Shared genetic basis for migraine and ischemic stroke:  A genome-wide analysis of common variants

Rifat Malik; T. Freilinger; B. S. Winsvold; V. Anttila; J. Vander Heiden; M. Traylor; B. De Vries; E. G. Holliday; G. M. Terwindt; J. Sturm; J. C. Bis; J. C. Hopewell; M. D. Ferrari; K. Rannikmae; M. Wessman; M. Kallela; C. Kubisch; M. Fornage; J. F. Meschia; T. Lehtimaki; C. Sudlow; R. Clarke; D. I. Chasman; Braxton D. Mitchell; J. Maguire; J. Kaprio; M. Farrall; O. T. Raitakari; T. Kurth; M. A. Ikram; A. P. Reiner; W. T. Longstreth; P. M. Rothwell; D. P. Strachan; P. Sharma; S. Seshadri; L. Quaye; Lynn Cherkas; M. Schurks; J. Rosand; L. Ligthart; G. B. Boncoraglio; G. Davey Smith; C. M. Van Duijn; K. Stefansson; B. B. Worrall; D. R. Nyholt; H. S. Markus; A. M. J. M. Van Den Maagdenberg; C. Cotsapas; J. A. Zwart; A. Palotie; M. Dichgans; U. Thorsteinsdottir; A. L. Destefano; C. Levi; S. Gretarsdottir; P. Donnelly; I. Barroso; J. M. Blackwell; E. Bramon; Matthew A  Brown; J. P. Casas; A. Corvin; P. Deloukas; A. Duncanson; J. Jankowski; H. S. Markus; C. G. Mathew; Colin NA Palmer; R. Plomin; A. Rautanen; S. J. Sawcer; R. C. Trembath F; A. C. Viswanathan; Nicholas W Wood; Chris CA Spencer; G. Band; C. Bellengues; C. Freeman; G. Hellenthal; E. Giannoulatou; M. Pirinen; Richard Pearson; A. Strange; Z. Su; D. Vukcevic; C. Langford; Sarah E Hunt; S. Edkind; R. Gwilliam; H. Blackburn; S. J. Bumpstead; S. Dronv; M. Gillman; Emma Gray; N. Hammond; A. Jayakumar; O. T. Mccann; J. Liddle; Simon C Potter; R. Ravindrarajah; M. Rickette; M. Waller; Paul Weston; S. Widaa; P. Whittaker; P. Gormley; F. Bettella; G. Mcmahon; U. Todt; P. Palta; E. Hamalainen; S. Steinberg; H. Stefansson; M. Farkkila; V. Artto; M. A. Kaunisto; J. Schoenen; R. R. Frants; G. Borck; H. Gobel; A. Heinze; K. Heinze-kuhn; B. Muller-myhsok

doi:10.1212/WNL.0000000000001606

Shared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants

Rifat Malik, T. Freilinger, B. S. Winsvold, V. Anttila, J. Vander Heiden, M. Traylor, B. De Vries, E. G. Holliday, G. M. Terwindt, J. Sturm, J. C. Bis, J. C. Hopewell, M. D. Ferrari, K. Rannikmae, M. Wessman, M. Kallela, C. Kubisch, M. Fornage, J. F. Meschia, T. LehtimakiC. Sudlow, R. Clarke, D. I. Chasman, Braxton D. Mitchell, J. Maguire, J. Kaprio, M. Farrall, O. T. Raitakari, T. Kurth, M. A. Ikram, A. P. Reiner, W. T. Longstreth, P. M. Rothwell, D. P. Strachan, P. Sharma, S. Seshadri, L. Quaye, Lynn Cherkas, M. Schurks, J. Rosand, L. Ligthart, G. B. Boncoraglio, G. Davey Smith, C. M. Van Duijn, K. Stefansson, B. B. Worrall, D. R. Nyholt, H. S. Markus, A. M. J. M. Van Den Maagdenberg, C. Cotsapas, J. A. Zwart, A. Palotie, M. Dichgans, U. Thorsteinsdottir, A. L. Destefano, C. Levi, S. Gretarsdottir, P. Donnelly, I. Barroso, J. M. Blackwell, E. Bramon, Matthew A Brown, J. P. Casas, A. Corvin, P. Deloukas, A. Duncanson, J. Jankowski, H. S. Markus, C. G. Mathew, Colin NA Palmer, R. Plomin, A. Rautanen, S. J. Sawcer, R. C. Trembath F, A. C. Viswanathan, Nicholas W Wood, Chris CA Spencer, G. Band, C. Bellengues, C. Freeman, G. Hellenthal, E. Giannoulatou, M. Pirinen, Richard Pearson, A. Strange, Z. Su, D. Vukcevic, C. Langford, Sarah E Hunt, S. Edkind, R. Gwilliam, H. Blackburn, S. J. Bumpstead, S. Dronv, M. Gillman, Emma Gray, N. Hammond, A. Jayakumar, O. T. Mccann, J. Liddle, Simon C Potter, R. Ravindrarajah, M. Rickette, M. Waller, Paul Weston, S. Widaa, P. Whittaker, P. Gormley, F. Bettella, G. Mcmahon, U. Todt, P. Palta, E. Hamalainen, S. Steinberg, H. Stefansson, M. Farkkila, V. Artto, M. A. Kaunisto, J. Schoenen, R. R. Frants, G. Borck, H. Gobel, A. Heinze, K. Heinze-kuhn, B. Muller-myhsok

