The contribution of CACNA1A, ATP1A2 and SCN1A mutations in hemiplegic migraine : A clinical and genetic study in Finnish migraine families

Objective To study the position of hemiplegic migraine in the clinical spectrum of migraine with aura and to reveal the importance of CACNA1A, ATP1A2 and SCN1A in the development of hemiplegic migraine in Finnish migraine families. Methods The International Classification of Headache Disorders 3rd edition criteria were used to determine clinical characteristics and occurrence of hemiplegic migraine, based on detailed questionnaires, in a Finnish migraine family collection consisting of 9087 subjects. Involvement of CACNA1A, ATP1A2 and SCN1A was studied using whole exome sequencing data from 293 patients with hemiplegic migraine. Results Overall, hemiplegic migraine patients reported clinically more severe headache and aura episodes than non-hemiplegic migraine with aura patients. We identified two mutations, c.1816G>A (p.Ala606Thr) and c.1148G>A (p.Arg383His), in ATP1A2 and one mutation, c.1994C>T (p.Thr665Met) in CACNA1A. Conclusions The results highlight hemiplegic migraine as a clinically and genetically heterogeneous disease. Hemiplegic migraine patients do not form a clearly separate group with distinct symptoms, but rather have an extreme phenotype in the migraine with aura continuum. We have shown that mutations in CACNA1A, ATP1A2 and SCN1A are not the major cause of the disease in Finnish hemiplegic migraine patients, suggesting that there are additional genetic factors contributing to the phenotype.Peer reviewe

Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families

Complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. The aggregation could be explained by rare, penetrant variants that segregate according to Mendelian inheritance or by the sufficient polygenic accumulation of common variants, each with an individually small effect, or a combination of the two hypotheses. In 8,319 individuals across 1,589 migraine families, we calculated migraine polygenic risk scores (PRS) and found a significantly higher common variant burden in familial cases (n = 5,317, OR = 1.76, 95% CI = 1.71-1.81, p = 1.7 × 10-109) compared to population cases from the FINRISK cohort (n = 1,101, OR = 1.32, 95% CI = 1.25-1.38, p = 7.2 × 10-17). The PRS explained 1.6% of the phenotypic variance in the population cases and 3.5% in the familial cases (including 2.9% for migraine without aura, 5.5% for migraine with typical aura, and 8.2% for hemiplegic migraine). The results demonstrate a significant contribution of common polygenic variation to the familial aggregation of migraine

Supplementary table 2 -Supplemental material for The contribution of <i>CACNA1A, ATP1A2</i> and <i>SCN1A</i> mutations in hemiplegic migraine: A clinical and genetic study in Finnish migraine families

<p>Supplemental material, Supplementary table 2 for The contribution of <i>CACNA1A, ATP1A2</i> and <i>SCN1A</i> mutations in hemiplegic migraine: A clinical and genetic study in Finnish migraine families by Marjo Eveliina Hiekkala, Pietari Vuola, Ville Artto, Paavo Häppölä, Elisa Häppölä, Salli Vepsäläinen, Ester Cuenca-León, Dennis Lal, Padhraig Gormley, Eija Hämäläinen, Matti Ilmavirta, Markku Nissilä, Erkki Säkö, Marja-Liisa Sumelahti, Hanna Harno, Hannele Havanka, Petra Keski-Säntti, Markus Färkkilä, Aarno Palotie, Maija Wessman, Mari Anneli Kaunisto and Mikko Kallela in Cephalalgia</p

Supplementary table 3 -Supplemental material for The contribution of <i>CACNA1A, ATP1A2</i> and <i>SCN1A</i> mutations in hemiplegic migraine: A clinical and genetic study in Finnish migraine families

<p>Supplemental material, Supplementary table 3 for The contribution of <i>CACNA1A, ATP1A2</i> and <i>SCN1A</i> mutations in hemiplegic migraine: A clinical and genetic study in Finnish migraine families by Marjo Eveliina Hiekkala, Pietari Vuola, Ville Artto, Paavo Häppölä, Elisa Häppölä, Salli Vepsäläinen, Ester Cuenca-León, Dennis Lal, Padhraig Gormley, Eija Hämäläinen, Matti Ilmavirta, Markku Nissilä, Erkki Säkö, Marja-Liisa Sumelahti, Hanna Harno, Hannele Havanka, Petra Keski-Säntti, Markus Färkkilä, Aarno Palotie, Maija Wessman, Mari Anneli Kaunisto and Mikko Kallela in Cephalalgia</p

