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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), followed by two stages of genotyping across 6668 individuals from multiple Finnish cohorts for major mental illnesses. We identified 4570 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 (g-score p = 0.044, β = –0.033). Specifically, the cognitive domains represented verbal learning and memory (p = 0.0091, β = –0.044) and verbal working memory (p = 0.0062, β = −0.036). 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; m-value = 0.9), 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.

Background Osteoarthritis (OA) is a leading cause of disability and pain especially among older adults, but it is also known to affect working age individuals, often leading to reduced productivity and increased healthcare usage. The aim of this study was to determine the burden of hip and knee OA in Finnish occupational healthcare. Methods This was a retrospective registry study utilizing the electronic medical records of the largest private and occupational healthcare provider in Finland. All consented patients with hip or knee OA were identified. A subcohort of occupational healthcare (OCH) patients was then compared to an age- and gender-matched control group without OA. Patient demographics including comorbidities were determined and healthcare contacts, medication prescriptions, and sick leaves were compared between the two groups. The study period was from January 1st, 2012 to April 30th, 2020. Results 51,068 patients with hip or knee OA were identified (all OA cohort) and 35,109 of these formed the occupational healthcare subcohort. Most of the OA patients were female and belonged to the age group 50–59 years. The point prevalence of hip/knee OA at the end of the study period was 5.6% for the occupational healthcare subcohort. OA patients had 2.2 times more healthcare contacts and 2.8 times more overall sick leave days compared to the age- and gender-matched control cohort. Etoricoxib was the most commonly prescribed medication at OA-related visits (21.8% of patients). Opioids were prescribed to 10.6% of patients at OA-related visits and the most prescribed opioid was a combination of codeine and paracetamol (4.8% of patients). 5054 OA patients (14.4%) had a contraindication for non-steroidal anti-inflammatory drugs (NSAIDs). Conclusions This retrospective registry study utilizing real-world data provides new evidence on the disease burden of hip or knee osteoarthritis from the electronic medical records of Finnish occupational healthcare customers. OA patients had more comorbidities, more healthcare contacts, more sick leave days, and more analgesic prescriptions compared to an age- and gender-matched control cohort without OA.

Music-listening and performance have been shown to affect human gene expression. In order to further elucidate the biological basis of the effects of music on the human body, we studied the effects of music-listening on gene regulation by sequencing microRNAs of the listeners (Music Group) and their controls (Control Group) without music exposure. We identified upregulation of six microRNAs (hsa-miR-132-3p, hsa-miR-361-5p, hsa-miR-421, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-25-3p) and downregulation of two microRNAs (hsa-miR-378a-3p, hsa-miR-16-2-3p) in Music Group with high musical aptitude. Some upregulated microRNAs were reported to be responsive to neuronal activity (miR-132, miR-23a, miR-23b) and modulators of neuronal plasticity, CNS myelination, and cognitive functions like long-term potentiation and memory. miR-132 plays a critical role in regulating TAU protein levels and is important for preventing tau protein aggregation that causes Alzheimer's disease. miR-132 andDICER, upregulated after music-listening, protect dopaminergic neurons and are important for retaining striatal dopamine levels. Some of the transcriptional regulators (FOS, CREB1, JUN, EGR1,andBDNF) of the upregulated microRNAs were immediate early genes and top candidates associated with musical traits.BDNFand SNCA, co-expressed and upregulated in music-listening and music-performance, are both are activated by GATA2, which is associated with musical aptitude. Several miRNAs were associated with song-learning, singing, and seasonal plasticity networks in songbirds. We did not detect any significant changes in microRNA expressions associated with music education or low musical aptitude. Our data thereby show the importance of inherent musical aptitude for music appreciation and for eliciting the human microRNA response to music-listening.

