Common Gene Variants in Schizophrenia Susceptibility with Focus on Neurodevelopment

Schizophrenia is a severe multifactorial mental disorder with an important and complex genetic component, and the understanding of the underlying biological mechanisms is limited. Several lines of evidence support that abnormal neurodevelopment is involved, such as cognitive deficits in children who later develop schizophrenia, abnormalities in brain structure in the early phase of disease, and aberrant neuronal distributions. Also, glutamatergic dysfunctions are suggested in the schizophrenia etiology, and glutamate signalling is important during neurodevelopment. Perineuronal nets are extracellular matrix structures involved in brain maturation, which includes the characteristic neural epitope Human Natural Killer-1 (HNK-1). To investigate if common gene variants important for neurodevelopment are involved in schizophrenia etiology, we used candidate gene-based association studies of tagSNPs spanning thirty genes, genotyped in a large Scandinavian case-control sample (SCOPE). Nineteen, out of the 289 tagSNPs in 18 neuronal migration genes, were nominally significant, and the strongest finding was a tagSNP located in MAM domain containing glycosylphosphatidylinositol anchor 1 (MDGA1), but no findings were significant after correction. Phosphodiesterase 4B (PDE4B) is a Disrupted-in-Schizophrenia-1 (DISC1) interactor, with previously reported genetic associations only in women. Six and 16, out of 40 and 72 PDE4B tagSNPs, were nominally associated with schizophrenia and bipolar disorder, respectively, in the combined samples or in gender-specific subgroups. No findings were significant after correction. However, two of the tagSNPs nominally associated in schizophrenia females had proxies which were nominally associated in the total bipolar disorder sample, and the four SNPs were located in the same block, surrounding the splice site for the PDE4B3 isoform. Five out of 104 tagSNPs in ten genes involved in perineuronal net formation and HNK-1 biosynthesis, located in beta-1,3-glucuronyltransferase 2 (B3GAT2), were nominally associated with schizophrenia. The association signal for tagSNPs in one of the LD blocks was replicated by proxy SNPs in a much larger European sample (SGENE-plus). Six out of 30 tagSNPs in glutamate receptor ionotrophic kainate 3 (GRIK3) were nominally associated, and the best tagSNP were significant after correction, with increased significance in the Swedish subsample, as well as when the risk allele was combined with another tagSNP risk allele. When investigating clinical characteristics, including positive and negative symptom scores, age at onset, and cognitive measures of learning, memory and IQ, for association with a subset of the tagSNPs and genes included in the thesis studies, there were no significant associations after correction. The current results indicate that gene variants involved in neurodevelopment are associated with schizophrenia, which further supports the neurodevelopmental hypothesis

Genetics of Tinnitus: Time to Biobank Phantom Sounds

Tinnitus is a common phantom sensation resulting most often from sensory deprivation, and for which little knowledge on the molecular mechanisms exists. While the existing evidence for a genetic influence on the condition has been until now sparse and underpowered, recent data suggest that specific forms of tinnitus have a strong genetic component revealing that not all tinnitus percepts are alike, at least in how they are genetically driven. These new findings pave the way for a better understanding on how phantom sensations are molecularly driven and call for international biobanking efforts

Comprehensive analysis of copy number variation in monozygotic twins discordant for bipolar disorder or schizophrenia

Copy number variation plays a clear role in the etiology of many psychiatric disorders, particularly schizophrenia. We performed array-CGH to look for copy number variants between five pairs of monozygotic twins discordant for bipolar disorder or schizophrenia. Our study found no differences in copy number variants between the sets of twins. Although alluring, realistic accounting for heterogeneity and chimerism highlight the technological limitations in studying monozygotic twins discordant for psychiatric disorders

Polygenic overlap between schizophrenia risk and antipsychotic response: a genomic medicine approach

Therapeutic treatments for schizophrenia do not alleviate symptoms for all patients and efficacy is limited by common, often severe, side-effects. Genetic studies of disease can identify novel drug targets, and drugs for which the mechanism has direct genetic support have increased likelihood of clinical success. Large-scale genetic studies of schizophrenia have increased the number of genes and gene sets associated with risk. We aimed to examine the overlap between schizophrenia risk loci and gene targets of a comprehensive set of medications to potentially inform and improve treatment of schizophrenia

Mental health indicators in Sweden over a 12-month period during the COVID-19 pandemic – Baseline data of the Omtanke2020 Study