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

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Abstract

Objective: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation.

Methods: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping.

Results: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 × 10−28 for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 × 10−20 for the CE score in MO).

Conclusions: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.

Original language	English
Article number	21
Pages (from-to)	2132-2145
Number of pages	14
Journal	Neurology
Volume	84
Issue number	21
DOIs	https://doi.org/10.1212/WNL.0000000000001606
Publication status	Published - 26 May 2015

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http://www.neurology.org/cgi/doi/10.1212/WNL.0000000000001606

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Malik, R., Freilinger, T., Winsvold, B. S., Anttila, V., Vander Heiden, J., Traylor, M., De Vries, B., Holliday, E. G., Terwindt, G. M., Sturm, J., Bis, J. C., Hopewell, J. C., Ferrari, M. D., Rannikmae, K., Wessman, M., Kallela, M., Kubisch, C., Fornage, M., Meschia, J. F., ... Muller-myhsok, B. (2015). Shared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants. Neurology, 84(21), 2132-2145. Article 21 . https://doi.org/10.1212/WNL.0000000000001606

@article{88af86e236ad483989defc196f2c69ef,

title = "Shared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants",

abstract = "Objective: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation.Methods: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping.Results: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 × 10−28 for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 × 10−20 for the CE score in MO).Conclusions: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.",

author = "Rifat Malik and T. Freilinger and Winsvold, {B. S.} and V. Anttila and {Vander Heiden}, J. and M. Traylor and {De Vries}, B. and Holliday, {E. G.} and Terwindt, {G. M.} and J. Sturm and Bis, {J. C.} and Hopewell, {J. C.} and Ferrari, {M. D.} and K. Rannikmae and M. Wessman and M. Kallela and C. Kubisch and M. Fornage and Meschia, {J. F.} and T. Lehtimaki and C. Sudlow and R. Clarke and Chasman, {D. I.} and Mitchell, {Braxton D.} and J. Maguire and J. Kaprio and M. Farrall and Raitakari, {O. T.} and T. Kurth and Ikram, {M. A.} and Reiner, {A. P.} and Longstreth, {W. T.} and Rothwell, {P. M.} and Strachan, {D. P.} and P. Sharma and S. Seshadri and L. Quaye and Lynn Cherkas and M. Schurks and J. Rosand and L. Ligthart and Boncoraglio, {G. B.} and {Davey Smith}, G. and {Van Duijn}, {C. M.} and K. Stefansson and Worrall, {B. B.} and Nyholt, {D. R.} and Markus, {H. S.} and {Van Den Maagdenberg}, {A. M. J. M.} and C. Cotsapas and Zwart, {J. A.} and A. Palotie and M. Dichgans and U. Thorsteinsdottir and Destefano, {A. L.} and C. Levi and S. Gretarsdottir and P. Donnelly and I. Barroso and Blackwell, {J. M.} and E. Bramon and Brown, {Matthew A} and Casas, {J. P.} and A. Corvin and P. Deloukas and A. Duncanson and J. Jankowski and Markus, {H. S.} and Mathew, {C. G.} and Palmer, {Colin NA} and R. Plomin and A. Rautanen and Sawcer, {S. J.} and {Trembath F}, {R. C.} and Viswanathan, {A. C.} and Wood, {Nicholas W} and Spencer, {Chris CA} and G. Band and C. Bellengues and C. Freeman and G. Hellenthal and E. Giannoulatou and M. Pirinen and Richard Pearson and A. Strange and Z. Su and D. Vukcevic and C. Langford and Hunt, {Sarah E} and S. Edkind and R. Gwilliam and H. Blackburn and Bumpstead, {S. J.} and S. Dronv and M. Gillman and Emma Gray and N. Hammond and A. Jayakumar and Mccann, {O. T.} and J. Liddle and Potter, {Simon C} and R. Ravindrarajah and M. Rickette and M. Waller and Paul Weston and S. Widaa and P. Whittaker and P. Gormley and F. Bettella and G. Mcmahon and U. Todt and P. Palta and E. Hamalainen and S. Steinberg and H. Stefansson and M. Farkkila and V. Artto and Kaunisto, {M. A.} and J. Schoenen and Frants, {R. R.} and G. Borck and H. Gobel and A. Heinze and K. Heinze-kuhn and B. Muller-myhsok",