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 females. Here we set out to identify any functional variations implicated by this haplotype. We used a sequencing and genotyping study design to identify variations of interest in a Finnish familial cohort ascertained for schizophrenia. We identified 295 variants through sequencing, none of which were located directly within microRNA-484. Two variants were observed to associate with schizophrenia in a sex-dependent manner (females only) in the whole schizophrenia familial cohort (rs2242549 P = .00044; OR = 1.20, 95% CI 1.03–1.40; rs881803 P = .00021; OR = 1.20, 95% CI 1.02–1.40). Both variants were followed up in additional psychiatric cohorts, with neuropsychological traits, and gene expression data, in order to further examine their role. Gene expression data from the familial schizophrenia cohort demonstrated a significant association between rs881803 and 1504 probes (FDR q < 0.05). These were significantly enriched for genes that are predicted miR-484 targets (n = 54; P = .000193), and with probes differentially expressed between the sexes (n = 48; P = .000187). While both SNPs are eQTLs for NDE1, rs881803 is located in a predicted transcription factor binding site. Based on its location and association pattern, we conclude that rs881803 is the prime functional candidate under this locus, affecting the roles of both NDE1 and miR-484 in psychiatric disorders.

Here, we used microRNA sequencing to study the effect of 20 minutes of classical music-listening on the peripheral blood microRNA transcriptome in subjects characterized for musical aptitude and music education and compared it to a control study without music for the same duration. In participants with high musical aptitude, we identified up-regulation of six microRNAs (hsa-miR-132-3p, hsa-miR-361-5p, hsa-miR-421, hsa-miR-23a-3p, hsa-miR-23b-3p, hsa-miR-25-3p) and down-regulation of two microRNAs (hsa-miR-378a-3p, hsa-miR-16-2-3p) post music-listening. The up-regulated microRNAs were found to be regulators of neuron apoptosis and neurotoxicity, consistent with previously reported neuroprotective role of music. Some up-regulated microRNAs were reported to be responsive to neuronal activity (miR-132, miR-23a, miR-23b) and modulators of neuronal plasticity, CNS myelination and cognitive functions like long-term potentiation and memory. miR-132 and DICER, up-regulated after music-listening, protect dopaminergic neurons and is important for retaining striatal dopamine levels. miR-23 putatively activates pro-survival PI3K/AKT signaling cascade, which is coupled with dopaminergic signaling. Some of the transcriptional regulators (FOS, CREB1, JUN, EGR1 and BDNF) of the up-regulated microRNAs are sensory-motor stimuli induced immediate early genes and top candidates associated with musical traits. Amongst these, BDNF is co-expressed with SNCA, up-regulated in music-listening and music-performance, and both are activated by GATA2, which is associated with musical aptitude. Some of the candidate microRNAs and their putative regulatory interactions were previously identified to be associated with song-learning, singing and seasonal plasticity networks in songbirds and imply evolutionary conservation of the auditory perception process: miR-23a, miR-23b and miR-25 repress PTEN and indirectly activates the MAPK signaling pathway, a regulator of neuronal plasticity which is activated after song-listening. We did not detect any significant changes in microRNA expressions associated with music education or low musical aptitude. Our data thereby show the importance of inherent musical aptitude for music appreciation and for eliciting the human microRNA response to music-listening.

We have previously reported a replicable association between variants at thePDE4Dgene and familial schizophrenia in a Finnish cohort. In order to identify the potential functional mutations alluded to by these previous findings, we sequenced the 1.5Mb of thePDE4Dgenomic locus in 20 families (consisting of 96 individuals, and 79 independent chromosomes), followed by two stages of genotyping across 6,668 individuals from multiple Finnish cohorts for major mental illnesses. We identified 4,570 SNPs across thePDE4Dgene, 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 (g-score p=0.044, beta=-0.033). Specifically, the cognitive domains represented verbal learning and memory (p=0.0091, beta=-0.044) and verbal working memory (p=0.0062, beta=-0.036). Moreover, expression data from the GTEx database demonstrated that rs165940 significantly correlates with the mRNA expression levels ofPDE4Din the cerebellum (p-value=0.04; m-value=0.9), demonstrating a potential functional consequence for this variant. Thus, rs165940 represents the most likely functional variant for major mental illness at thePDE4Dlocus in the Finnish population, increasing risk broadly to psychotic disorders.

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.

