Migreenin sairastuvuuteen vaikuttavien geneettisten tekijöiden tunnistaminen

Migraine is the common cause of chronic episodic headache, affecting 12%-15% of the Caucasian population (41 million Europeans and some half a million Finns), and causes considerable loss of quality of life to its sufferers, as well as being linked to increased risk for a wide range of conditions, from depression to stroke. Migraine is the 19th most severe disease in terms of disability-adjusted life years, and 9th among women. It is characterized by attacks of headache accompanied by sensitivity to external stimuli lasting 4-72 hours, and in a third of cases by neurological aura symptoms, such as loss of vision, speech or muscle function. The underlying pathophysiology, including what triggers migraine attacks and why they occur in the first place, is largely unknown. The aim of this study was to identify genetic factors associated with the hereditary susceptibility to migraine, in order to gain a better understanding of migraine mechanisms. In this thesis, we report the results of genetic linkage and association analyses on a Finnish migraine patient collection as well as migraineurs from Australia, Denmark, Germany, Iceland and the Netherlands. Altogether we studied genetic information of nearly 7,000 migraine patients and over 50,000 population-matched controls. We also developed a new migraine analysis method called the trait component analysis, which is based on individual patient responses instead of the clinical diagnosis. Using this method, we detected a number of new genetic loci for migraine, including on chromosome 17p13 (HLOD 4.65) and 10q22-q23 (female-specific HLOD 7.68) with significant evidence of linkage, along with five other loci (2p12, 8q12, 4q28-q31, 18q12-q22, and Xp22) detected with suggestive evidence of linkage. The 10q22-q23 locus was the first genetic finding in migraine to show linkage to the same locus and markers in multiple populations, with consistent detection in six different scans. Traditionally, ion channels have been thought to play a role in migraine susceptibility, but we were able to exclude any significant role for common variants in a candidate gene study of 155 ion transport genes. This was followed up by the first genome-wide association study in migraine, conducted on 2,748 migraine patients and 10,747 matched controls followed by a replication in 3,209 patients and 40,062 controls. In this study, we found interesting results with genome-wide significance, providing targets for future genetic and functional studies. Overall, we found several promising genetic loci for migraine providing a promising base for future studies in migraine.Migreeni on yleisin kroonisen kohtauksellisen päänsäryn syy ja siitä kärsii 12-15% väestöstä. Monitekijäisten kansantautien - kuten migreenin, diabeteksen ja masennuksen - tautimekanismien ymmärtäminen on yksi nykylääketieteen ja -genetiikan vaikeimmista haasteista. Nämä taudit ovat osa päivittäistä elämää niin lääkärin vastaanotolla kuin kotonakin, ja niiden tutkimuksella ja edistysaskeleilla on mahdollisuus parantaa potilaiden elämänlaatua. Nykykäsityksen mukaan kansantautien perinnöllinen alttius perustuu ympäristötekijöiden ohella lukuisten eri perimänvaihteluiden yhteisvaikutukseen ja siksi vaihteluiden tunnistaminen vaatii suuria potilasaineistoja. Tämä väitöskirjatutkimus perustuu laajaan kansainväliseen yhteistyöhön, jonka tuloksena pystyimme tutkimaan migreenille altistavia perimän alueita lähes 7 000 migreenipotilaasta uusimmilla geenitutkimuksen menetelmillä. Migreeni on 19. vakavin elämänlaadun laskija maailmassa ja yhdeksänneksi pahin naisten keskuudessa. Euroopassa migreenikkoja on 41 miljoonaa (Suomessa 441 000) ja tauti on eniten kustannuksia ja elämänlaadun laskua aiheuttava neurologinen tauti. Jopa puolet migreenipotilaista joutuu käymään sairaalapäivystyksessä kerran vuodessa migreenin vuoksi ja 15% migreeniä sairastavista tarvitsi viisi terveyskeskuskäyntikertaa tai enemmän vuodessa. Migreenillä on kaksi päätyyppiä: esioireellinen (aurallinen) ja esioireeton (auraton) migreeni, jossa edellisessä kohtaukseen liittyy kivun lisäksi erilaisia neurologisia oireita, kuten näkö- ja puhevaikeuksia. Molemmat muodot kuuluvat edellä mainittuihin monitekijäisiin tauteihin, eikä yhtään yleiseen migreenialttiuteen vaikuttavaa geneettistä tekijää ole ennen tätä tutkimusta varmuudella tunnistettu. Tässä väitöskirjatutkimuksessa esittelemme uudenlaisen lähestymistavan, oirekomponenttianalyysin, migreenin luokitteluun sekä sovellamme sitä uusien geneettisten alttiusalueiden tunnistamiseen suomalaisissa ja kansainvälisissä potilasaineistoissa. Sitä käyttämällä tunnistimme kaksi uutta migreenille altistavaa geenialuetta sekä kykenimme vahvistamaan useita aikaisemmin havaittuja. Migreenin perinnöllisen alttiuden taustalla on pitkään ajateltu olevan muutoksia solun ionikanavissa, mutta pystyimme tutkimuksessamme poissulkemaan niiden osuuden migreenin alttiustekijänä. Suoritimme ensimmäisen migreenin kokogenomiassosiaatiotutkimuksen (käsittäen n. 5 700 potilasta ja 50 000 populaatioverrokkia) jossa tunnistimme genominlaajuisesti merkittäviä variantteja, jotka muodostavat vahvan pohjan geneettisille ja funktionaalisille jatkotutkimuksille

