% using the polygenic score only to 4.8% (P = .11 and .001, respectively) but did not explain additional variation in control participants. CONCLUSIONS AND RELEVANCE These data support a role for the ZNF804A pathway in IQ, memory, and social cognition in cases. Furthermore, we showed that epistasis increases the variation explained above the contribution of the polygenic score.
[Show abstract][Hide abstract] ABSTRACT: Objective
The aim of this study is to explore the prevalence of hospital-treated suicide attempts in a large clinical population of eating disorder patients.
Follow-up study of adults (N = 2462, 95% women, age 18–62 years) admitted to the Eating Disorder Clinic of Helsinki University Central Hospital in the period 1995–2010. For each patient four controls were selected and matched for age, sex and place of residence. The end-point events were modeled using Cox’s proportional hazard model, taking matching into account.
We identified 156 patients with eating disorder (6.3%) and 139 controls (1.4%) who had required hospital treatment for attempted suicide. Of them, 66 (42.3%) and 37 (26.6%) had more than one attempt. The rate ratio (RR) for suicide attempt in patients with eating disorder was 4.70 (95% CI 1.41–15.74). In anorexia nervosa RR was 8.01 (95% CI 5.40–11.87) and in bulimia nervosa 5.08 (95% CI 3.46–7.42). In eating disorder patients with a history of suicide attempt, the risk of death from any cause was 12.8%, suicide being the main cause in 45% of the deaths.
Suicide attempts and repeated attempts are common among patients with eating disorders. Suicidal ideation should be routinely assessed from patients with eating disorders.
General hospital psychiatry 05/2014; 36(3). DOI:10.1016/j.genhosppsych.2014.01.002 · 2.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To study pregnancy, obstetric, and perinatal health outcomes and complications in women with lifetime eating disorders.
Female patients (n=2 257) treated at the Eating Disorder Clinic of Helsinki University Central Hospital during 1995-2010 were compared with unexposed women retrieved from the population (n=9028). Register-based information on pregnancy, obstetric, and perinatal health outcomes and complications were acquired for all singleton births during the follow up time among women with broad anorexia nervosa (AN, n=302 births), broad bulimia nervosa (BN, n=724), binge eating disorder (BED, n=52), and unexposed women (n=6319).
Women with AN and BN gave birth to babies with lower birth weight compared to unexposed women, while the opposite was observed in BED. Maternal AN was related to anemia, slow fetal growth, premature contractions, short duration of the first stage of labor, very premature birth, small for gestational age, low birth weight, and perinatal death. Increased odds of premature contractions, resuscitation of the neonate, and very low Apgar score at 1 min were observed in mothers with BN. BED was positively associated with maternal hypertension, long duration of the first and second stage of labor, and birth of large for gestational age infants.
Eating disorders appear to be associated with several adverse perinatal outcomes, particularly in offspring. We recommend close monitoring of pregnant women with either past or current eating disorder. Attention should be paid to children born to these mothers.
American journal of obstetrics and gynecology 04/2014; 211(4). DOI:10.1016/j.ajog.2014.03.067 · 3.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction
Current psychosis risk criteria have often been studied on a pre-selected population at specialized clinics. We investigated whether the Structured Interview for Prodromal Syndromes (SIPS) is a useful tool for psychosis risk screening among adolescents in general psychiatric care.
161 adolescents aged 15–18 with first admission to adolescent psychiatric services in Helsinki were interviewed with the SIPS to ascertain Clinical High-Risk (CHR) state. The participants were followed via the national hospital discharge register, patient files, and follow-up interviews. DSM-IV Axis I diagnoses were made at baseline and 12 months. Register follow-up spanned 2.8–8.9 years, and hospital care for a primary psychotic disorder and any psychiatric disorder were used as outcomes.
CHR criteria were met by 54 (33.5%) of the adolescents. Three conversions of psychosis as defined by SIPS emerged during follow-up, two of whom belonged to the CHR group. The positive predictive value of the CHR status was weak (1.9%) but its negative predictive value was 98.0%. Using the DSM-IV definition of psychosis, there were five conversions, three of which were in the CHR group. In regression analyses, hospital admissions for primary psychotic disorder were predicted by positive symptom intensity in the baseline SIPS. In addition, CHR status and SIPS positive and general symptoms predicted hospitalization for psychiatric disorder.
Psychosis incidence was low in our unselected sample of adolescent psychiatric patients. CHR status failed to predict SIPS or DSM-IV psychoses significantly at 12 months. However, in a longer follow-up, CHR did predict psychiatric hospitalization.