Here we characterized the genome-wide architecture of copy number variations (CNVs) in 286 healthy, unrelated Finnish individuals belonging to the MUSGEN study, where molecular background underlying musical aptitude and related traits are studied. By using Illumina HumanOmniExpress-12v.1.0 beadchip, we identified 5493 CNVs that were spread across 467 different cytogenetic regions, spanning a total size of 287.83 Mb (∼9.6% of the human genome). Merging the overlapping CNVs across samples resulted in 999 discrete copy number variable regions (CNVRs), of which ∼6.9% were putatively novel. The average number of CNVs per person was 20, whereas the average size of CNV per locus was 52.39 kb. Large CNVs (1 Mb) were present in 4% of the samples. The proportion of homozygous deletions in this data set (∼12.4%) seemed to be higher when compared with three other populations. Interestingly, several CNVRs were significantly enriched in this sample set, whereas several others were totally depleted. For example, a CNVR at chr2p22.1 intersecting GALM was more common in this population (P=3.3706 × 10(-44)) than in African and other European populations. The enriched CNVRs, however, showed no significant association with music-related phenotypes. Moreover, the most common CNV locations in world's normal population cohorts (6q14.1, 11q11) were overrepresented in this population. Thus, the genome-wide CNV investigation in this Finnish sample set demonstrated features that are characteristic to isolated populations. Novel CNVRs and the functional implications of CNVs revealed in this study elucidate structural variation present in this population isolate, and may also serve as candidate gene loci for music-related traits.

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.

Abilities related to musical aptitude appear to have a long history in human evolution. To elucidate the molecular and evolutionary background of musical aptitude, we compared genome-wide genotyping data (641 K SNPs) of 148 Finnish individuals characterized for musical aptitude. We assigned signatures of positive selection in a case-control setting using three selection methods: haploPS, XP-EHH and FST. Gene ontology classification revealed that the positive selection regions contained genes affecting inner-ear development. Additionally, literature survey has shown that several of the identified genes were known to be involved in auditory perception (e.g. GPR98, USH2A), cognition and memory (e.g. GRIN2B, IL1A, IL1B, RAPGEF5), reward mechanisms (RGS9), and song perception and production of songbirds (e.g. FOXP1, RGS9, GPR98, GRIN2B). Interestingly, genes related to inner-ear development and cognition were also detected in a previous genome-wide association study of musical aptitude. However, the candidate genes detected in this study were not reported earlier in studies of musical abilities. Identification of genes related to language development (FOXP1 and VLDLR) support the popular hypothesis that music and language share a common genetic and evolutionary background. The findings are consistent with the evolutionary conservation of genes related to auditory processes in other species and provide first empirical evidence for signatures of positive selection for abilities that contribute to musical aptitude.

Creative activities in music represent a complex cognitive function of the human brain, whose biological basis is largely unknown. In order to elucidate the biological background of creative activities in music we performed genome-wide linkage and linkage disequilibrium (LD) scans in musically experienced individuals characterised for self-reported composing, arranging and non-music related creativity. The participants consisted of 474 individuals from 79 families, and 103 sporadic individuals. We found promising evidence for linkage at 16p12.1-q12.1 for arranging (LOD 2.75, 120 cases), 4q22.1 for composing (LOD 2.15, 103 cases) and Xp11.23 for non-music related creativity (LOD 2.50, 259 cases). Surprisingly, statistically significant evidence for linkage was found for the opposite phenotype of creative activity in music (neither composing nor arranging; NCNA) at 18q21 (LOD 3.09, 149 cases), which contains cadherin genes like CDH7 and CDH19. The locus at 4q22.1 overlaps the previously identified region of musical aptitude, music perception and performance giving further support for this region as a candidate region for broad range of music-related traits. The other regions at 18q21 and 16p12.1-q12.1 are also adjacent to the previously identified loci with musical aptitude. Pathway analysis of the genes suggestively associated with composing suggested an overrepresentation of the cerebellar long-term depression pathway (LTD), which is a cellular model for synaptic plasticity. The LTD also includes cadherins and AMPA receptors, whose component GSG1L was linked to arranging. These results suggest that molecular pathways linked to memory and learning via LTD affect music-related creative behaviour. Musical creativity is a complex phenotype where a common background with musicality and intelligence has been proposed. Here, we implicate genetic regions affecting music-related creative behaviour, which also include genes with neuropsychiatric associations. We also propose a common genetic background for music-related creative behaviour and musical abilities at chromosome 4.

