Search for Genetic Variants Underlying Musical Aptitude and Related Traits

Music perception and practice represents complex cognitive functions of the brain. There is an abundance of data about the neurophysiological effects of music on the human brain, but heritability and especially molecular studies have been lacking. The development of genome technologies and bioinformatics has enabled the identification of genetic variants underlying complex human traits. These methods can be applied to normal human traits like music perception and performance. Prior to this study, the first genome wide scan in the Finnish pedigrees suggested that musical aptitude is associated with several chromosomal areas in the human genome. High heritability of music test scores was also demonstrated. In order to further dissect the molecular genetic background of music related traits this thesis work focused on three phenotypes in music, musical aptitude, listening to music and creativity in music in the enlarged family material. For the aforementioned phenotypes functionally relevant candidate genes were analyzed, and novel genomic variants and candidate genes sought using genome-wide analysis of single nucleotide polymorphisms and structural variation (copy number variation; CNV). In this thesis, musical aptitude of each participant was defined using three music tests: the auditory structuring ability test (Karma Music test) and Seashore's pitch and time discrimination subtests. A combined music test score (COMB) was computed as the sum of the separate scores of the three individual test results. Information about other musical traits, creative functions in music and listening to music, and background information was collected using a web-based questionnaire. Both musical aptitude and creative functions in music showed to have strong genetic components, the heritability estimates were 0.44 and 0.84 respectively. On the average, the amount of time spent on active listening to music was 4.6 hours per week and passive 7.3 hours per week among the participants. Furthermore, high scores in music tests correlated with creative functions in music, and high amount of active listening to music correlated with the high level of music education. Five candidate genes, AVPR1A, SLC6A4, COMT, DRD2 and TPH1, were studied in musical aptitude, creativity in music and listening to music. All studied traits were associated with the arginine vasopressin receptor 1A (AVPR1A) gene, suggesting that the neurobiology of music perception and practice is likely to be related to pathways affecting social affiliation and communication. In the genome-wide CNV study several copy number variable regions containing genes that affect neurodevelopment, learning and memory were detected. The most promising of them was a deletion at 5q31.1 covering the protocadherin-α gene cluster (PCDHA) that was associated with low music test scores. PCDHA is involved in neural migration, differentiation and synaptogenesis. Creativity in music was associated with a duplication covering glucose mutarotase gene (GALM) at 2p22. A 1.3 Mb duplication was identified in a subject with low COMB scores overlapping the core linkage region of absolute pitch at 8q24. Genome-wide association analysis of creative functions in music showed association with several genes previously shown to be related to learning, memory, synaptic plasticity and neuropsychiatric disorders. The strongest association was detected with the cGMP-dependent protein kinase type I (PRKG1) gene at 10p21 that affects amygdala function, a brain area also induced by music. PRKG1 has previously been associated with schizophrenia and attention deficit hyperactivity disorder. In conclusion, our results suggest new candidate genes for musical aptitude and creativity in music. Being aware that musical aptitude is a complex phenotype affected by several predisposing alleles, this result, although interesting, is preliminary and may only partially explain the genetic background of musical aptitude. Further studies are needed to confirm the role of the candidate genes identified in musical aptitude and related traits.Ihmiset eroavat musikaalisilta taipumuksiltaan ja musikaalisuus ilmenee monin eri tavoin. Monet tunnetut ilmiöt, kuten musiikin ihmelapset, musikaaliset kaksoset tai sisarukset, antavat viitteitä musiikin ja biologian läheisestä yhteydestä. Silti musikaalisuuden periytyvyyden ja erityisesti sen taustalla olevan molekyylibiologian tutkiminen on käynnistynyt vasta viime vuosina. Geneettisten tutkimusmenetelmien kehittyminen on luonut uusia työkaluja ja mahdollistanut monitekijäisten ominaisuuksien, kuten musikaalisuuden taustalla vaikuttavien geneettisten muutosten etsimisen. Ensimmäinen musikaalisuuden koko perimän kattava kartoitus suoritettiin suomalaisissa suvuissa. Tutkimus osoitti perimän usean eri alueen vaikuttavan musikaalisuuteen. Tämän väitöskirjan tarkoituksena on selvittää tarkemmin musikaalisuuden, musiikin kuuntelemisen ja musiikillisen luovuuden molekyyligeneettistä taustaa edellisestä tutkimusta laajemmassa perhemateriaalissa. Tutkimuksessa analysoitiin toimintansa perusteella merkityksellisiä ehdokasgeenejä. Lisäksi koko perimän kattavissa tutkimuksissa etsittiin uusia musikaalisuuteen ja musiikilliseen luovuuteen vaikuttavia perimän muutoksia ja ehdokasgeenejä yhden nukleotidin geenimerkkejä sekä kopiolukumuutoksia (CNV) käyttäen. Tutkimushenkilöiden musikaalisuus määritettiin kolmea musikaalisuustestiä käyttäen: auditiivisen strukturointikyvyn testi (Karman testi) sekä Seashoren äänen korkeuden ja keston testit. Näiden kolmen musikaalisuustestin pistemäärän summana laskettiin kunkin osallistujan yhdistetyt musikaalisuuspisteet (COMB). Osallistujien musiikki- sekä muusta taustasta kerättiin tietoa laajalla Internet-pohjaisella kyselylomakkeella. Havaitsimme musikaalisuuden ja musiikillisen luovuuden perinnöllisen komponentin olevan merkittävä, musikaalisuuden 44 % ja musiikillisen luovuuden 84 %. Tutkimukseen osallistuneet kuuntelivat musiikkia aktiivisesti keskimäärin 4.6 tuntia viikossa ja passiivisesti 7.3 tuntia viikossa. Lisäksi korkeat musikaalisuustestipisteet korreloivat musiikillisen luovuuden kanssa ja aktiivinen musiikin kuunteleminen musiikkikoulutuksen kanssa. Tutkimme viiden ehdokasgeenin, AVPR1A, SLC6A4, COMT, DRD2 ja TPH1, vaikutusta musikaalisuuteen, musiikilliseen luovuuteen ja musiikin kuuntelemiseen. Havaitsimme, että kaikki tutkitut ominaisuudet liittyivät AVPR1A geeniin. Koska AVPR1A-geeni on aikaisemmissa tutkimuksissa liitetty sosiaaliseen kommunikaatioon ja kiintymykseen, tuloksemme viittaavat, että musiikin aistimisen ja tuottamisen neurobiologia liittyy samoihin biologisiin reitteihin. Koko perimän kattavassa CNV -työssä havaitsimme kopioluvultaan vaihtelevia alueita, jotka sisälsivät hermosolujen kehittymiseen, oppimiseen ja muistiin liittyviä geenejä. Mielenkiintoista oli, että PCDHA geeniperheen poistuma kromosomissa 5q31.1 liittyi mataliin musiikkitestipisteisiin. Aikaisemmin PCDHA on liitetty hermosolujen migraatioon, erilaistumiseen ja synapsien muodostumiseen. Havaitsimme musiikillisen luovuuden liittyvän GALM geenin kahdentumaan kromosomissa 2p22. Lisäksi löysimme matalat COMB pisteet omaavalta henkilöltä suuren, 1.3 Mb, kahdentuman kromosomista 8q24 absoluuttiseen sävelkorvaan kytkeytyvältä alueelta. Etsiessämme musiikilliseen luovuuteen liittyviä geenejä, havaitsimme useita oppimiseen, muistiin, hermosoluliitosten muovautumiseen ja neuropsykiatrisiin sairauksiin liitettyjä geenejä. Näistä mantelitumakkeen toimintaan vaikuttava PRKG1 geeni assosioitui voimakkaimmin musiikilliseen luovuuteen. Tähänastiset tutkimukset osoittavat, että musikaalisuus on monitekijäinen ominaisuus, mihin vaikuttavat ympäristön lisäksi useat altistavat geenimuodot. Löydöksemme ovat alustavia eivätkä yksinään riitä selittämään musikaalisuuden perinnöllistä taustaa. Uusien ehdokasgeenien tunnistaminen musikaalisuudessa ja musiikillisessa luovuudessa tulee antamaan lisätietoa musikaalisuuden biologisesta taustasta

