Expenditure and survival of adult patients with intestinal failure due to short bowel syndrome: real-world evidence from Southern Finland.

OBJECTIVES: Comprehensive follow-up data from the largest hospital district in Finland was used to assess hospital-based healthcare resource utilization (HCRU) and expenses, incidence and prevalence, survival, and effect of comorbidities/complications on survival of adult patients with intestinal failure due to short bowel syndrome (SBS-IF). METHODS: This study utilized electronic healthcare data covering all ≥18-year-old patients with SBS-IF at the Hospital District of Helsinki and Uusimaa in Finland between 2010 and 2019. Patients were followed from SBS-IF onset until the end of 2020 or death and compared to birth year and sex-matched control patients without SBS-IF. RESULTS: The study included 77 patients with SBS-IF (cases) and 363 controls. Cases had high HCRU; the cumulative expenses were about tenfold compared to the controls, at the end of the study (€123,000 vs. €14,000 per patient). The expenses were highest during the first year after SBS-IF onset (€53,000 per patient). Of the cases with a median age 62.5 years, 51.9% died during study time. The median survival was 4.4 years from SBS-IF onset and cases died 13.5 times more likely during the follow-up compared to controls. Mortality risk was lower in female cases (hazard ratio (HR) 0.46; 95% confidence intervals (CI) 0.24, 0.9) and higher with presence of comorbidities (Charlson comorbidity index HR 1.55; 95% CI 1.2, 2.0) and mesenteric infarction (HR 4.5; 95% CI 1.95, 10.36). The incidence of adult SBS-IF was 0.6 per 100,000 adults. CONCLUSION: Our study demonstrates a high demand for healthcare support and elevated mortality in adult SBS-IF-patients. Our results suggest that the presence of comorbidities is a key driver for mortality.

Pediatric Short Bowel Syndrome: Real-World Evidence on Incidence and Hospital Resource Use From a Finnish Data Lake.

OBJECTIVES: Little is known about the epidemiology and healthcare burden of pediatric intestinal failure (IF). We aimed to assess the incidence, prevalence, healthcare resource utilization (HCRU), and related costs of pediatric short bowel syndrome (SBS) using follow-up data from the largest hospital district in Finland. METHODS: This retrospective registry study utilized electronic healthcare data covering all pediatric patients with SBS-IF born between 2010 and 2019 at the Hospital District of Helsinki and Uusimaa in Finland. Patients were followed from birth until the end of 2020 and compared to control patients, all from the same hospital system. RESULTS: In total, 38 patients with SBS-IF and 1:5 matched controls were included, with median follow-up time of almost 6 years from birth. Over half of the patients were born early preterm (gestational age ≤30 weeks). The incidence of pediatric SBS-IF was 24 per 100,000 live births. The HCRU was higher compared to controls and most of the inpatient days incurred during the first year of the SBS-IF patients' life. The average hospital-based HCRU costs were €221,000 for the first year and €57,000 for whole follow-up annually. The costs were higher for the early preterm patients and accumulated mainly from inpatient days. CONCLUSIONS: SBS-IF is a rare disease with a relatively low number of patients treated at each hospital district. The burden on the hospital system, as well as the patient's family, is especially high at the onset as the newborns with SBS-IF spend a significant part of their first year of life in the hospital.

Effect of Disease Severity on Comorbid Conditions in Atopic Dermatitis: Nationwide Registry-Based Investigation in Finnish Adults.

The majority of registry studies on atopic dermatitis include only patients and diagnoses from specialized healthcare. The aim of this retrospective, real-world cohort study was to evaluate the effect of atopic dermatitis severity on comorbidities and total morbidity, with comprehensive data from both primary and specialty healthcare registries covering the entire Finnish adult population. In total, 124,038 patients were identified (median age 46 years; 68% female) and stratified by disease severity. All regression analyses (median follow-up 7.0 years) were adjusted at a minimum for age, sex, obesity, and educational level. Compared with mild atopic dermatitis, severe atopic dermatitis was significantly associated with multiple morbidities, including neurotic, stress-related and somatoform disorders, abscesses, erysipelas/cellulitis, impetigo, herpes zoster, extragenital herpes, bacterial conjunctivitis, septicaemia, lymphomas, alopecia areata, urticaria, other dermatitis, contact allergy, osteoporosis, and intervertebral disc disorders (p < 0.001). In addition, there were significant associations with alcohol dependence, depression, condylomas, rosacea, migraine, sleep apnoea, hypertension, enthesopathies, atherosclerosis, and drug-induced cataract (p < 0.05). Odds ratios were modest and mostly were between 1.10 and 2.75. Furthermore, patients with severe atopic dermatitis had lower incidences of prostate cancer, cystitis, and anogenital herpes than patients with mild atopic dermatitis (p < 0.05). These results suggest that severe atopic dermatitis results in significant overall morbidity.

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 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, ß = -0.033). Specifically, the cognitive domains represented verbal learning and memory (p = 0.0091, ß = -0.044) and verbal working memory (p = 0.0062, ß = -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.

Retrospective, Registry-based, Cohort Investigation of Clinical Outcomes in Patients with Cutaneous Squamous Cell Carcinoma and Basal Cell Carcinoma in Finland.

