Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

Verneri Anttila; Hreinn Stefansson; Mikko Kallela; Unda Todt; Gisela M Terwindt; M Stella Calafato; Dale R Nyholt; Antigone S Dimas; Tobias Freilinger; Bertram Müller-Myhsok; Ville Artto; Michael Inouye; Kirsi Alakurtti; Mari A Kaunisto; Eija Hämäläinen; Boukje de Vries; Anine H Stam; Claudia M Weller; Axel Heinze; Katja Heinze-Kuhn; Ingrid Goebel; Guntram Borck; Hartmut Göbel; Stacy Steinberg; Christiane Wolf; Asgeir Björnsson; Gretar Gudmundsson; Malene Kirchmann; Anne Hauge; Thomas Werge; Jean Schoenen; Johan G Eriksson; Knut Hagen; Lars Stovner; H-Erich Wichmann; Thomas Meitinger; Michael Alexander; Susanne Moebus; Stefan Schreiber; Yurii S Aulchenko; Monique M B Breteler; Andre G Uitterlinden; Albert Hofman; Cornelia M van Duijn; Päivi Tikka-Kleemola; Salli Vepsäläinen; Susanne Lucae; Federica Tozzi; Pierandrea Muglia; Jes Olesen; International Headache Genetics Consortium

doi:10.1038/ng.652

Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

Verneri Anttila, Hreinn Stefansson, Mikko Kallela, Unda Todt, Gisela M Terwindt, M Stella Calafato, Dale R Nyholt, Antigone S Dimas, Tobias Freilinger, Bertram Müller-Myhsok, Ville Artto, Michael Inouye, Kirsi Alakurtti, Mari A Kaunisto, Eija Hämäläinen, Boukje de Vries, Anine H Stam, Claudia M Weller, Axel Heinze, Katja Heinze-KuhnIngrid Goebel, Guntram Borck, Hartmut Göbel, Stacy Steinberg, Christiane Wolf, Asgeir Björnsson, Gretar Gudmundsson, Malene Kirchmann, Anne Hauge, Thomas Werge, Jean Schoenen, Johan G Eriksson, Knut Hagen, Lars Stovner, H-Erich Wichmann, Thomas Meitinger, Michael Alexander, Susanne Moebus, Stefan Schreiber, Yurii S Aulchenko, Monique M B Breteler, Andre G Uitterlinden, Albert Hofman, Cornelia M van Duijn, Päivi Tikka-Kleemola, Salli Vepsäläinen, Susanne Lucae, Federica Tozzi, Pierandrea Muglia, Jes Olesen, International Headache Genetics Consortium

Graduate School of Health and Medical Sciences

Research output: Contribution to journal › Letter › Research › peer-review

319 Citations (Scopus)

Abstract

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 × 10¿¿, odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 × 10¿¹¹ (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 × 10¿5, permuted threshold for genome-wide significance 7.7 × 10¿5. To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

Original language	English
Journal	Nature Genetics
Volume	42
Issue number	10
Pages (from-to)	869-73
Number of pages	5
ISSN	1061-4036
DOIs	https://doi.org/10.1038/ng.652
Publication status	Published - 1 Oct 2010

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10.1038/ng.652

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Anttila, V., Stefansson, H., Kallela, M., Todt, U., Terwindt, G. M., Calafato, M. S., Nyholt, D. R., Dimas, A. S., Freilinger, T., Müller-Myhsok, B., Artto, V., Inouye, M., Alakurtti, K., Kaunisto, M. A., Hämäläinen, E., de Vries, B., Stam, A. H., Weller, C. M., Heinze, A., ... International Headache Genetics Consortium (2010). Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. Nature Genetics, 42(10), 869-73. https://doi.org/10.1038/ng.652

Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. / Anttila, Verneri; Stefansson, Hreinn; Kallela, Mikko; Todt, Unda; Terwindt, Gisela M; Calafato, M Stella; Nyholt, Dale R; Dimas, Antigone S; Freilinger, Tobias; Müller-Myhsok, Bertram; Artto, Ville; Inouye, Michael; Alakurtti, Kirsi; Kaunisto, Mari A; Hämäläinen, Eija; de Vries, Boukje; Stam, Anine H; Weller, Claudia M; Heinze, Axel; Heinze-Kuhn, Katja; Goebel, Ingrid; Borck, Guntram; Göbel, Hartmut; Steinberg, Stacy; Wolf, Christiane; Björnsson, Asgeir; Gudmundsson, Gretar; Kirchmann, Malene; Hauge, Anne; Werge, Thomas; Schoenen, Jean; Eriksson, Johan G; Hagen, Knut; Stovner, Lars; Wichmann, H-Erich; Meitinger, Thomas; Alexander, Michael; Moebus, Susanne; Schreiber, Stefan; Aulchenko, Yurii S; Breteler, Monique M B; Uitterlinden, Andre G; Hofman, Albert; van Duijn, Cornelia M; Tikka-Kleemola, Päivi; Vepsäläinen, Salli; Lucae, Susanne; Tozzi, Federica; Muglia, Pierandrea; Olesen, Jes; International Headache Genetics Consortium.

In: Nature Genetics, Vol. 42, No. 10, 01.10.2010, p. 869-73.

Research output: Contribution to journal › Letter › Research › peer-review

Anttila, V, Stefansson, H, Kallela, M, Todt, U, Terwindt, GM, Calafato, MS, Nyholt, DR, Dimas, AS, Freilinger, T, Müller-Myhsok, B, Artto, V, Inouye, M, Alakurtti, K, Kaunisto, MA, Hämäläinen, E, de Vries, B, Stam, AH, Weller, CM, Heinze, A, Heinze-Kuhn, K, Goebel, I, Borck, G, Göbel, H, Steinberg, S, Wolf, C, Björnsson, A, Gudmundsson, G, Kirchmann, M, Hauge, A, Werge, T, Schoenen, J, Eriksson, JG, Hagen, K, Stovner, L, Wichmann, H-E, Meitinger, T, Alexander, M, Moebus, S, Schreiber, S, Aulchenko, YS, Breteler, MMB, Uitterlinden, AG, Hofman, A, van Duijn, CM, Tikka-Kleemola, P, Vepsäläinen, S, Lucae, S, Tozzi, F, Muglia, P, Olesen, J & International Headache Genetics Consortium 2010, 'Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1', Nature Genetics, vol. 42, no. 10, pp. 869-73. https://doi.org/10.1038/ng.652

Anttila, Verneri ; Stefansson, Hreinn ; Kallela, Mikko ; Todt, Unda ; Terwindt, Gisela M ; Calafato, M Stella ; Nyholt, Dale R ; Dimas, Antigone S ; Freilinger, Tobias ; Müller-Myhsok, Bertram ; Artto, Ville ; Inouye, Michael ; Alakurtti, Kirsi ; Kaunisto, Mari A ; Hämäläinen, Eija ; de Vries, Boukje ; Stam, Anine H ; Weller, Claudia M ; Heinze, Axel ; Heinze-Kuhn, Katja ; Goebel, Ingrid ; Borck, Guntram ; Göbel, Hartmut ; Steinberg, Stacy ; Wolf, Christiane ; Björnsson, Asgeir ; Gudmundsson, Gretar ; Kirchmann, Malene ; Hauge, Anne ; Werge, Thomas ; Schoenen, Jean ; Eriksson, Johan G ; Hagen, Knut ; Stovner, Lars ; Wichmann, H-Erich ; Meitinger, Thomas ; Alexander, Michael ; Moebus, Susanne ; Schreiber, Stefan ; Aulchenko, Yurii S ; Breteler, Monique M B ; Uitterlinden, Andre G ; Hofman, Albert ; van Duijn, Cornelia M ; Tikka-Kleemola, Päivi ; Vepsäläinen, Salli ; Lucae, Susanne ; Tozzi, Federica ; Muglia, Pierandrea ; Olesen, Jes ; International Headache Genetics Consortium. / Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. In: Nature Genetics. 2010 ; Vol. 42, No. 10. pp. 869-73.

