Cluster headache genome-wide association study and meta-analysis identifies eight loci and implicates smoking as causal risk factor

Bendik S Winsvold; Aster V E Harder; Caroline Ran; Mona A Chalmer; Maria Carolina Dalmasso; Egil Ferkingstad; Kumar Parijat Tripathi; Elena Bacchelli; Sigrid Børte; Carmen Fourier; Anja S Petersen; Lisanne S Vijfhuizen; Sigurdur H Magnusson; Emer O'Connor; Gyda Bjornsdottir; Paavo Häppölä; Yen-Feng Wang; Ida Callesen; Tim Kelderman; Victor J Gallardo; Irene de Boer; Felicia Jennysdotter Olofsgård; Katja Heinze; Nunu Lund; Laurent F Thomas; Chia-Lin Hsu; Matti Pirinen; Heidi Hautakangas; Marta Ribasés; Simona Guerzoni; Prasanth Sivakumar; Janice Yip; Axel Heinze; Fahri Küçükali; Sisse R Ostrowski; Ole B Pedersen; Espen S Kristoffersen; Amy E Martinsen; María S Artigas; Susie Lagrata; Maria Michela Cainazzo; Joycee Adebimpe; Olivia Quinn; Carl Göbel; Anna Cirkel; Alexander E Volk; Stefanie Heilmann-Heimbach; Anne Heidi Skogholt; Maiken E Gabrielsen; Leopoldine A Wilbrink; Daisuke Danno; Dwij Mehta; Daníel F Guðbjartsson; Frits R Rosendaal; Ko Willems van Dijk; Rolf Fronczek; Michael Wagner; Martin Scherer; Hartmut Göbel; Kristel Sleegers; Olafur A Sveinsson; Luca Pani; Michele Zoli; Josep A Ramos-Quiroga; Efthimios Dardiotis; Anna Steinberg; Steffi Riedel-Heller; Christina Sjöstrand; Thorgeir E Thorgeirsson; Hreinn Stefansson; Laura Southgate; Richard C Trembath; Jana Vandrovcova; Raymond Noordam; Koen Paemeleire; Kari Stefansson; Cathy Shen-Jang Fann; Elisabet Waldenlind; Erling Tronvik; Rigmor H Jensen; Shih-Pin Chen; Henry Houlden; Gisela M Terwindt; Christian Kubisch; Elena Maestrini; Michail Vikelis; Patricia Pozo-Rosich; Andrea C Belin; Manjit Matharu; Arn M J M van den Maagdenberg; Thomas F Hansen; Alfredo Ramirez; John-Anker Zwart; HUNT All-In Headache, The International Headache Genetics Consortium, DBDS Genomic Consortium

doi:10.1002/ana.26743

Cluster headache genome-wide association study and meta-analysis identifies eight loci and implicates smoking as causal risk factor

Standard

Cluster headache genome-wide association study and meta-analysis identifies eight loci and implicates smoking as causal risk factor. / Winsvold, Bendik S; Harder, Aster V E; Ran, Caroline; Chalmer, Mona A; Dalmasso, Maria Carolina; Ferkingstad, Egil; Tripathi, Kumar Parijat; Bacchelli, Elena; Børte, Sigrid; Fourier, Carmen; Petersen, Anja S; Vijfhuizen, Lisanne S; Magnusson, Sigurdur H; O'Connor, Emer; Bjornsdottir, Gyda; Häppölä, Paavo; Wang, Yen-Feng; Callesen, Ida; Kelderman, Tim; Gallardo, Victor J; de Boer, Irene; Jennysdotter Olofsgård, Felicia; Heinze, Katja; Lund, Nunu; Thomas, Laurent F; Hsu, Chia-Lin; Pirinen, Matti; Hautakangas, Heidi; Ribasés, Marta; Guerzoni, Simona; Sivakumar, Prasanth; Yip, Janice; Heinze, Axel; Küçükali, Fahri; Ostrowski, Sisse R; Pedersen, Ole B; Kristoffersen, Espen S; Martinsen, Amy E; Artigas, María S; Lagrata, Susie; Cainazzo, Maria Michela; Adebimpe, Joycee; Quinn, Olivia; Göbel, Carl; Cirkel, Anna; Volk, Alexander E; Heilmann-Heimbach, Stefanie; Skogholt, Anne Heidi; Gabrielsen, Maiken E; Wilbrink, Leopoldine A; Danno, Daisuke; Mehta, Dwij; Guðbjartsson, Daníel F; Rosendaal, Frits R; Willems van Dijk, Ko; Fronczek, Rolf; Wagner, Michael; Scherer, Martin; Göbel, Hartmut; Sleegers, Kristel; Sveinsson, Olafur A; Pani, Luca; Zoli, Michele; Ramos-Quiroga, Josep A; Dardiotis, Efthimios; Steinberg, Anna; Riedel-Heller, Steffi; Sjöstrand, Christina; Thorgeirsson, Thorgeir E; Stefansson, Hreinn; Southgate, Laura; Trembath, Richard C; Vandrovcova, Jana; Noordam, Raymond; Paemeleire, Koen; Stefansson, Kari; Fann, Cathy Shen-Jang; Waldenlind, Elisabet; Tronvik, Erling; Jensen, Rigmor H; Chen, Shih-Pin; Houlden, Henry; Terwindt, Gisela M; Kubisch, Christian; Maestrini, Elena; Vikelis, Michail; Pozo-Rosich, Patricia; Belin, Andrea C; Matharu, Manjit; van den Maagdenberg, Arn M J M; Hansen, Thomas F; Ramirez, Alfredo; Zwart, John-Anker; HUNT All-In Headache, The International Headache Genetics Consortium, DBDS Genomic Consortium.

