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Hypothesis To identify genetic factors predisposing to migraine-epilepsy phenotype utilizing a multi-generational family with known linkage to chr12q24.2-q24.3. Methods We used single nucleotide polymorphism (SNP) genotyping and next-generation sequencing technologies to perform linkage, haplotype, and variant analyses in an extended Finnish migraine-epilepsy family (n = 120). In addition, we used a large genome-wide association study (GWAS) dataset of migraine and two biobank studies, UK Biobank and FinnGen, to test whether variants within the susceptibility region associate with migraine or epilepsy related phenotypes in a population setting. Results The family showed the highest evidence of linkage (LOD 3.42) between rs7966411 and epilepsy. The haplotype shared among 12 out of 13 epilepsy patients in the family covers almost the entire NCOR2 and co-localizes with one of the risk loci of the recent GWAS on migraine. The haplotype harbors nine low-frequency variants with potential regulatory functions. Three of them, in addition to two common variants, show nominal associations with neurological disorders in either UK Biobank or FinnGen. Conclusion We provide several independent lines of evidence supporting association between migraine-epilepsy phenotype and NCOR2. Our study suggests that NCOR2 may have a role in both migraine and epilepsy and thus would provide evidence for shared pathophysiology underlying these two diseases.

Supplemental material, sj-pdf-7-cep-10.1177_03331024211068065 for NCOR2 is a novel candidate gene for migraine-epilepsy phenotype by Marjo Eveliina Nuottamo, Paavo H��pp��l��, Ville Artto, Heidi Hautakangas, Matti Pirinen, Tero Hiekkalinna, Pekka Ellonen, Maija Lepist��, Eija H��m��l��inen, International Headache Genetics Consortium (IHGC), FinnGenConsortiumAuli Siren, Anna-Elina Lehesjoki, Mikko Kallela, Aarno Palotie, Mari Anneli Kaunisto and Maija Wessman in Cephalalgia

Supplemental material, sj-pdf-2-cep-10.1177_03331024211068065 for NCOR2 is a novel candidate gene for migraine-epilepsy phenotype by Marjo Eveliina Nuottamo, Paavo H��pp��l��, Ville Artto, Heidi Hautakangas, Matti Pirinen, Tero Hiekkalinna, Pekka Ellonen, Maija Lepist��, Eija H��m��l��inen, International Headache Genetics Consortium (IHGC), FinnGenConsortiumAuli Siren, Anna-Elina Lehesjoki, Mikko Kallela, Aarno Palotie, Mari Anneli Kaunisto and Maija Wessman in Cephalalgia

Supplemental material, sj-pdf-1-cep-10.1177_03331024211068065 for NCOR2 is a novel candidate gene for migraine-epilepsy phenotype by Marjo Eveliina Nuottamo, Paavo H��pp��l��, Ville Artto, Heidi Hautakangas, Matti Pirinen, Tero Hiekkalinna, Pekka Ellonen, Maija Lepist��, Eija H��m��l��inen, International Headache Genetics Consortium (IHGC), FinnGenConsortiumAuli Siren, Anna-Elina Lehesjoki, Mikko Kallela, Aarno Palotie, Mari Anneli Kaunisto and Maija Wessman in Cephalalgia

Supplemental material, sj-pdf-3-cep-10.1177_03331024211068065 for NCOR2 is a novel candidate gene for migraine-epilepsy phenotype by Marjo Eveliina Nuottamo, Paavo H��pp��l��, Ville Artto, Heidi Hautakangas, Matti Pirinen, Tero Hiekkalinna, Pekka Ellonen, Maija Lepist��, Eija H��m��l��inen, International Headache Genetics Consortium (IHGC), FinnGenConsortiumAuli Siren, Anna-Elina Lehesjoki, Mikko Kallela, Aarno Palotie, Mari Anneli Kaunisto and Maija Wessman in Cephalalgia

Supplemental material, sj-pdf-5-cep-10.1177_03331024211068065 for NCOR2 is a novel candidate gene for migraine-epilepsy phenotype by Marjo Eveliina Nuottamo, Paavo H��pp��l��, Ville Artto, Heidi Hautakangas, Matti Pirinen, Tero Hiekkalinna, Pekka Ellonen, Maija Lepist��, Eija H��m��l��inen, International Headache Genetics Consortium (IHGC), FinnGenConsortiumAuli Siren, Anna-Elina Lehesjoki, Mikko Kallela, Aarno Palotie, Mari Anneli Kaunisto and Maija Wessman in Cephalalgia