year = "2015",

month = may,

day = "26",

doi = "10.1212/WNL.0000000000001606",

language = "English",

volume = "84",

pages = "2132--2145",

journal = "Neurology",

issn = "0028-3878",

publisher = "LIPPINCOTT WILLIAMS & WILKINS",

number = "21",

}

Malik, R, Freilinger, T, Winsvold, BS, Anttila, V, Vander Heiden, J, Traylor, M, De Vries, B, Holliday, EG, Terwindt, GM, Sturm, J, Bis, JC, Hopewell, JC, Ferrari, MD, Rannikmae, K, Wessman, M, Kallela, M, Kubisch, C, Fornage, M, Meschia, JF, Lehtimaki, T, Sudlow, C, Clarke, R, Chasman, DI, Mitchell, BD, Maguire, J, Kaprio, J, Farrall, M, Raitakari, OT, Kurth, T, Ikram, MA, Reiner, AP, Longstreth, WT, Rothwell, PM, Strachan, DP, Sharma, P, Seshadri, S, Quaye, L , Cherkas, L, Schurks, M, Rosand, J, Ligthart, L, Boncoraglio, GB, Davey Smith, G, Van Duijn, CM, Stefansson, K, Worrall, BB, Nyholt, DR, Markus, HS, Van Den Maagdenberg, AMJM, Cotsapas, C, Zwart, JA, Palotie, A, Dichgans, M, Thorsteinsdottir, U, Destefano, AL, Levi, C, Gretarsdottir, S, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath F, RC , Viswanathan, AC, Wood, NW, Spencer, CCA, Band, G, Bellengues, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkind, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronv, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, Mccann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Rickette, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, Gormley, P, Bettella, F, Mcmahon, G, Todt, U, Palta, P, Hamalainen, E, Steinberg, S, Stefansson, H, Farkkila, M, Artto, V, Kaunisto, MA, Schoenen, J, Frants, RR, Borck, G, Gobel, H, Heinze, A, Heinze-kuhn, K & Muller-myhsok, B 2015, 'Shared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants', Neurology, vol. 84, no. 21, 21 , pp. 2132-2145. https://doi.org/10.1212/WNL.0000000000001606

TY - JOUR

T1 - Shared genetic basis for migraine and ischemic stroke

T2 - A genome-wide analysis of common variants

AU - Malik, Rifat

AU - Freilinger, T.

AU - Winsvold, B. S.

AU - Anttila, V.

AU - Vander Heiden, J.

AU - Traylor, M.

AU - De Vries, B.

AU - Holliday, E. G.

AU - Terwindt, G. M.

AU - Sturm, J.

AU - Bis, J. C.

AU - Hopewell, J. C.

AU - Ferrari, M. D.

AU - Rannikmae, K.

AU - Wessman, M.

AU - Kallela, M.

AU - Kubisch, C.

AU - Fornage, M.

AU - Meschia, J. F.

AU - Lehtimaki, T.

AU - Sudlow, C.

AU - Clarke, R.

AU - Chasman, D. I.

AU - Mitchell, Braxton D.

AU - Maguire, J.

AU - Kaprio, J.

AU - Farrall, M.

AU - Raitakari, O. T.

AU - Kurth, T.

AU - Ikram, M. A.

AU - Reiner, A. P.

AU - Longstreth, W. T.

AU - Rothwell, P. M.

AU - Strachan, D. P.

AU - Sharma, P.

AU - Seshadri, S.

AU - Quaye, L.

AU - Cherkas, Lynn

AU - Schurks, M.

AU - Rosand, J.

AU - Ligthart, L.

AU - Boncoraglio, G. B.