Schizophrenia Research 04/2014; 158(1-3). DOI:10.1016/j.schres.2014.06.028 · 4.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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).Molecular Psychiatry advance online publication, 20 November 2012; doi:10.1038/mp.2012.157.
[Show abstract][Hide abstract] ABSTRACT: We compared the course and outcome of schizophrenia in two groups: (i) hospitalised patients (HP) (n = 5980) who were identified based on their first hospital admission for schizophrenia and (ii) outpatient-treated patients (OTP) who received disability pension because of schizophrenia but who had no hospital admissions for schizophrenia or other psychotic disorder before having been granted a disability pension for schizophrenia (n = 1220). Outcomes were compared using data on mortality, psychiatric hospital utilisation, relapse rate and occupational functioning.
A nationwide register-based 5-year follow-up study of all first-onset schizophrenia cases between 1998 and 2003 in Finland. The data were linked with the register information of hospital admissions, disability pensions and National Causes of Death Registers.
When outcome of treatment was evaluated using mortality rate, relapses, hospital treatment and involuntary admissions as outcome measures, results indicated that OTP group had got along better with their illnesses than HP group. The mortality rates, number of psychiatric treatment days and relapse rate during the 5-year follow up were significantly lower in OTP group. Within the OTP group, there was a notable subgroup of never HP (n = 737, 60.4%), who did not require any psychiatric hospitalisation during the 5-year follow up.
Patients first identified as outpatients had better outcomes than patients first identified following a hospitalisation. Future studies are required to establish whether outpatient treatment is associated with more favourable prognosis, even after fully adjusting for severity of initial symptoms. The higher suicide mortality of hospital-treated patients suggests that hospital treatment of first-onset patients does not protect from suicide.
International Journal of Clinical Practice 11/2013; 67(11):1105-12. DOI:10.1111/ijcp.12226 · 2.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Schizophrenia is an idiopathic mental disorder with a heritable component and a substantial public health impact. We conducted a multi-stage genome-wide association study (GWAS) for schizophrenia beginning with a Swedish national sample (5,001 cases and 6,243 controls) followed by meta-analysis with previous schizophrenia GWAS (8,832 cases and 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls and 581 parent-offspring trios). We identified 22 loci associated at genome-wide significance; 13 of these are new, and 1 was previously implicated in bipolar disorder. Examination of candidate genes at these loci suggests the involvement of neuronal calcium signaling. We estimate that 8,300 independent, mostly common SNPs (95% credible interval of 6,300-10,200 SNPs) contribute to risk for schizophrenia and that these collectively account for at least 32% of the variance in liability. Common genetic variation has an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this disorder.
[Show abstract][Hide abstract] ABSTRACT: Genes that are differentially expressed between schizophrenia patients and healthy controls may have key roles in the pathogenesis of schizophrenia. We analyzed two large-scale genome-wide expression studies, which examined changes in gene expression in schizophrenia patients and their matched controls. We found calcium/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) is significantly downregulated in individuals with schizophrenia in both studies. To seek the potential genetic variants that may regulate the expression of CAMKK2, we investigated the association between single-nucleotide polymorphisms (SNPs) within CAMKK2 and the expression level of CAMKK2. We found one SNP, rs1063843, which is located in intron 17 of CAMKK2, is strongly associated with the expression level of CAMKK2 in human brains (P = 1.1 x 10(-6)) and lymphoblastoid cell lines (the lowest P = 8.4 x 10(-6)). We further investigated the association between rs1063843 and schizophrenia in multiple independent populations (a total of 130 623 subjects) and found rs1063843 is significantly associated with schizophrenia (P = 5.17 x 10(-5)). Interestingly, we found the T allele of rs1063843, which is associated with lower expression level of CAMKK2, has a higher frequency in individuals with schizophrenia in all of the tested samples, suggesting rs1063843 may be a causal variant. We also found that rs1063843 is associated with cognitive function and personality in humans. In addition, protein-protein interaction (PPI) analysis revealed that CAMKK2 participates in a highly interconnected PPI network formed by top schizophrenia genes, which further supports the potential role of CAMKK2 in the pathogenesis of schizophrenia. Taken together, these converging lines of evidence strongly suggest that CAMKK2 may have pivotal roles in schizophrenia susceptibility.
