Jouko Lonnqvist

Finnish Institute for Health and Welfare | THL · Department of Mental Health and Substance Abuse Services (MHSA)

Genetic factors contribute to the susceptibility of psychotic disorders, but less is known how they affect psychotic disease-course development. Utilizing polygenic scores (PGSs) in combination with longitudinal healthcare data with decades of follow-up we investigated the contributing genetics to psychotic disease-course severity and diagnostic sh...

Several lines of evidence indicate the involvement of neuroinflammatory processes in the pathophysiology of schizophrenia (SCZ). Microglia are brain resident immune cells responding toward invading pathogens and injury-related products, and additionally, have a critical role in improving neurogenesis and synaptic functions. Aberrant activation of m...

Purpose SUPER-Finland is a large Finnish collection of psychosis cases. This cohort also represents the Finnish contribution to the Stanley Global Neuropsychiatric Genetics Initiative, which seeks to diversify genetic sample collection to include Asian, Latin American and African populations in addition to known population isolates, such as Finland...

Variants in the SLCO1B1 (solute carrier organic anion transporter family member 1B1) gene encoding the OATP1B1 (organic anion transporting polypeptide 1B1) protein are associated with altered transporter function that can predispose patients to adverse drug effects with statin treatment. We explored the effect of six rare SLCO1B1 single nucleotide...

Background Substance use and sleep problems are common in patients with psychotic disorders, but their associations in these patients have not been evaluated. Our aim was to investigate associations between substance use and sleep problems in a large nationwide cohort of patients with a psychotic disorder. Study design This study is part of the Fi...

Several lines of evidence indicate the involvement of neuroinflammatory processes in the pathophysiology of schizophrenia (SCZ). Microglia are brain resident immune cells responding toward invading pathogens and injury-related products, and additionally, have a critical role in improving neurogenesis and synaptic functions. Hyperactivation of micro...

Aim Variants in the SLCO1B1 (solute carrier organic anion transporter family member 1B1) gene encoding the OATP1B1 (organic anion transporting polypeptide 1B1) protein are associated with altered transporter function that can predispose patients to adverse drug effects with statin treatment. We explored the effect of six rare SLCO1B1 single nucleot...

We demonstrate that CYP2D6 copy-number variation (CNV) can be imputed using existing imputation algorithms. Additionally, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. We combined GWAS chip and CYP2D6 CNV data from the Breast Cancer Pain Genet...

Objective Characterizing sleep in patients with schizophrenia, schizoaffective disorder, bipolar disorder, and psychotic depression. Methods This cross-sectional questionnaire study is based on the SUPER study sample, which is part of the Stanley Global Neuropsychiatric Genomics Initiative. The study is a multicentre, nationwide Finnish study cons...

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 mo...

The purpose of this study was to explore the association of cognition with hazardous drinking Polygenic Scores (PGS) in 2649 schizophrenia, 558 schizoaffective disorder, and 1125 bipolar disorder patients in Finland. Hazardous drinking PGS was computed using the LDPred program. Participants performed two computerized tasks from the Cambridge Automa...

The purpose of this study was to explore the association of cognition with hazardous drinking and alcohol-related disorder in persons with bipolar disorder (BD). The study population included 1268 persons from Finland with bipolar disorder. Alcohol use was assessed through hazardous drinking and alcohol-related disorder including alcohol use disord...

The purpose of this study was to explore the association of cognition with hazardous drinking and alcohol related disorder in persons with bipolar disorder (BD). The study population included 1,268 persons from Finland with bipolar disorder. Alcohol use was assessed through hazardous drinking and alcohol related disorder including alcohol use disor...

The purpose of this study was to explore the association between cognition and hazardous drinking and alcohol use disorder in schizophrenia and schizoaffective disorder. Cognition is more or less compromised in schizophrenia, and schizoaffective disorder and alcohol use might aggravate this phenomenon. The study population included 3362 individuals...

The molecular pathophysiological mechanisms underlying schizophrenia have remained unknown, and no treatment exists for primary prevention. We used Ingenuity Pathway Analysis to analyze canonical and causal pathways in two different datasets, including patients from Finland and USA. The most significant findings in canonical pathway analysis were o...