Funding Information: This study was funded with grants from NordForsk (CovidMent, 105668 ), Horizon 2020 (CoMorMent, 847776 ), and the Karolinska Institutet . Funding Information: The Omtanke2020 study is supported by NordForsk (project No. 105668 ) and Karolinska Institute (Strategic Research Area in Epidemiology and Senior Researcher Award). We acknowledge The Swedish Twin Registry for access to contact information to participating twins. The Swedish Twin Registry is managed by Karolinska Institutet and receives funding through the Swedish Research Council under the grant no 2017-00641. The Funding Sources had no direct or indirect impact on the analysis and interpretation of the results. Publisher Copyright: © 2022 The AuthorsBackground: The ongoing COVID-19 pandemic has had an unprecedented impact on the lives of people globally and is expected to have profound effects on mental health. Here we aim to describe the mental health burden experienced in Sweden using baseline data of the Omtanke2020 Study. Method: We analysed self-reported, cross-sectional baseline data collected over a 12-month period (June 9, 2020–June 8, 2021) from the Omtanke2020 Study including 27,950 adults in Sweden. Participants were volunteers or actively recruited through existing cohorts and, after providing informed consent, responded to online questionnaires on socio-demographics, mental and physical health, as well as COVID-19 infection and impact. Poisson regression was fitted to assess the relative risk of demonstrating high level symptoms of depression, anxiety, and COVID-19 related distress. Result: The proportion of persons with high level of symptoms was 15.6 %, 9.5 % and 24.5 % for depression, anxiety, and COVID-19 specific post-traumatic stress disorder (PTSD), respectively. Overall, 43.4 % of the participants had significant, clinically relevant symptoms for at least one of the three mental health outcomes and 7.3 % had significant symptoms for all three outcomes. We also observed differences in the prevalence of these outcomes across strata of sex, age, recruitment type, COVID-19 status, region, and seasonality. Conclusion: While the proportion of persons with high mental health burden remains higher than the ones reported in pre-pandemic publications, our estimates are lower than previously reported levels of depression, anxiety, and PTSD during the pandemic in Sweden and elsewhere.Peer reviewe

Genome-wide Association Analysis Identifies 14 New Risk Loci for Schizophrenia

Schizophrenia is a heritable disorder with 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, 6,243 controls) followed by meta-analysis with prior schizophrenia GWAS (8,832 cases, 12,067 controls) and finally by replication of SNPs in 168 genomic regions in independent samples (7,413 cases, 19,762 controls, and 581 trios). In total, 22 regions met genome-wide significance (14 novel and one previously implicated in bipolar disorder). The results strongly implicate calcium signaling in the etiology of schizophrenia, and include genome-wide significant results for CACNA1C and CACNB2 whose protein products interact. We estimate that ∼8,300 independent and predominantly common SNPs contribute to risk for schizophrenia and that these collectively account for most of its heritability. Common genetic variation plays an important role in the etiology of schizophrenia, and larger studies will allow more detailed understanding of this devastating disorder

Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss

Hearing loss is one of the top contributors to years lived with disability and is a risk factor for dementia. Molecular evidence on the cellular origins of hearing loss in humans is growing. Here, we performed a genome-wide association meta-analysis of clinically diagnosed and self-reported hearing impairment on 723,266 individuals and identified 48 significant loci, 10 of which are novel. A large proportion of associations comprised missense variants, half of which lie within known familial hearing loss loci. We used single-cell RNA-sequencing data from mouse cochlea and brain and mapped common-variant genomic results to spindle, root, and basal cells from the stria vascularis, a structure in the cochlea necessary for normal hearing. Our findings indicate the importance of the stria vascularis in the mechanism of hearing impairment, providing future paths for developing targets for therapeutic intervention in hearing loss

A polygenic burden of rare disruptive mutations in schizophrenia

By analyzing the exome sequences of 2,536 schizophrenia cases and 2,543 controls, we have demonstrated a polygenic burden primarily arising from rare (<1/10,000), disruptive mutations distributed across many genes. Especially enriched genesets included the voltage-gated calcium ion channel and the signaling complex formed by the activity-regulated cytoskeleton-associated (ARC) scaffold protein of the postsynaptic density (PSD), sets previously implicated by genome-wide association studies (GWAS) and copy-number variation (CNV) studies. Similar to reports in autism, targets of the fragile × mental retardation protein (FMRP, product of FMR1) were enriched for case mutations. No individual gene-based test achieved significance after correction for multiple testing and we did not detect any alleles of moderately low frequency (~0.5-1%) and moderately large effect. Taken together, these data suggest that population-based exome sequencing can discover risk alleles and complements established gene mapping paradigms in neuropsychiatric disease

Partitioning Heritability of Regulatory and Cell-Type-Specific Variants across 11 Common Diseases

Regulatory and coding variants are known to be enriched with associations identified by genome-wide association studies (GWASs) of complex disease, but their contributions to trait heritability are currently unknown. We applied variance-component methods to imputed genotype data for 11 common diseases to partition the heritability explained by genotyped SNPs (hg2) across functional categories (while accounting for shared variance due to linkage disequilibrium). Extensive simulations showed that in contrast to current estimates from GWAS summary statistics, the variance-component approach partitions heritability accurately under a wide range of complex-disease architectures. Across the 11 diseases DNaseI hypersensitivity sites (DHSs) from 217 cell types spanned 16% of imputed SNPs (and 24% of genotyped SNPs) but explained an average of 79% (SE = 8%) of hg2 from imputed SNPs (5.1× enrichment; p = 3.7 × 10−17) and 38% (SE = 4%) of hg2 from genotyped SNPs (1.6× enrichment, p = 1.0 × 10−4). Further enrichment was observed at enhancer DHSs and cell-type-specific DHSs. In contrast, coding variants, which span 1% of the genome, explained <10% of hg2 despite having the highest enrichment. We replicated these findings but found no significant contribution from rare coding variants in independent schizophrenia cohorts genotyped on GWAS and exome chips. Our results highlight the value of analyzing components of heritability to unravel the functional architecture of common disease