Genome-Wide Association Study Identifies Risk Loci for Cluster Headache

Emer O'Connor; Carmen Fourier; Caroline Ran; Prasanth Sivakumar; Franziska Liesecke; Laura Southgate; Aster V.E. Harder; Lisanne S. Vijfhuizen; Janice Yip; Nicola Giffin; Nicholas Silver; Fayyaz Ahmed; Isabel C. Hostettler; Brendan Davies; M. Zameel Cader; Benjamin S. Simpson; Roisin Sullivan; Stephanie Efthymiou; Joycee Adebimpe; Olivia Quinn; Ciaran Campbell; Gianpiero L. Cavalleri; Michail Vikelis; Tim Kelderman; Koen Paemeleire; Emer Kilbride; Lou Grangeon; Susie Lagrata; Daisuke Danno; Richard Trembath; Nicholas W. Wood; Ingrid Kockum; Bendik S. Winsvold; Anna Steinberg; Christina Sjöstrand; Elisabet Waldenlind; Jana Vandrovcova; Henry Houlden; Manjit Matharu; Andrea Carmine Belin

doi:10.1002/ana.26150

Genome-Wide Association Study Identifies Risk Loci for Cluster Headache

Emer O'Connor, Carmen Fourier, Caroline Ran, Prasanth Sivakumar, Franziska Liesecke, Laura Southgate, Aster V.E. Harder, Lisanne S. Vijfhuizen, Janice Yip, Nicola Giffin, Nicholas Silver, Fayyaz Ahmed, Isabel C. Hostettler, Brendan Davies, M. Zameel Cader, Benjamin S. Simpson, Roisin Sullivan, Stephanie Efthymiou, Joycee Adebimpe, Olivia QuinnCiaran Campbell, Gianpiero L. Cavalleri, Michail Vikelis, Tim Kelderman, Koen Paemeleire, Emer Kilbride, Lou Grangeon, Susie Lagrata, Daisuke Danno, Richard Trembath, Nicholas W. Wood, Ingrid Kockum, Bendik S. Winsvold, Anna Steinberg, Christina Sjöstrand, Elisabet Waldenlind, Jana Vandrovcova, Henry Houlden^*, Manjit Matharu, Andrea Carmine Belin

^*Corresponding author for this work

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

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Abstract

Objective: This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. Methods: We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. Results: Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10 ⁻¹⁷, odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37–1.66) and rs4519530 (p = 6.98 × 10 ⁻¹⁷, OR = 1.47, 95% CI = 1.34–1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10 ⁻⁸, OR = 1.36, 95% CI = 1.22–1.52), and rs11153082 (p = 1.85 × 10 ⁻⁸, OR = 1.30, 95% CI = 1.19–1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. Interpretation: We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype–phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193–202.

Original language	English
Pages (from-to)	193-202
Number of pages	10
Journal	Annals of Neurology
Volume	90
Issue number	2
Early online date	14 Jul 2021
DOIs	https://doi.org/10.1002/ana.26150
Publication status	Published - Aug 2021

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O'Connor, E., Fourier, C., Ran, C., Sivakumar, P., Liesecke, F., Southgate, L., Harder, A. V. E., Vijfhuizen, L. S., Yip, J., Giffin, N., Silver, N., Ahmed, F., Hostettler, I. C., Davies, B., Cader, M. Z., Simpson, B. S., Sullivan, R., Efthymiou, S., Adebimpe, J., ... Belin, A. C. (2021). Genome-Wide Association Study Identifies Risk Loci for Cluster Headache. Annals of Neurology, 90(2), 193-202. https://doi.org/10.1002/ana.26150

