Mielialahäiriöiden genetiikka

Mood disorders (major depressive disorder and bipolar disorder) are complex psychiatric disorders that are the leading cause of disability to work in Finland. Their specific genetic background remains widely unknown. Recent genome wide association (GWA) studies have revealed some novel susceptibility genes and risk variants as the field has moved into the era of genome-wide genotyping of huge samples sizes from collaborative studies. The risk variants revealed with this approach, however, cover only a small fraction of the total heritability of these diseases. Thus, it is still highly relevant to study samples from more genetically and environmentally homogenous populations, since the amount of risk variants that are enriched in isolated populations is smaller than in more confounded populations. Detailed characterization of the phenotype has also become an important factor in psychiatric genetics, since the psychiatric disease phenotypes themselves are so broad and heterogeneous. The principal goal of this work was to survey functionally relevant candidate genes for mood disorders and risk variants revealed from the first GWA studies in Finnish samples. The bipolar family sample comprises 723 individuals (227 affected for BD). Part of this sample has been characterized in more detail enabling the search for genetic susceptibility genes for potential endophenotypes of mood disorders. The clinical cohort sample is comprised of 272 MDD and 178 BD patients, who were characterized for clinical comorbidities and followed for long term clinical outcome. In the bipolar family sample, the highly studied variant val66met of BDNF was found to be associated with BD with the allelic replication observed in previous association studies. The most statistically significant result demonstrated the association of variants of the DAOA gene and the general intellectual function of visuospatial ability. The clinical cohort sample revealed statistically significant association of two functional variants from P2RX7 gene with familial form of mood disorder, and both variants affected also the clinical outcome of the patients by lengthening the time of illness. Our effort to replicate the results from the first GWA studies in the bipolar family sample revealed five genomic areas that associated with mood disorder also in Finland. Most of these variants also associated with some potential mood-disorder endophenotype, such as neurocognitive trait or seasonality in fluctuation of sleep, social activity, or mood. In conclusion, the use of detailed characterized samples may provide an advantage to the genetic studies, since it increases the possibility of finding the susceptibility genes behind more homogenous phenotypes. This work has also revealed some potential endophenotypes, or trait features, that might convey the effect of the susceptibility genes to the end diagnosis of mood disorder.Mielialahäiriöt, eli vakava masennus sekä kaksisuuntainen mielialahäiriö, ovat monitekijäisiä psykiatrisia sairauksia, jotka ovat yleisin syy työkyvyttömyyteen Suomessa. Vaikka näiden sairauksien geneettistä taustaa on tutkittu paljon, vieläkään ei tiedetä mitkä geneettiset tekijät altistavat näille sairauksille. Uudet koko genomin laajuiset assosiaatioanalyysit ovat paljastaneet täysin uusia alttiusgeeni ehdokkaita. Ongelmana on kuitenkin ollut se, että paljastuneet riskimuodot kattavat vain pienen osan sairauksien perinnöllisestä taustasta. Tämän vuoksi psykiatrisessa genetiikassa on lisäksi tärkeää tutkia myös geneettisesti homogeenisempia populaatioita, joihin on kasautunut vähäisempi määrä geneettisiä riskitekijöitä. Tärkeäksi tekijäksi on muodostunut myös aineiston tarkka ilmiasun karakterisointi, sillä mielialahäiriöt itsessään ovat ilmiasuina erittäin heterogeenisia. Tämän väitöskirjan tarkoituksena oli tutkia toiminnallisesti tärkeitä mielialahäiriöiden ehdokasgeenejä sekä uusia riskivariantteja jotka on löydetty ensimmäisissä koko genomin laajuisissa assosiaatiotutkimuksissa ja selvittää näiden vaikutus mielialahäiriöön suomalaisissa aineistoissa. Kaksisuuntaisen mielialahäiriön perheaineisto koostuu 723 yksilöstä, joista 227 sairastaa kaksisuuntaista mielialahäiriötä. Osa tästä aineistosta on tarkemmin karakterisoitu neurokognitiivisten ominaisuuksien ja vuodenaikais- ja vuorokausimuuttujien osalta. Kliininen kohorttiaineisto muodostuu 272 vakavaan masennukseen ja 178 kaksisuuntaiseen mielialahäiriöön sairastuneesta. Näiden potilaiden kliininen ilmiasu on tarkkaan karakterisoitu komorbiditeettihäiriöiden ja sairauden vaikeusasteen osalta. Aiemmissa tutkimuksissa paljon tutkittu BDNF geeni ja sen funktionaalinen variantti val66met assosioitui perheaineistossa kaksisuuntaiseen mielialahäiriöön. Perheaineiston vahvin geneettinen löydös oli DAOA geenin assosiaatio visuaalis-tilallista kyvykkyyttä mittaavaan neurokognitiiviseen testimuuttujaan. Kohorttiaineistossa löysimme familiaalisen mielialahäiriön vahvan assosiaation kahteen P2RX7 geenin aminohappoa muuttavaan varianttiin. Kumpikin variantti vaikutti myös kliinisesti lisäten riskialleelia kantavien sairastamisaikaa. Neljännessä ja viidennessä osatyössä yritimme toistaa ensimmäisten koko genomin laajuisten assosiaatioanalyysien tuloksia. Tuloksena oli viiden geenin tai genomialueen assosiaatio mielialahäiriöihin myös suomalaisessa aineistossa. Suurin osa näistä assosioitui myös joko johonkin neurokognitiiviseen testimuuttujaan tai unen, sosiaalisen aktiivisuuden tai mielialan vuodenaikaisvaihteluun, jotka kaikki ovat mahdollisia mielialahäiriöiden endofenotyyppejä. Yhteenvetona voidaan todeta, että psykiatrisessa genetiikassa on tärkeää käyttää tarkkaan karakterisoitua aineistoa, sillä se vähentää tutkittavan ilmiasun heterogeenisyyttä ja siten todennäköisyys löytää ilmiasuun vaikuttavia geneettisiä riskitekijöitä kasvaa. Tässä työssä tuli myös ilmi joitain mahdollisia mielialahäiriöiden endofenotyyppejä ja ominaispiirteitä joiden kautta ehdokasgeenien vaikutus sairauteen välittyy