Towards an understanding of genetic predisposition to migraine

Plausible genome-wide associations for episodic neurological diseases (such as migraine, epilepsy and ataxias) have been slow to emerge. The first such association was reported in a recent genome-wide association study of migraine, with quantitative expression analysis linking the variant to a nearby regulatory gene, MTDH/AEG-1. This putative mechanism, regulating the expression of the primary glutamate transporter in the brain, EAAT2/GLT-1, has interesting implications bridging the gap between Mendelian and common forms in this key group of disorders

SNP Variants in Major Histocompatibility Complex Are Associate with Sarcoidosis Susceptibility - A Joint Analysis in Four European Populations

Sarcoidosis is a multiorgan inflammatory disorder with heritability estimates up to 66%. Previous studies have shown the major histocompatibility complex (MHC) region to be associated with sarcoidosis, suggesting a functional role for antigen-presenting molecules and immune mediators in the disease pathogenesis. To detect variants predisposing to sarcoidosis and to identify genetic differences between patient subgroups, we studied four genes in the MHC Class III region (LTA, TNF, AGER, BTNL2) and HLA-DRA with tag-SNPs and their relation to HLA-DRB1 alleles. We present results from a joint analysis of four study populations (Finnish, Swedish, Dutch, and Czech). Patients with sarcoidosis (n = 805) were further subdivided based on the disease activity and the presence of Lofgren's syndrome. In a joint analysis, seven SNPs were associated with non-Lofgren sarcoidosis (NL; the strongest association with rs3177928, P = 1.79E-07, OR = 1.9) and eight with Lofgren's syndrome [ Lofgren syndrome (LS); the strongest association with rs3129843, P = 3.44E-12, OR = 3.4] when compared with healthy controls (n = 870). Five SNPs were associated with sarcoidosis disease course (the strongest association with rs3177928, P = 0.003, OR = 1.9). The high linkage disequilibrium (LD) between SNPs and an HLA-DRB1 challenged the result interpretation. When the SNPs and HLA-DRB1 alleles were analyzed together, independent association was observed for four SNPs in the HLA-DRA/BTNL2 region: rs3135365 (NL; P = 0.015), rs3177928 (NL; P <0.001), rs6937545 (LS; P = 0.012), and rs5007259 (disease activity; P = 0.002). These SNPs act as expression quantitative trait loci (eQTL) for HLA-DRB1 and/or HLA-DRB5. In conclusion, we found novel SNPs in BTNL2 and HLA-DRA regions associating with sarcoidosis. Our finding further establishes that polymorphisms in the HLA-DRA and BTNL2 have a role in sarcoidosis susceptibility. This multi-population study demonstrates that at least a part of these associations are HLA-DRB1 independent (e.g., not due to LD) and shared across ancestral origins. The variants that were independent of HLA-DRB1 associations acted as eQTL for HLA-DRB1 and/or -DRB5, suggesting a role in regulating gene expression.Peer reviewe