Telomeres are repeat sequences and an associated protein complex located at the end of the chromosomes. They shorten with every cell division and are regarded markers for cellular aging. Shorter leukocyte telomere length (LTL) has been observed in many complex diseases, including psychiatric disorders. However, analyses focusing on psychiatric diso...

Purpose of the study was to explore the association of cognition with hazardous drinking, binge drinking and alcohol use disorder in schizophrenia and schizoaffective disorder. Cognitive deficits are common in schizophrenia. Alcohol might be associated with additional cognitive impairment in schizophrenia patients. The study population included 336...

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 underlying these previous findings, we sequenced 1.5 Mb of the PDE4D genomic locus in 20 families (consisting of 96 individuals and 79 independent chromosomes...

Purpose We constructed a CYP2D6 copy-number imputation panel by combining copy-number information to GWAS chip data. In addition, we report frequencies of key pharmacogenetic variants in individuals with a psychotic disorder from the genetically bottle-necked population of Finland. Methods We combined GWAS chip and CYP2D6 copy-number variation (CN...

Human astrocytes are multifunctional brain cells and may contribute to the pathophysiology of schizophrenia (SCZ). We differentiated astrocytes from induced pluripotent stem cells of monozygotic twins discordant for SCZ, and found sex-specific gene expression and signaling pathway alterations related particularly to inflammation and synaptic functi...

The molecular pathophysiological mechanisms underlying schizophrenia have remained unknown, and no treatment exists for primary prevention. Studies using stem cell−derived neurons have investigated differentially expressed genes (DEGs) and GO and KEGG pathways between patients and controls, but not analyzed data−driven causal molecular pathways inv...

Background Schizophrenia patients have been found to have long lasting, clinical state independent impairments in intellectual abilities as well as in specific cognitive domains of which visual learning and memory are central to our current study. The main aim of this study was to investigate the sociodemographic and lifestyle factors associated wi...

Through copy number variations, the 16p13.11 locus has been consistently linked to mental disorders. This locus contains the NDE1 gene, which also encodes microRNA-484. Both of them have been highlighted to play a role in the etiology of mental illness. A 4-SNP haplotype spanning this locus has been shown to associate with schizophrenia in Finnish...

It has remained unclear why schizophrenia typically manifests after adolescence and which neurobiological mechanisms are underlying the cascade leading to the actual onset of the illness. Here we show that the use of induced pluripotent stem cell-derived neurons of monozygotic twins from pairs discordant for schizophrenia enhances disease-specific...

Background The estimated heritability of schizophrenia is 80–85%, and if one of monozygotic twins has the illness, the risk for the other twin is about 50%. It has remained unclear which factors are associated just with the increased risk, and which neurobiological mechanisms are related to the cascade leading to actual onset of illness. It has als...

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 utilize gene expression and psychoactive medication use data to study their biological consequences and potential treatment implications. Gene expre...

Background Linkage and association studies of major mental illness in Finland have continually identified the 1q42 region, and the Disrupted in Schizophrenia 1 (DISC1) gene in particular, as being a key locus of interest. Haplotypes and variants in the DISC1 gene have been associated with Schizophrenia (SCZ), bipolar disorder, and autism spectrum d...

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 indi...

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 a...

Background People with psychotic disorders demonstrate a wide spectrum of sleep abnormalities. Abnormalities include changes in total sleep time, increased sleep onset latency, increased wake-up time after sleep onset and abnormalities in sleep architecture. The study aimed to characterize the sleep difficulties in a large sample of persons with ps...

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 expressi...

Schizophrenia is a highly heritable disease, but despite extensive study, its genetic background remains unresolved. The lack of environmental measures in genetic studies may offer some explanation. In recent Finnish studies, high birth weight was found to increase the risk for familial schizophrenia. We examined the interaction between a polygenic...

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 utilize gene expression and psychoactive medication use data to study their biological consequences and potential treatment implications. Gene exp...

Background The genetic etiology of schizophrenia (SCZ) has been studied in a familial Finnish cohort since the late 1980s. Over the years, linkage and association studies of these families have continually identified the 1q42 region, and the Disrupted in Schizophrenia 1 (DISC1) gene in particular, as being a key locus of interest. Haplotypes and va...

Previous studies in a Finnish family cohort for schizophrenia have observed significant association with haplotypes and SNPs from five genes within the DISC1 network: DISC1, NDE1, NDEL1, PDE4B and PDE4D. Here, in sub-samples of these Finnish families, we utilize gene expression levels and psychoactive medication use, in order to translate the role...