@article{d5dc5bee4cab431c9e8b80208ffd9647,

title = "Genome-Wide Association Study Identifies Risk Loci for Cluster Headache",

abstract = "Objective: This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. Methods: We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. Results: Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10 −17, odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37–1.66) and rs4519530 (p = 6.98 × 10 −17, OR = 1.47, 95% CI = 1.34–1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10 −8, OR = 1.36, 95% CI = 1.22–1.52), and rs11153082 (p = 1.85 × 10 −8, OR = 1.30, 95% CI = 1.19–1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. Interpretation: We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype–phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193–202. ",

author = "Emer O'Connor and Carmen Fourier and Caroline Ran and Prasanth Sivakumar and Franziska Liesecke and Laura Southgate and Harder, {Aster V.E.} and Vijfhuizen, {Lisanne S.} and Janice Yip and Nicola Giffin and Nicholas Silver and Fayyaz Ahmed and Hostettler, {Isabel C.} and Brendan Davies and Cader, {M. Zameel} and Simpson, {Benjamin S.} and Roisin Sullivan and Stephanie Efthymiou and Joycee Adebimpe and Olivia Quinn and Ciaran Campbell and Cavalleri, {Gianpiero L.} and Michail Vikelis and Tim Kelderman and Koen Paemeleire and Emer Kilbride and Lou Grangeon and Susie Lagrata and Daisuke Danno and Richard Trembath and Wood, {Nicholas W.} and Ingrid Kockum and Winsvold, {Bendik S.} and Anna Steinberg and Christina Sj{\"o}strand and Elisabet Waldenlind and Jana Vandrovcova and Henry Houlden and Manjit Matharu and Belin, {Andrea Carmine}",

note = "Funding Information: Sweden: This study was supported by the Swedish Research Council (2017-01096), the Swedish Brain Foundation, and the Mellby G?rd Foundation (FO2018-0008), Karolinska Institutet Research Funds (2018-01738). We thank F. Xiang for excellent technical assistance and A.-C. Karlsson for help with patient recruitment. UK: E.O. is supported by Brain Research UK. Patients were collected as part of the SYNaPS Study Group collaboration funded by the Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA). J.V. is supported by Health Education England and the Medical Research Council. L.S. is supported by the Wellcome Trust Institutional Strategic Support Fund (204809/Z/16/Z) awarded to St George's, University of London. We thank Dr. J. E. Burns for his assistance in preparing the manuscript. The data handling was enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at Uppmax, Uppsala University partially funded by the Swedish Research Council through grant agreement no. 2018-05973. [Correction added on July 26, 2021 after first online publication: The Acknowledgments section has been updated.] Funding Information: Sweden: This study was supported by the Swedish Research Council (2017‐01096), the Swedish Brain Foundation, and the Mellby G{\aa}rd Foundation (FO2018‐0008), Karolinska Institutet Research Funds (2018‐01738). We thank F. Xiang for excellent technical assistance and A.‐C. Karlsson for help with patient recruitment. UK: E.O. is supported by Brain Research UK. Patients were collected as part of the SYNaPS Study Group collaboration funded by the Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA). J.V. is supported by Health Education England and the Medical Research Council. L.S. is supported by the Wellcome Trust Institutional Strategic Support Fund (204809/Z/16/Z) awarded to St George's, University of London. We thank Dr. J. E. Burns for his assistance in preparing the manuscript. Publisher Copyright: {\textcopyright} 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = aug,

doi = "10.1002/ana.26150",

language = "English",

volume = "90",

pages = "193--202",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley and Sons Inc.",

number = "2",

}

O'Connor, E, Fourier, C, Ran, C, Sivakumar, P, Liesecke, F, Southgate, L, Harder, AVE, Vijfhuizen, LS, Yip, J, Giffin, N, Silver, N, Ahmed, F, Hostettler, IC, Davies, B, Cader, MZ, Simpson, BS, Sullivan, R, Efthymiou, S, Adebimpe, J, Quinn, O, Campbell, C, Cavalleri, GL, Vikelis, M, Kelderman, T, Paemeleire, K, Kilbride, E, Grangeon, L, Lagrata, S, Danno, D, Trembath, R , Wood, NW, Kockum, I, Winsvold, BS, Steinberg, A, Sjöstrand, C, Waldenlind, E, Vandrovcova, J, Houlden, H, Matharu, M & Belin, AC 2021, 'Genome-Wide Association Study Identifies Risk Loci for Cluster Headache', Annals of Neurology, vol. 90, no. 2, pp. 193-202. https://doi.org/10.1002/ana.26150

TY - JOUR

T1 - Genome-Wide Association Study Identifies Risk Loci for Cluster Headache

AU - O'Connor, Emer

AU - Fourier, Carmen

AU - Ran, Caroline

AU - Sivakumar, Prasanth

AU - Liesecke, Franziska

AU - Southgate, Laura

AU - Harder, Aster V.E.