Most cases of keratinocyte cancer can be treated effectively with surgery. However, survival is reduced in patients with advanced disease. This retrospective cohort study evaluated overall survival of patients with invasive keratinocyte cancers, and high-risk features for progression of the disease and mortality in Finnish patients in a real-world setting. A total of 43,143 patients with keratinocyte cancer types of basal cell carcinoma and 10,380 with cutaneous squamous cell carcinoma were identified nationwide. More detailed patient records were available for a subset of patients (basal cell carcinoma n = 5,020 and cutaneous squamous cell carcinoma n = 1,482) from a regional database. Fifty percent of patients with advanced cutaneous squamous cell carcinoma died approximately 4.5 years after diagnosis. Multivariable models suggested that risk factors for keratinocyte cancer progression were male sex, presence of comorbidities, immunosuppression, and pre-cancerous lesions, while risk factors for disease-specific mortality were advanced disease stage with immunosuppression, other malignancies, and consecutive surgical excisions. These results suggest that identifying patient and tumour factors associated with poor disease outcome could be important when determining appropriate treatment and follow-up; however, further studies are necessary.

The burden of hip and knee osteoarthritis in Finnish occupational healthcare.

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.

Observational study on the evolution of systemic treatments for advanced renal cell carcinoma in Southwest Finland between 2010 and 2021.

Background: Novel receptor tyrosine kinase inhibitors and immune checkpoint inhibitors have been introduced to the treatment of advanced renal cell carcinoma (aRCC) during the past decade. However, the adoption of novel treatments into clinical practice has been unknown in Finland. Objectives: Our aim was to evaluate the use of systemic treatments and treatment outcomes of aRCC patients in Southwest Finland during 2010-2021. Design and Methods: Clinical characteristics, treatments for aRCC, healthcare resource utilization, and overall survival (OS) were retrospectively obtained from electronic medical records. Patients were stratified using the International Metastatic RCC Database Consortium (IMDC) risk classification. Results: In total, 1112 RCC patients were identified, 336 (30%) patients presented with aRCC, and 57% of them (n = 191) had received systemic treatment. Pre-2018, sunitinib (79%) was the most common first-line treatment, and pazopanib (17%), axitinib (17%), and cabozantinib (5%) were frequently used in the second-line. Post-2018, sunitinib (52%), cabozantinib (31%), and the combination of ipilimumab and nivolumab (10%) were most commonly used in the first-line, and cabozantinib (23%) in the second-line. Median OS for patients with favorable, intermediate, and poor risk were 61.9, 28.6, and 8.1 months, respectively. A total of 73%, 74%, and 35% of the patients with favorable, intermediate, and poor risk had received second-line systemic treatment. In poor-risk patients, the number of hospital inpatient days was twofold higher compared to intermediate and fourfold higher compared to favorable-risk patients. Conclusion: New treatment options were readily adopted into routine clinical practice after becoming reimbursed in Finland. OS and the need for hospitalization depended significantly on the IMDC risk category. Upfront combination treatments are warranted for poor-risk patients as the proportion of patients receiving second-line treatment is low. Registration: Clinical trial identifier: ClinicalTrials.gov NCT05363072.

Observational study on the evolution of systemic treatments for advanced renal cell carcinoma in Southwest Finland between 2010 and 2021 The aim of the study was to evaluate the use of novel medical treatments for advanced kidney cancer in routine clinical practice in Southwest Finland from 2010 to 2021 and to study the impact of IMDC risk factors on patients' survival and healthcare resource utilization. Before 2018, sunitinib (79%) was the most common first-line treatment for advanced kidney cancer, and pazopanib (17%), axitinib (17%), and cabozantinib (5%) were frequently used in the second-line. After 2018, sunitinib (52%), cabozantinib (31%), and the combination of ipilimumab and nivolumab (10%) were most commonly used in the first-line, and cabozantinib (23%) in the second-line treatment. The IMDC risk category predicted the patient's prognosis accurately as the median overall survival times for patients with favorable, intermediate, and poor risk were 61.9 months, 28.6 months, and 8.1 months, respectively. 73­74% of the patients with favorable and intermediate risk had received second-line medical treatment for advanced disease, whereas only 35% of the patients with poor risk had received second-line treatment after disease progression on the first-line treatment. Among patients with poor risk, the number of hospital inpatient days was twofold higher compared to intermediate and fourfold higher compared to favorable-risk patients. This study demonstrated that new treatment options for advanced kidney cancer were readily adopted into clinical practice and IMDC risk scoring was a valuable tool in determining patient prognosis and healthcare resource utilization.

Burden of idiopathic inflammatory rheumatic diseases in occupational healthcare: increased absenteeism and healthcare resource utilization.