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....

By analyzing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls and 1,077 trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in SETD1A and risk for schizophrenia (P = 3.3 × 10(-9)). We found only two heterozygous LoF variants in 45,376 exomes from individuals without a neurops...

Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here w...

Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the major histocompatibility complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to identify. Here we show that this association ar...

Schizophrenia is a common, debilitating psychiatric disorder with a substantial genetic component. By analysing the whole-exome sequences of 4,264 schizophrenia cases, 9,343 controls, and 1,077 parent-proband trios, we identified a genome-wide significant association between rare loss-of-function (LoF) variants in KMT2F and risk for schizophrenia....

Suicide: an unnecessary death is a comprehensive summary of the study of suicide from the health-care and public mental health perspectives. The book offers an easy to read overview of prevention, diagnostics, and treatment, based on extensive research and experience of the foremost experts in suicidology. Suicidal behaviours are elucidated from th...

Genome-wide association studies (GWAS) of schizophrenia have yielded more than 100 common susceptibility variants, and strongly support a substantial polygenic contribution of a large number of small allelic effects. It has been hypothesized that familial schizophrenia is largely a consequence of inherited rather than environmental factors. We inve...

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel s...

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7×) or exomes (high read depth, 80×) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel s...

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...

Pre- and perinatal environmental factors have been shown to increase schizophrenia risk particularly when combined with genetic liability. The investigation of specific gene environment interactions in the etiology of psychiatric disorders has gained momentum. We used multivariate GEE regression modeling to investigate the interaction between genes...

The analysis of individuals with ciliary chondrodysplasias can shed light on sensitive mechanisms controlling ciliogenesis and cell signalling that are essential to embryonic development and survival. Here we identify TCTEX1D2 mutations causing Jeune asphyxiating thoracic dystrophy with partially penetrant inheritance. Loss of TCTEX1D2 impairs retr...

Mortality rates, in particular due to suicide, are especially high in bipolar patients. This nationwide, registry-based study analyses the associations of medication use with hospitalization due to attempted suicides, deaths from suicide, and overall mortality across different psychotropic agents in bipolar patients. Altogether 826 bipolar patients...

Background There is little information on lung function and respiratory diseases in people with psychosis. Aims To compare the respiratory health of people with psychosis with that of the general population. Method In a nationally representative sample of 8028 adult Finns, lung function was measured by spirometry. Information on respiratory disease...

Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analys...

Converging evidence implicates immune abnormalities in schizophrenia (SCZ), and recent genome-wide association studies (GWAS) have identified immune-related single-nucleotide polymorphisms (SNPs) associated with SCZ. Using the conditional false discovery rate (FDR) approach, we evaluated pleiotropy in SNPs associated with SCZ (n=21 856) and multipl...

The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7x) or exomes (high read depth, 80x) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel s...

The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency B0.25% (UK)) associated with plasma triglyceride (TG) levels (À 1.43 s.d. (s.e. ¼ 0.27 per minor allele (P-value ¼ 8.0 Â 10 À 8)...

The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency B0.25% (UK)) associated with plasma triglyceride (TG) levels (À 1.43 s.d. (s.e. ¼ 0.27 per minor allele (P-value ¼ 8.0 Â 10 À 8)...

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 ass...

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 epistas...

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 con...

Background: Mental disorders influence diet and food consumption, but there is a lack of consistent findings. Aims: To investigate food consumption, nutrient intakes and serum metabolic biomarkers in depressive, anxiety and alcohol use disorders in comparison with the remaining from a population-based nationwide sample. Methods: The study was...

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 dele...

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...

Background: This study investigated the epidemiology of eating disorders in a population-based sample of young adults. Method: A mental health questionnaire was sent to a nationally representative two-stage cluster sample of 1863 Finns aged 20-35 years. All screen-positives and a random sample of screen-negatives were invited to participate in a...

To investigate the role of socioeconomic status and psychological stress to potential associations between confidence in the future and a wide range of health-related behaviours. Web-based cross-sectional study including an 'Electronic Health Check' at the Finnish Happiness-Flourishing Study website linked to a TV programme on happiness and depress...

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 pop...