AU - Davey Smith, G.

AU - Van Duijn, C. M.

AU - Stefansson, K.

AU - Worrall, B. B.

AU - Nyholt, D. R.

AU - Markus, H. S.

AU - Van Den Maagdenberg, A. M. J. M.

AU - Cotsapas, C.

AU - Zwart, J. A.

AU - Palotie, A.

AU - Dichgans, M.

AU - Thorsteinsdottir, U.

AU - Destefano, A. L.

AU - Levi, C.

AU - Gretarsdottir, S.

AU - Donnelly, P.

AU - Barroso, I.

AU - Blackwell, J. M.

AU - Bramon, E.

AU - Brown, Matthew A

AU - Casas, J. P.

AU - Corvin, A.

AU - Deloukas, P.

AU - Duncanson, A.

AU - Jankowski, J.

AU - Markus, H. S.

AU - Mathew, C. G.

AU - Palmer, Colin NA

AU - Plomin, R.

AU - Rautanen, A.

AU - Sawcer, S. J.

AU - Trembath F, R. C.

AU - Viswanathan, A. C.

AU - Wood, Nicholas W

AU - Spencer, Chris CA

AU - Band, G.

AU - Bellengues, C.

AU - Freeman, C.

AU - Hellenthal, G.

AU - Giannoulatou, E.

AU - Pirinen, M.

AU - Pearson, Richard

AU - Strange, A.

AU - Su, Z.

AU - Vukcevic, D.

AU - Langford, C.

AU - Hunt, Sarah E

AU - Edkind, S.

AU - Gwilliam, R.

AU - Blackburn, H.

AU - Bumpstead, S. J.

AU - Dronv, S.

AU - Gillman, M.

AU - Gray, Emma

AU - Hammond, N.

AU - Jayakumar, A.

AU - Mccann, O. T.

AU - Liddle, J.

AU - Potter, Simon C

AU - Ravindrarajah, R.

AU - Rickette, M.

AU - Waller, M.

AU - Weston, Paul

AU - Widaa, S.

AU - Whittaker, P.

AU - Gormley, P.

AU - Bettella, F.

AU - Mcmahon, G.

AU - Todt, U.

AU - Palta, P.

AU - Hamalainen, E.

AU - Steinberg, S.

AU - Stefansson, H.

AU - Farkkila, M.

AU - Artto, V.

AU - Kaunisto, M. A.

AU - Schoenen, J.

AU - Frants, R. R.

AU - Borck, G.

AU - Gobel, H.

AU - Heinze, A.

AU - Heinze-kuhn, K.

AU - Muller-myhsok, B.

PY - 2015/5/26

Y1 - 2015/5/26

N2 - Objective: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation.Methods: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping.Results: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 × 10−28 for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 × 10−20 for the CE score in MO).Conclusions: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.

AB - Objective: To quantify genetic overlap between migraine and ischemic stroke (IS) with respect to common genetic variation.Methods: We applied 4 different approaches to large-scale meta-analyses of genome-wide data on migraine (23,285 cases and 95,425 controls) and IS (12,389 cases and 62,004 controls). First, we queried known genome-wide significant loci for both disorders, looking for potential overlap of signals. We then analyzed the overall shared genetic load using polygenic scores and estimated the genetic correlation between disease subtypes using data derived from these models. We further interrogated genomic regions of shared risk using analysis of covariance patterns between the 2 phenotypes using cross-phenotype spatial mapping.Results: We found substantial genetic overlap between migraine and IS using all 4 approaches. Migraine without aura (MO) showed much stronger overlap with IS and its subtypes than migraine with aura (MA). The strongest overlap existed between MO and large artery stroke (LAS; p = 6.4 × 10−28 for the LAS polygenic score in MO) and between MO and cardioembolic stroke (CE; p = 2.7 × 10−20 for the CE score in MO).Conclusions: Our findings indicate shared genetic susceptibility to migraine and IS, with a particularly strong overlap between MO and both LAS and CE pointing towards shared mechanisms. Our observations on MA are consistent with a limited role of common genetic variants in this subtype.

UR - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4451048/

U2 - 10.1212/WNL.0000000000001606

DO - 10.1212/WNL.0000000000001606

M3 - Article

SN - 0028-3878

VL - 84

SP - 2132

EP - 2145

JO - Neurology

JF - Neurology

IS - 21

M1 - 21

ER -

Shared genetic basis for migraine and ischemic stroke: A genome-wide analysis of common variants

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