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 variants in the DISC1 gene have also been noted to associate with the risk to other mental illnesses in the Finnish population, including bipolar disorder and autism spectrum disorders, as well as to variations in phenotypes such as visual working memory, anhedonia, and gray matter volume in the dorsal lateral prefrontal cortex. Furthermore, studies in the SCZ family cohort have also observed association at genes for DISC1 interacting partners, the DISC1 network, including NDE1, PDE4D, PDE4B, and NDEL1. Despite this consistent line of evidence for these loci in the Finnish population, any true causal variants have yet to be identified. Methods To identify any potential mutations a subset of SCZ families (n=20 families, 96 individuals) were sequenced at 24 genes from the extended DISC1 network. All identified variants were then prioritized using association analysis (p Results With the aid of the three step sequencing and genotyping approach, we identified 12,795 variants in the DISC1 gene network, of which 67 variants from 9 genes were identified as associated (p Discussion This research aims to identify the potential mutations within the DISC1 network which have been alluded to through our previous studies of Finnish cohorts for major mental illness. Our initial findings confirm the observation of association at a number of DISC1 network genes, including DISC1 itself, while focusing on the specific variants at these loci that have potential functional consequences. Thus, the variants we are observing may represent the principal mutations at these loci in the Finnish population, and predispose to psychiatric disorders beyond schizophrenia.

Music perception and practice represent complex cognitive functions of the human brain. Recently, evidence for the molecular genetic background of music related phenotypes has been obtained. In order to further elucidate the molecular background of musical phenotypes we analyzed genome wide copy number variations (CNVs) in five extended pedigrees and in 172 unrelated subjects characterized for musical aptitude and creative functions in music. Musical aptitude was defined by combination of the scores of three music tests (COMB scores): auditory structuring ability, Seashores test for pitch and for time. Data on creativity in music (herein composing, improvising and/or arranging music) was surveyed using a web-based questionnaire. Several CNVRs containing genes that affect neurodevelopment, learning and memory were detected. A deletion at 5q31.1 covering the protocadherin-α gene cluster (Pcdha 1-9) was found co-segregating with low music test scores (COMB) in both sample sets. Pcdha is involved in neural migration, differentiation and synaptogenesis. Creativity in music was found to co-segregate with a duplication covering glucose mutarotase gene (GALM) at 2p22. GALM has influence on serotonin release and membrane trafficking of the human serotonin transporter. Interestingly, genes related to serotonergic systems have been shown to associate not only with psychiatric disorders but also with creativity and music perception. Both, Pcdha and GALM, are related to the serotonergic systems influencing cognitive and motor functions, important for music perception and practice. Finally, a 1.3 Mb duplication was identified in a subject with low COMB scores in the region previously linked with absolute pitch (AP) at 8q24. No differences in the CNV burden was detected among the high/low music test scores or creative/non-creative groups. In summary, CNVs and genes found in this study are related to cognitive functions. Our result suggests new candidate genes for music perception related traits and supports the previous results from AP study.

Music is listened in all cultures. We hypothesize that willingness to produce and perceive sound and music is social communication that needs musical aptitude. Here, listening to music was surveyed using a web-based questionnaire and musical aptitude using the auditory structuring ability test (Karma Music test) and Carl Seashores tests for pitch and for time. Three highly polymorphic microsatellite markers (RS3, RS1 and AVR) of the arginine vasopressin receptor 1A (AVPR1A) gene, previously associated with social communication and attachment, were genotyped and analyzed in 31 Finnish families (n=437 members) using family-based association analysis. A positive association between the AVPR1A haplotype (RS1 and AVR) and active current listening to music (permuted P=0.0019) was observed. Other AVPR1A haplotype (RS3 and AVR) showed association with lifelong active listening to music (permuted P=0.0022). In addition to AVPR1A, two polymorphisms (5-HTTLPR and variable number of tandem repeat) of human serotonin transporter gene (SLC6A4), a candidate gene for many neuropsychiatric disorders and previously associated with emotional processing, were analyzed. No association between listening to music and the polymorphisms of SLC6A4 were detected. The results suggest that willingness to listen to music is related to neurobiological pathways affecting social affiliation and communication.