OBJECTIVES: Patients with idiopathic inflammatory rheumatic diseases (IIRD) often have decreased working capacity resulting in indirect costs. However, data on patients' short-term sick leave has been limited. This retrospective cohort study evaluated the number and length of sick leave, including short-term leave, and occupational healthcare resource utilization (HCRU) of the working-aged patients with IIRD compared to controls. METHODS: The data on sick leave and occupational HCRU were gathered from the electronic medical records of the largest occupational healthcare provider in Finland from January 2012 to December 2019. Employed patients with an IIRD (including rheumatoid arthritis, spondyloarthritis, psoriatic and enteropathic arthritis, juvenile arthritis, and reactive arthritis) with at least a 12-months follow-up were identified and compared to age-, sex-, and follow-up matched controls without IIRD. RESULTS: Altogether 5405 patients with IIRD were identified and compared with an equal number of controls. The patients incurred approximately 2.5 times more sick leave than controls: 21.7 versus 8.5 days per patient year, respectively. Short-term sick leave was common: 83% of sickness absence periods of the patients lasted 1-9 days and represented 30% of the total absenteeism. Loss of productivity due to lost workdays was on average €4572 (95% confidence interval €4352-4804) per patient year. Occupational HCRU was approximately 1.8 times higher among IIRD patients than controls. CONCLUSIONS: Workers with an IIRD incur considerably more sick leave and use more occupational healthcare services than controls. Short sick leave not registered in national insurance registers constitute a significant portion of days off work among patients with IIRD.

Cardiovascular event rate and death in high-risk secondary prevention patient cohort in Finland: A registry study.

BACKGROUND: A large number of patients are living with atherosclerotic cardiovascular (CV) disease and thus are at risk of life-threatening CV events. HYPOTHESIS: This study evaluated the risk for a recurrent CV event or death in Finnish real-world data. METHODS: Patients with an incident atherosclerotic CV event between 2012 and 2016 were included in this retrospective registry study and followed for recurrent CV events or death. The risk and risk factors of recurrent CV events or death and time from the first CV event to recurrence were assessed. RESULTS: A total of 48,405 patients were followed from their first CV event. The event rate was 14.34 events per 100 patient-years. Multistate models suggested that at 5 years post index CV event, 41.5% of the patients had died or suffered a recurrent CV event. Death was the most common type of subsequent event (61.5%). After the first CV event, there were rapid increases both in recurrent CV events and deaths during the next 6 months. The subsequent CV event was usually of the same type as the first, which was of the cardiac or cerebrovascular cluster. CONCLUSIONS: The incidence of recurrent CV events and all-cause mortality was high in patients suffering from their first CV event, particularly during the first 6 months after the index event. Death was the most common subsequent event. The event rate accelerated after each additional CV event. This suggests that the acute treatment of the index event should be followed by prompt secondary prevention measures to achieve guideline-recommended goals as soon as possible.

Association of the arginine vasopressin receptor 1A (AVPR1A) haplotypes with listening to music.

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.

Music-listening regulates human microRNA expression.

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 and DICER, upregulated after music-listening, protect dopaminergic neurons and are important for retaining striatal dopamine levels. Some of the transcriptional regulators (FOS, CREB1, JUN, EGR1, and BDNF) of the upregulated microRNAs were immediate early genes and top candidates associated with musical traits. BDNF and 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.

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.

Creative Activities in Music--A Genome-Wide Linkage Analysis.

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.

Detecting signatures of positive selection associated with musical aptitude in the human genome.

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.

The effect of listening to music on human transcriptome.

Although brain imaging studies have demonstrated that listening to music alters human brain structure and function, the molecular mechanisms mediating those effects remain unknown. With the advent of genomics and bioinformatics approaches, these effects of music can now be studied in a more detailed fashion. To verify whether listening to classical music has any effect on human transcriptome, we performed genome-wide transcriptional profiling from the peripheral blood of participants after listening to classical music (n = 48), and after a control study without music exposure (n = 15). As musical experience is known to influence the responses to music, we compared the transcriptional responses of musically experienced and inexperienced participants separately with those of the controls. Comparisons were made based on two subphenotypes of musical experience: musical aptitude and music education. In musically experiencd participants, we observed the differential expression of 45 genes (27 up- and 18 down-regulated) and 97 genes (75 up- and 22 down-regulated) respectively based on subphenotype comparisons (rank product non-parametric statistics, pfp 0.05, >1.2-fold change over time across conditions). Gene ontological overrepresentation analysis (hypergeometric test, FDR < 0.05) revealed that the up-regulated genes are primarily known to be involved in the secretion and transport of dopamine, neuron projection, protein sumoylation, long-term potentiation and dephosphorylation. Down-regulated genes are known to be involved in ATP synthase-coupled proton transport, cytolysis, and positive regulation of caspase, peptidase and endopeptidase activities. One of the most up-regulated genes, alpha-synuclein (SNCA), is located in the best linkage region of musical aptitude on chromosome 4q22.1 and is regulated by GATA2, which is known to be associated with musical aptitude. Several genes reported to regulate song perception and production in songbirds displayed altered activities, suggesting a possible evolutionary conservation of sound perception between species. We observed no significant findings in musically inexperienced participants.

Genome-wide copy number variation analysis in extended families and unrelated individuals characterized for musical aptitude and creativity in music.

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.

The genome-wide landscape of copy number variations in the MUSGEN study provides evidence for a founder effect in the isolated Finnish population.

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.