The Val66Met polymorphism in the BDNF gene is associated with epilepsy in fragile X syndrome

The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene may modulate the epilepsy phenotype. We investigated the impact of polymorphisms in the BDNF gene on clinical features in fragile X syndrome (FXS). In our study sample, the Met66 allele associated with epilepsy of finnish FXS men. Abnormalities in BDNF-mediated plasticity are shown in FXS and the present data suggest that the Met66 allele might predispose FXS mates to epilepsy. (C) 2009 Published by Elsevier B.V.The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene may modulate the epilepsy phenotype. We investigated the impact of polymorphisms in the BDNF gene on clinical features in fragile X syndrome (FXS). In our study sample, the Met66 allele associated with epilepsy of finnish FXS men. Abnormalities in BDNF-mediated plasticity are shown in FXS and the present data suggest that the Met66 allele might predispose FXS mates to epilepsy. (C) 2009 Published by Elsevier B.V.The Val66Met polymorphism in the brain-derived neurotrophic factor (BDNF) gene may modulate the epilepsy phenotype. We investigated the impact of polymorphisms in the BDNF gene on clinical features in fragile X syndrome (FXS). In our study sample, the Met66 allele associated with epilepsy of finnish FXS men. Abnormalities in BDNF-mediated plasticity are shown in FXS and the present data suggest that the Met66 allele might predispose FXS mates to epilepsy. (C) 2009 Published by Elsevier B.V.Peer reviewe