[Show abstract][Hide abstract] ABSTRACT: Elevated mortality risk in anorexia nervosa has been established, but less is known about the outcomes of bulimia nervosa and binge eating disorder. In this follow-up study we determined mortality in adults (N=2450, 95% women) admitted to the eating disorder clinic of the Helsinki University Central Hospital in the period 1995-2010. Most of the patients (80.7%) were outpatients. For each patient four controls were selected and matched for age, sex and place of residence. The matching was taken into account by modelling end-point events using Cox's proportional hazard model. The hazard ratio (HR) for all-cause mortality was 6.51 (95% CI 3.46-12.26) in broad anorexia nervosa (AN), 2.97 (95% CI 1.90-4.65) in broad bulimia nervosa (BN), and 1.77 (95% CI 0.60-5.27) in binge eating disorder (BED). Mortality risk in broad AN was highest during the first years after admission but declined thereafter, while in broad BN the mortality risk started to rise two years after the first admission. The HR for suicide was elevated both in broad AN (HR 5.07; 95% CI 1.37-18.84) and in broad BN (HR 6.07; 95% CI 2.47-14.89). Results show that eating disorders are associated with increased mortality risk even when specialised treatment is available.
[Show abstract][Hide abstract] ABSTRACT: Our aim was to assess the impact of the most commonly used typical and atypical antipsychotics on mortality of patients with first-onset schizophrenia.
We conducted a nationwide, register-based, five-year follow-up study of all patients presenting with first-onset of schizophrenia between 1998 and 2003. Details of reimbursed medicines were obtained from the register of Social Insurance Institution.
After adjusting for age, gender, comorbid physical diseases and patient group, the use of second generation antipsychotics (SGAs), especially clozapine, olanzapine and quetiapine, was associated with reduced risk of all-cause mortality in patients with schizophrenia, while clozapine associated with lower suicide risk. First generation antipsychotics (FGAs), specifically levomepromazine, thioridazine or clorprothixene, were associated with increased risk of all-cause mortality. The FGAs, particularly clorprothixene, were associated with decreased suicide mortality. An increased likelihood for cardiovascular deaths was found among users of levomepromazine. In antidepressants, the use of mirtazapine associated with increased risk of suicide.
Differences exist between FGAs' and SGAs' use in relation to mortality. These differences remain even when the patient's physical illness are taken into account when prescribing antipsychotic medication.
Schizophrenia Research 08/2013; 150(1). DOI:10.1016/j.schres.2013.07.043 · 4.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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 found that the enrichment of a rare chromosome 22q11.22 deletion in a recently expanded Northern Finnish sub-isolate enabled the detection of association between TOP3B and both schizophrenia and cognitive impairment. Biochemical analysis of TOP3β revealed that this topoisomerase was a component of cytosolic messenger ribonucleoproteins (mRNPs) and was 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. Our results indicate a previously unknown role for TOP3β in mRNA metabolism and suggest that it is involved in neurodevelopmental disorders.
[Show abstract][Hide abstract] ABSTRACT: Congenital muscular dystrophies with hypoglycosylation of α-dystroglycan (α-DG) are a heterogeneous group of disorders often associated with brain and eye defects in addition to muscular dystrophy. Causative variants in 14 genes thought to be involved in the glycosylation of α-DG have been identified thus far. Allelic mutations in these genes might also cause milder limb-girdle muscular dystrophy phenotypes. Using a combination of exome and Sanger sequencing in eight unrelated individuals, we present evidence that mutations in guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) can result in muscular dystrophy variants with hypoglycosylated α-DG. GMPPB catalyzes the formation of GDP-mannose from GTP and mannose-1-phosphate. GDP-mannose is required for O-mannosylation of proteins, including α-DG, and it is the substrate of cytosolic mannosyltransferases. We found reduced α-DG glycosylation in the muscle biopsies of affected individuals and in available fibroblasts. Overexpression of wild-type GMPPB in fibroblasts from an affected individual partially restored glycosylation of α-DG. Whereas wild-type GMPPB localized to the cytoplasm, five of the identified missense mutations caused formation of aggregates in the cytoplasm or near membrane protrusions. Additionally, knockdown of the GMPPB ortholog in zebrafish caused structural muscle defects with decreased motility, eye abnormalities, and reduced glycosylation of α-DG. Together, these data indicate that GMPPB mutations are responsible for congenital and limb-girdle muscular dystrophies with hypoglycosylation of α-DG.
The American Journal of Human Genetics 06/2013; 93(1). DOI:10.1016/j.ajhg.2013.05.009 · 10.99 Impact Factor