AU - Vijfhuizen, Lisanne S.

AU - Yip, Janice

AU - Giffin, Nicola

AU - Silver, Nicholas

AU - Ahmed, Fayyaz

AU - Hostettler, Isabel C.

AU - Davies, Brendan

AU - Cader, M. Zameel

AU - Simpson, Benjamin S.

AU - Sullivan, Roisin

AU - Efthymiou, Stephanie

AU - Adebimpe, Joycee

AU - Quinn, Olivia

AU - Campbell, Ciaran

AU - Cavalleri, Gianpiero L.

AU - Vikelis, Michail

AU - Kelderman, Tim

AU - Paemeleire, Koen

AU - Kilbride, Emer

AU - Grangeon, Lou

AU - Lagrata, Susie

AU - Danno, Daisuke

AU - Trembath, Richard

AU - Wood, Nicholas W.

AU - Kockum, Ingrid

AU - Winsvold, Bendik S.

AU - Steinberg, Anna

AU - Sjöstrand, Christina

AU - Waldenlind, Elisabet

AU - Vandrovcova, Jana

AU - Houlden, Henry

AU - Matharu, Manjit

AU - Belin, Andrea Carmine

N1 - Funding Information: Sweden: This study was supported by the Swedish Research Council (2017-01096), the Swedish Brain Foundation, and the Mellby G?rd Foundation (FO2018-0008), Karolinska Institutet Research Funds (2018-01738). We thank F. Xiang for excellent technical assistance and A.-C. Karlsson for help with patient recruitment. UK: E.O. is supported by Brain Research UK. Patients were collected as part of the SYNaPS Study Group collaboration funded by the Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA). J.V. is supported by Health Education England and the Medical Research Council. L.S. is supported by the Wellcome Trust Institutional Strategic Support Fund (204809/Z/16/Z) awarded to St George's, University of London. We thank Dr. J. E. Burns for his assistance in preparing the manuscript. The data handling was enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at Uppmax, Uppsala University partially funded by the Swedish Research Council through grant agreement no. 2018-05973. [Correction added on July 26, 2021 after first online publication: The Acknowledgments section has been updated.] Funding Information: Sweden: This study was supported by the Swedish Research Council (2017‐01096), the Swedish Brain Foundation, and the Mellby Gård Foundation (FO2018‐0008), Karolinska Institutet Research Funds (2018‐01738). We thank F. Xiang for excellent technical assistance and A.‐C. Karlsson for help with patient recruitment. UK: E.O. is supported by Brain Research UK. Patients were collected as part of the SYNaPS Study Group collaboration funded by the Wellcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA). J.V. is supported by Health Education England and the Medical Research Council. L.S. is supported by the Wellcome Trust Institutional Strategic Support Fund (204809/Z/16/Z) awarded to St George's, University of London. We thank Dr. J. E. Burns for his assistance in preparing the manuscript. Publisher Copyright: © 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/8

Y1 - 2021/8

N2 - Objective: This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. Methods: We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. Results: Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10 −17, odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37–1.66) and rs4519530 (p = 6.98 × 10 −17, OR = 1.47, 95% CI = 1.34–1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10 −8, OR = 1.36, 95% CI = 1.22–1.52), and rs11153082 (p = 1.85 × 10 −8, OR = 1.30, 95% CI = 1.19–1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. Interpretation: We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype–phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193–202.

AB - Objective: This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. Methods: We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. Results: Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10 −17, odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37–1.66) and rs4519530 (p = 6.98 × 10 −17, OR = 1.47, 95% CI = 1.34–1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10 −8, OR = 1.36, 95% CI = 1.22–1.52), and rs11153082 (p = 1.85 × 10 −8, OR = 1.30, 95% CI = 1.19–1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. Interpretation: We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype–phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193–202.

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U2 - 10.1002/ana.26150

DO - 10.1002/ana.26150

M3 - Article

C2 - 34184781

AN - SCOPUS:85109891399

SN - 0364-5134

VL - 90

SP - 193

EP - 202

JO - Annals of Neurology

JF - Annals of Neurology

IS - 2

ER -

Genome-Wide Association Study Identifies Risk Loci for Cluster Headache

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