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title = "Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1",

abstract = "Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 × 10¿¿, odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 × 10¿¹¹ (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 × 10¿5, permuted threshold for genome-wide significance 7.7 × 10¿5. To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.",

author = "Verneri Anttila and Hreinn Stefansson and Mikko Kallela and Unda Todt and Terwindt, {Gisela M} and Calafato, {M Stella} and Nyholt, {Dale R} and Dimas, {Antigone S} and Tobias Freilinger and Bertram M{\"u}ller-Myhsok and Ville Artto and Michael Inouye and Kirsi Alakurtti and Kaunisto, {Mari A} and Eija H{\"a}m{\"a}l{\"a}inen and {de Vries}, Boukje and Stam, {Anine H} and Weller, {Claudia M} and Axel Heinze and Katja Heinze-Kuhn and Ingrid Goebel and Guntram Borck and Hartmut G{\"o}bel and Stacy Steinberg and Christiane Wolf and Asgeir Bj{\"o}rnsson and Gretar Gudmundsson and Malene Kirchmann and Anne Hauge and Thomas Werge and Jean Schoenen and Eriksson, {Johan G} and Knut Hagen and Lars Stovner and H-Erich Wichmann and Thomas Meitinger and Michael Alexander and Susanne Moebus and Stefan Schreiber and Aulchenko, {Yurii S} and Breteler, {Monique M B} and Uitterlinden, {Andre G} and Albert Hofman and {van Duijn}, {Cornelia M} and P{\"a}ivi Tikka-Kleemola and Salli Veps{\"a}l{\"a}inen and Susanne Lucae and Federica Tozzi and Pierandrea Muglia and Jes Olesen and Thomas Werge",

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T1 - Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

AU - Anttila, Verneri

AU - Stefansson, Hreinn

AU - Kallela, Mikko

AU - Todt, Unda

AU - Terwindt, Gisela M

AU - Calafato, M Stella

AU - Nyholt, Dale R

AU - Dimas, Antigone S

AU - Freilinger, Tobias

AU - Müller-Myhsok, Bertram

AU - Artto, Ville

AU - Inouye, Michael

AU - Alakurtti, Kirsi

AU - Kaunisto, Mari A

AU - Hämäläinen, Eija

AU - de Vries, Boukje

AU - Stam, Anine H

AU - Weller, Claudia M

AU - Heinze, Axel

AU - Heinze-Kuhn, Katja

AU - Goebel, Ingrid

AU - Borck, Guntram

AU - Göbel, Hartmut

AU - Steinberg, Stacy

AU - Wolf, Christiane

AU - Björnsson, Asgeir

AU - Gudmundsson, Gretar

AU - Kirchmann, Malene

AU - Hauge, Anne

AU - Werge, Thomas

AU - Schoenen, Jean

AU - Eriksson, Johan G

AU - Hagen, Knut

AU - Stovner, Lars

AU - Wichmann, H-Erich

AU - Meitinger, Thomas

AU - Alexander, Michael

AU - Moebus, Susanne

AU - Schreiber, Stefan

AU - Aulchenko, Yurii S

AU - Breteler, Monique M B

AU - Uitterlinden, Andre G

AU - Hofman, Albert

AU - van Duijn, Cornelia M

AU - Tikka-Kleemola, Päivi

AU - Vepsäläinen, Salli

AU - Lucae, Susanne

AU - Tozzi, Federica

AU - Muglia, Pierandrea

AU - Olesen, Jes

AU - International Headache Genetics Consortium

PY - 2010/10/1

Y1 - 2010/10/1

N2 - Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 × 10¿¿, odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 × 10¿¹¹ (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 × 10¿5, permuted threshold for genome-wide significance 7.7 × 10¿5. To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

AB - Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 × 10¿¿, odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 × 10¿¹¹ (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 × 10¿5, permuted threshold for genome-wide significance 7.7 × 10¿5. To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

U2 - 10.1038/ng.652

DO - 10.1038/ng.652

M3 - Letter

VL - 42

SP - 869

EP - 873

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 10

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