Serum calcium and risk of migraine : a Mendelian randomization study

Migraine affects similar to 14% of the world's population, though not all predisposing causal risk factors are known. We used electronic health records, genetic co-heritability analysis, and a two-sampleMendelian Randomization (MR) design to determine if elevated serum calcium levels were associated with risk of migraine headache. Co-morbidity was evaluated using electronic health records obtained from the PennOmics database comprising>1 million patient entries. Genetic co-heritability and causality via MR was assessed using data from the International Headache Consortium (23,285 cases, 95,425 controls) and circulating serum calcium levels (39,400 subjects). We observed co-occurrence of migraine and hypercalcaemia ICD-9 diagnoses (OR = 1.58, P = 4 x 10-(13)), even after inclusion of additional risk factors for migraine (OR = 1.23, P = 2 x 10 -(3)). Second, we observed co-heritability (r(g) =0.191, P = 0.03) between serum calcium and migraine headache, indicating that these traits have a genetic basis in common. Finally, we found that elevation of serum calcium levels by 1 mg/dl resulting from our genetic score was associated with an increase in risk of migraine (OR = 1.80, 95% CI: 1.31-2.46, P = 2.5 x 10 -(4)), evidence supporting a causal hypothesis. We also present multiple MR sensitivity analyses in support of this central finding. Our results provide evidence that hypercalcaemia is comorbid with migraine headache diagnoses, and that genetically elevated serum calcium over lifetime appears to increase risk for migraine. Further studies will be required to understand the biologicalmechanism, pathways, and clinical implication for riskmanagement.Peer reviewe

In silico phenotyping via co-training for improved phenotype prediction from genotype

Motivation: Predicting disease phenotypes from genotypes is a key challenge in medical applications in the postgenomic era. Large training datasets of patients that have been both genotyped and phenotyped are the key requisite when aiming for high prediction accuracy. With current genotyping projects producing genetic data for hundreds of thousands of patients, large-scale phenotyping has become the bottleneck in disease phenotype prediction. Results: Here we present an approach for imputing missing disease phenotypes given the genotype of a patient. Our approach is based on co-training, which predicts the phenotype of unlabeled patients based on a second class of information, e.g. clinical health record information. Augmenting training datasets by this type of in silico phenotyping can lead to significant improvements in prediction accuracy. We demonstrate this on a dataset of patients with two diagnostic types of migraine, termed migraine with aura and migraine without aura, from the International Headache Genetics Consortium. Conclusions: Imputing missing disease phenotypes for patients via co-training leads to larger training datasets and improved prediction accuracy in phenotype prediction. Availability and implementation: The code can be obtained at: http://www.bsse.ethz.ch/mlcb/research/bioinformatics-and-computational-biology/co-training.html Contact: [email protected] or [email protected] Supplementary information: Supplementary data are available at Bioinformatics onlin

Genome wide meta-analysis identifies genomic relationships, novel loci, and pleiotropic mechanisms across eight psychiatric disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed a meta-analysis of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders identifying three groups of inter-related disorders. We detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning in the second trimester prenatally, and play prominent roles in a suite of neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction

Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia

Background Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15). Methods We conducted a large- scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). Results We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 × 10−6). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a ‘neurodevelopmental hub’ on chromosome 8p11.23. Conclusions This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4

Migreenin geneettinen tausta on monitekijäinen

Vertaisarvioitu.Migreeni on yleinen neurovaskulaarinen aivosairaus, jolla on vahva geneettinen tausta. Migreenin molekyyligeneettiset tutkimukset 1990-luvulla kohdistuivat harvinaiseen hemiplegiseen migreeniin, joka osoittautui ionikanavataudiksi. Yleisten migreenimuotojen geneettinen tausta alkoi hahmottua 2010-luvulla genominlaajuisten assosiaatiotutkimusten (GWAS) avulla. Tutkimukset ovat paljastaneet kymmeniä yleisiä, vaikutukseltaan vähäisiä migreenin geneettisiä riskivariantteja, erityisesti vaskulaarisissa kudoksissa ilmenevistä geeneistä. On selvinnyt, että aurallisen, aurattoman ja hemiplegisen migreenin riskivariantit ovat osittain samoja. Yleisten riskivarianttien yhteisvaikutus taas selittää migreenin kertymistä perheisiin. Mielenkiintoista on myös se, että migreenillä on yhteisiä geneettisiä riskitekijöitä psyykkisten sairauksien, erityisesti ADHD:n, vakavan masennuksen ja Touretten oireyhtymän kanssa. Riskivarianttien todellinen merkitys migreenin patofysiologiaan selviää vasta toiminnallisten tutkimusten avulla.Peer reviewe

Selectivity in Genetic Association with Sub-classified Migraine in Women

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A Potential Novel Spontaneous Preterm Birth Gene, AR, Identified by Linkage and Association Analysis of X Chromosomal Markers

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