CRY2 Is Associated with Depression

Abnormalities in the circadian clockwork often characterize patients with major depressive and bipolar disorders. Circadian clock genes are targets of interest in these patients. CRY2 is a circadian gene that participates in regulation of the evening oscillator. This is of interest in mood disorders where a lack of switch from evening to morning oscillators has been postulated.We observed a marked diurnal variation in human CRY2 mRNA levels from peripheral blood mononuclear cells and a significant up-regulation (P = 0.020) following one-night total sleep deprivation, a known antidepressant. In depressed bipolar patients, levels of CRY2 mRNA were decreased (P = 0.029) and a complete lack of increase was observed following sleep deprivation. To investigate a possible genetic contribution, we undertook SNP genotyping of the CRY2 gene in two independent population-based samples from Sweden (118 cases and 1011 controls) and Finland (86 cases and 1096 controls). The CRY2 gene was significantly associated with winter depression in both samples (haplotype analysis in Swedish and Finnish samples: OR = 1.8, P = 0.0059 and OR = 1.8, P = 0.00044, respectively).We propose that a CRY2 locus is associated with vulnerability for depression, and that mechanisms of action involve dysregulation of CRY2 expression

Systematic Analysis of Circadian Genes in a Population-Based Sample Reveals Association of TIMELESS with Depression and Sleep Disturbance

Peer reviewe

CRY2 Is Associated with Depression

BackgroundAbnormalities in the circadian clockwork often characterize patients with major depressive and bipolar disorders. Circadian clock genes are targets of interest in these patients. CRY2 is a circadian gene that participates in regulation of the evening oscillator. This is of interest in mood disorders where a lack of switch from evening to morning oscillators has been postulated.Principal FindingsWe observed a marked diurnal variation in human CRY2 mRNA levels from peripheral blood mononuclear cells and a significant up-regulation (P = 0.020) following one-night total sleep deprivation, a known antidepressant. In depressed bipolar patients, levels of CRY2 mRNA were decreased (P = 0.029) and a complete lack of increase was observed following sleep deprivation. To investigate a possible genetic contribution, we undertook SNP genotyping of the CRY2 gene in two independent population-based samples from Sweden (118 cases and 1011 controls) and Finland (86 cases and 1096 controls). The CRY2 gene was significantly associated with winter depression in both samples (haplotype analysis in Swedish and Finnish samples: OR = 1.8, P = 0.0059 and OR = 1.8, P = 0.00044, respectively).ConclusionsWe propose that a CRY2 locus is associated with vulnerability for depression, and that mechanisms of action involve dysregulation of CRY2 expression

Interaction of early environment, gender and genes of monoamine neurotransmission in the aetiology of depression in a large population-based Finnish birth cohort

Objectives Depression is a worldwide leading cause of morbidity and disability. Genetic studies have recently begun to elucidate its molecular aetiology. The authors investigated candidate genes of monoamine neurotransmission and early environmental risk factors for depressiveness in the genetically isolated population-based Northern Finland Birth Cohort 1966 (12 058 live births). Design The authors ascertained and subdivided the study sample (n=5225) based on measures of early development and of social environment, and examined candidate genes of monoamine neurotransmission, many of which have shown prior evidence of a gene–environment interaction for affective disorders, namely SLC6A4, TPH2, COMT, MAOA and the dopamine receptor genes DRD1–DRD5. Results and conclusion The authors observed no major genetic effects of the analysed variants on depressiveness. However, when measures of early development and of social environment were considered, some evidence of interaction was observed. Allelic variants of COMT interacted with high early developmental risk (p=0.005 for rs2239393 and p=0.02 for rs4680) so that the association with depression was detected only in individuals at high developmental risk group (p=0.0046 and β=0.056 for rs5993883–rs2239393–rs4680 risk haplotype CGG including Val158), particularly in males (p=0.0053 and β=0.083 for the haplotype CGG). Rs4274224 from DRD2 interacted with gender (p=0.017) showing a significant association with depressiveness in males (p=0.0006 and β=0.0023; p=0.00005 and β=0.069 for rs4648318–rs4274224 haplotype GG). The results support the role of genes of monoamine neurotransmission in the aetiology of depression conditional on environmental risk and sex, but not direct major effects of monoaminergic genes in this unselected population