Supplementary table 1 -Supplemental material for The contribution of <i>CACNA1A, ATP1A2</i> and <i>SCN1A</i> mutations in hemiplegic migraine: A clinical and genetic study in Finnish migraine families

<p>Supplemental material, Supplementary table 1 for The contribution of <i>CACNA1A, ATP1A2</i> and <i>SCN1A</i> mutations in hemiplegic migraine: A clinical and genetic study in Finnish migraine families by Marjo Eveliina Hiekkala, Pietari Vuola, Ville Artto, Paavo Häppölä, Elisa Häppölä, Salli Vepsäläinen, Ester Cuenca-León, Dennis Lal, Padhraig Gormley, Eija Hämäläinen, Matti Ilmavirta, Markku Nissilä, Erkki Säkö, Marja-Liisa Sumelahti, Hanna Harno, Hannele Havanka, Petra Keski-Säntti, Markus Färkkilä, Aarno Palotie, Maija Wessman, Mari Anneli Kaunisto and Mikko Kallela in Cephalalgia</p

Supplementary figure 1 -Supplemental material for The contribution of <i>CACNA1A, ATP1A2</i> and <i>SCN1A</i> mutations in hemiplegic migraine: A clinical and genetic study in Finnish migraine families

<p>Supplemental material, Supplementary figure 1 for The contribution of <i>CACNA1A, ATP1A2</i> and <i>SCN1A</i> mutations in hemiplegic migraine: A clinical and genetic study in Finnish migraine families by Marjo Eveliina Hiekkala, Pietari Vuola, Ville Artto, Paavo Häppölä, Elisa Häppölä, Salli Vepsäläinen, Ester Cuenca-León, Dennis Lal, Padhraig Gormley, Eija Hämäläinen, Matti Ilmavirta, Markku Nissilä, Erkki Säkö, Marja-Liisa Sumelahti, Hanna Harno, Hannele Havanka, Petra Keski-Säntti, Markus Färkkilä, Aarno Palotie, Maija Wessman, Mari Anneli Kaunisto and Mikko Kallela in Cephalalgia</p

Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families

Complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. The aggregation could be explained by rare, penetrant variants that segregate according to Mendelian inheritance or by the sufficient polygenic accumulation of common variants, each with an individually small effect, or a combination of the two hypotheses. In 8,319 individuals across 1,589 migraine families, we calculated migraine polygenic risk scores (PRS) and found a significantly significantly higher common variant burden in familial cases (n = 5,317, OR = 1.76, 95% CI = 1.71-1.81, p = 1.7 x 10(-109)) compared to population cases from the FINRISK cohort (n = 1,101, OR = 1.32, 95% CI = 1.25-1.38, p = 7.2 x 10(-17)). The PRS explained 1.6% of the phenotypic variance in the population cases and 3.5% in the familial cases (including 2.9% for migraine without aura, 5.5% for migraine with typical aura, and 8.2% for hemiplegic migraine). The results demonstrate a significant contribution of common polygenic variation to the familial aggregation of migraine

Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families

Complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. The aggregation could be explained by rare, penetrant variants that segregate according to Mendelian inheritance or by the sufficient polygenic accumulation of common variants, each with an individually small effect, or a combination of the two hypotheses. In 8,319 individuals across 1,589 migraine families, we calculated migraine polygenic risk scores (PRS) and found a significantly higher common variant burden in familial cases (n = 5,317, OR = 1.76, 95% CI = 1.71–1.81, p = 1.7 × 10−109) compared to population cases from the FINRISK cohort (n = 1,101, OR = 1.32, 95% CI = 1.25–1.38, p = 7.2 × 10−17). The PRS explained 1.6% of the phenotypic variance in the population cases and 3.5% in the familial cases (including 2.9% for migraine without aura, 5.5% for migraine with typical aura, and 8.2% for hemiplegic migraine). The results demonstrate a significant contribution of common polygenic variation to the familial aggregation of migraine. Gormley et al. use polygenic risk scores to show that common variation, captured by genome-wide association studies, in combination contributes to the aggregation of migraine in families. The results may have similar implications for other complex traits in general.</p

Correction: Common variant burden contributes to the familial aggregation of migraine in 1,589 families

(Neuron 98, 743–753.e1–e4; May 16, 2018) In the original publication of this paper, the middle initial of Michael D. Ferrari's name was inadvertently left out. This has since been corrected online. The authors apologize for the error.</p