Miten musiikki vaikuttaa terveyteen

VertaisarvioituKiinnostus musiikin terapeuttiseen käyttöön on lisääntynyt 2000-luvulla. Musiikin kuuntelemista ja tuottamista käytetään perinteistä hoitoa täydentävänä terapiana oireiden lievittämiseen. Musiikkia hyödynnetään myös aivojen normaalin kehityksen ja toiminnan tukemiseen. Mielihyvävasteessa tärkeitä ovat dopamiini- ja opioidijärjestelmät. Toimiessaan musiikki-interventio vaikuttaa nopeasti. Pitkäaikaisvaikutuksista ei ole tietoa.Peer reviewe

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 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.Peer reviewe

The effect of listening to music on human transcriptome

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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.Peer reviewe

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.</p

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 F-ST. 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.Peer reviewe

Genome-Wide Copy Number Variation Analysis in Extended Families and Unrelated Individuals Characterized for Musical Aptitude and Creativity in Music

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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, DISCI1, NDE1,NDEL1, PDE4B and PDE4D, the 'DISCI 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 x 10(-8)), located on a non -coding exon of NDE1. Variants within the NM. 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 IVDET 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.Peer reviewe

SNP Variants at 16p13.11 Clarify the Role of the NDE1/miR-484 Locus in Major Mental Illness in Finland

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