Supplemental material, sj-pdf-6-cep-10.1177_03331024211068065 for NCOR2 is a novel candidate gene for migraine-epilepsy phenotype by Marjo Eveliina Nuottamo, Paavo H��pp��l��, Ville Artto, Heidi Hautakangas, Matti Pirinen, Tero Hiekkalinna, Pekka Ellonen, Maija Lepist��, Eija H��m��l��inen, International Headache Genetics Consortium (IHGC), FinnGenConsortiumAuli Siren, Anna-Elina Lehesjoki, Mikko Kallela, Aarno Palotie, Mari Anneli Kaunisto and Maija Wessman in Cephalalgia

Migraine is a complex headache disorder affecting approximately 15% of the adult population worldwide. It has a great impact on both individual patients and society. According to the Global Burden of Disease Study, migraine is one of the most costly and disabling neurological diseases. There are two main subtypes of migraine: migraine without aura and migraine with aura. Migraine without aura is the most common subtype of migraine. However, one-third of migraine patients experience neurological aura symptoms. In most cases, aura is visual, including scintillating scotoma and loss of vision type symptoms, but it can also be sensory, motor or result in speech disturbance. In hemiplegic migraine, a rare form of migraine with aura, the aura is characterized by motor weakness. The exact pathophysiological mechanisms underlying migraine are still unknown. Both family and twin studies have shown that migraine is hereditary. Recent genome-wide association studies (GWAS) have revealed the polygenic nature of common forms of migraine, while high-impact mutations have been found mainly in familial hemiplegic migraine (FHM). FHM is suggested to be a monogenic disorder with three major causative genes: CACNA1A, ATP1A2 and SCN1A. Genetic variants in these ion-transport/channel genes have also been associated with rare monogenic forms of epilepsy. The aim of this doctoral thesis was to identify genetic susceptibility factors for migraine with aura and migraine-epilepsy phenotype. We applied targeted and genome-wide approaches in a large and well-characterized Finnish migraine family sample (1,967 families with 8,937 family members). The first part of the thesis defined hemiplegic migraine as a clinically and genetically heterogeneous disease. In terms of headache characteristics and neurological aura symptoms, hemiplegic migraine patients appeared at the extreme end of the migraine with aura symptom spectrum. Our study also showed that mutations in CACNA1A, ATP1A2 and SCN1A are not the major cause of hemiplegic migraine in Finnish patients, as only 9% (4/45) of the studied FHM families and none of the sporadic cases (n=201) carried pathogenic exonic variants in these genes. These data suggest that there are additional genetic factors contributing to the hemiplegic migraine phenotype. In the second part of this thesis, we utilized data obtained from a previously published migraine GWAS to calculate polygenic risk scores (PRS) for 8,319 participants from the Finnish migraine family collection and 14,470 FINRISK population-based samples. Results showed that common polygenic variation significantly contributes to the familial aggregation of migraine. The polygenic burden was higher in familial migraine cases than in population cases. Furthermore, the polygenic burden was increased across all of the studied migraine with aura and migraine without aura subtypes in the family dataset compared with the population controls. Patients with typical migraine aura or hemiplegic migraine carried a higher load compared with patients having migraine without aura. Our findings are especially interesting considering that FHM has been suggested to be a monogenic disorder primarily driven by rare, high-impact variants. The third part of this thesis focused on a previously identified migraine-epilepsy susceptibility locus on chromosome 12q24.2-q24.3 identified in a large multi-generational Finnish migraine-epilepsy family including 120 individuals. We defined a 450 kbp haplotype that was shared among 12 out of 13 epilepsy patients. This segment covers almost the entire NCOR2 gene, which plays an important regulatory role during brain development. Interestingly, one of the 123 migraine risk loci recently reported by the International Headache Genetics Consortium also co-localized with this region. Our results suggest that NCOR2 could potentially have a role in both migraine and epilepsy and could thus contribute to the susceptibility of both of these paroxysmal brain diseases. However, further studies are needed to identify the actual causal variants. Overall, the results of this doctoral thesis highlight migraine as a clinically and genetically heterogeneous disease. Our results suggest that migraine with typical aura and hemiplegic migraine share a similar genetic background with a high polygenic load. Even FHM may not be a true monogenic disease, but rather a disease in which common risk variants, together with rare pathogenic variants and environmental risk factors, contribute to the disease outcome. Furthermore, our results provide genetic evidence from a large multi-generational Finnish family for potentially shared pathophysiology underlying both epilepsy and migraine. Migreeni on yleinen kohtauksellinen päänsärkysairaus. Kolmasosalla migreenipotilaista kohtauksiin liittyy auraoire, joka voi olla näkö-, puhe- tai tuntohäiriö. Harvinaisessa hemiplegisessä migreenissä aura esiintyy toisella puolella kehoa puutumista ja voimattomuutta aiheuttavana oireena. Migreenin patofysiologiaa ei vielä täysin tunneta. Laajat geenitutkimukset ovat tunnistaneet yli sata migreeniriskiä hieman lisäävää perimän vaihtelevaa kohtaa (geenivarianttia). Sairastumisriskiin merkittävästi yksinään vaikuttavia variantteja on tunnistettu vain monogeenisenä sairautena pidetylle hemiplegiselle migreenille. Tässä väitöskirjatutkimuksessa selvitettiin aurallisen migreenin sekä migreenin ja epilepsian yhteisesiintymisen geneettistä taustaa hyödyntämällä suurta suomalaista migreeniperheaineistoa (1967 perhettä, 8937 henkilöä). Tutkimuksen ensimmäisen osatyön tulokset osoittivat, että hemipleginen migreeni on osa aurallisen migreenin oirejatkumoa, vaikkakin hemiplegistä migreeniä sairastavien oireet ovat keskimäärin vakavampia kuin tyypillistä aurallista migreeniä sairastavilla. Tulokset osoittivat myös, että kolme tunnettua hemiplegisen migreenin alttiusgeeniä (CACNA1A, ATP1A2 ja SCN1A) eivät yksinään riitä selittämään hemiplegisen migreenin esiintymistä suomalaisissa perheissä. Ainoastaan 9 %:lta tutkituista perheistä (4/45) löydettiin todennäköinen sairausvariantti kyseisistä geeneistä. Tutkimuksen toisen osatyön tulokset osoittivat, että monien geneettisten riskitekijöiden yhteisvaikutus selittää migreenin esiintymistä suvuissa. Tutkimuksessa havaittiin myös eroja eri migreenityyppien välillä. Yleisten geneettisten riskitekijöiden muodostama taakka oli suurempi aurallisessa migreenissä, mukaan lukien hemiplegistä migreeniä sairastavat henkilöt, kuin aurattomassa migreenissä. Aiemmin hemiplegisen migreenin on ajateltu aiheutuvan pelkästään harvinaisista varianteista. Tutkimuksen viimeisessä osatyössä keskityttiin yhteen suureen perheeseen ja siinä tunnistettuun migreenille ja epilepsialle altistavaan 12q24.31 kromosomialueeseen. Jatkotutkimukset osoittivat aivojen kehitykseen vaikuttavan NCOR2-geenin todennäköisimmäksi epilepsian alttiusgeeniksi kyseisessä perheessä. Yksi migreenin riskialueista sijaitsee samalla genomialueella, mikä tukee alueen merkitystä myös migreenin taustalla. Kokonaisuudessaan tämän väitöstutkimuksen tulokset viittaavat siihen, että migreeni on kliinisesti ja geneettisesti heterogeeninen sairaus, jonka kehittymiseen vaikuttavat useat geenivariantit yhdessä ulkoisten tekijöiden kanssa. Aurallisen migreenin kliiniset oireet muodostavat jatkumon, jossa hemiplegisen migreenin oireet ovat kestoltaan, määrältään ja tyypiltään kaikkein vakavimpia. Yllättäen myös geneettisten riskitekijöiden yhteisvaikutus on aurallisilla ja hemiplegisillä migreenipotilailla kaikkein suurin.