In: ANN NEUROL, Vol. 94, No. 4, 10.2023, p. 713-726.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Winsvold, BS, Harder, AVE, Ran, C, Chalmer, MA, Dalmasso, MC, Ferkingstad, E, Tripathi, KP, Bacchelli, E, Børte, S, Fourier, C, Petersen, AS, Vijfhuizen, LS, Magnusson, SH, O'Connor, E, Bjornsdottir, G, Häppölä, P, Wang, Y-F, Callesen, I, Kelderman, T, Gallardo, VJ, de Boer, I, Jennysdotter Olofsgård, F, Heinze, K, Lund, N, Thomas, LF, Hsu, C-L, Pirinen, M, Hautakangas, H, Ribasés, M, Guerzoni, S, Sivakumar, P, Yip, J, Heinze, A, Küçükali, F, Ostrowski, SR, Pedersen, OB, Kristoffersen, ES, Martinsen, AE, Artigas, MS, Lagrata, S, Cainazzo, MM, Adebimpe, J, Quinn, O, Göbel, C, Cirkel, A, Volk, AE, Heilmann-Heimbach, S, Skogholt, AH, Gabrielsen, ME, Wilbrink, LA, Danno, D, Mehta, D, Guðbjartsson, DF, Rosendaal, FR, Willems van Dijk, K, Fronczek, R, Wagner, M, Scherer, M, Göbel, H, Sleegers, K, Sveinsson, OA, Pani, L, Zoli, M, Ramos-Quiroga, JA, Dardiotis, E, Steinberg, A, Riedel-Heller, S, Sjöstrand, C, Thorgeirsson, TE, Stefansson, H, Southgate, L, Trembath, RC, Vandrovcova, J, Noordam, R, Paemeleire, K, Stefansson, K, Fann, CS-J, Waldenlind, E, Tronvik, E, Jensen, RH, Chen, S-P, Houlden, H, Terwindt, GM, Kubisch, C, Maestrini, E, Vikelis, M, Pozo-Rosich, P, Belin, AC, Matharu, M, van den Maagdenberg, AMJM, Hansen, TF, Ramirez, A, Zwart, J-A & HUNT All-In Headache, The International Headache Genetics Consortium, DBDS Genomic Consortium 2023, 'Cluster headache genome-wide association study and meta-analysis identifies eight loci and implicates smoking as causal risk factor', ANN NEUROL, vol. 94, no. 4, pp. 713-726. https://doi.org/10.1002/ana.26743

APA

Winsvold, B. S., Harder, A. V. E., Ran, C., Chalmer, M. A., Dalmasso, M. C., Ferkingstad, E., Tripathi, K. P., Bacchelli, E., Børte, S., Fourier, C., Petersen, A. S., Vijfhuizen, L. S., Magnusson, S. H., O'Connor, E., Bjornsdottir, G., Häppölä, P., Wang, Y-F., Callesen, I., Kelderman, T., ... HUNT All-In Headache, The International Headache Genetics Consortium, DBDS Genomic Consortium (2023). Cluster headache genome-wide association study and meta-analysis identifies eight loci and implicates smoking as causal risk factor. ANN NEUROL, 94(4), 713-726. https://doi.org/10.1002/ana.26743

Vancouver

Winsvold BS, Harder AVE, Ran C, Chalmer MA, Dalmasso MC, Ferkingstad E et al. Cluster headache genome-wide association study and meta-analysis identifies eight loci and implicates smoking as causal risk factor. ANN NEUROL. 2023 Oct;94(4):713-726. https://doi.org/10.1002/ana.26743

Bibtex

@article{4f4b1a99830642a7861de7f2d99834f3,

title = "Cluster headache genome-wide association study and meta-analysis identifies eight loci and implicates smoking as causal risk factor",

abstract = "OBJECTIVE: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights.METHODS: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses.RESULTS: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine.INTERPRETATION: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023;94:713-726.",

author = "Winsvold, {Bendik S} and Harder, {Aster V E} and Caroline Ran and Chalmer, {Mona A} and Dalmasso, {Maria Carolina} and Egil Ferkingstad and Tripathi, {Kumar Parijat} and Elena Bacchelli and Sigrid B{\o}rte and Carmen Fourier and Petersen, {Anja S} and Vijfhuizen, {Lisanne S} and Magnusson, {Sigurdur H} and Emer O'Connor and Gyda Bjornsdottir and Paavo H{\"a}pp{\"o}l{\"a} and Yen-Feng Wang and Ida Callesen and Tim Kelderman and Gallardo, {Victor J} and {de Boer}, Irene and {Jennysdotter Olofsg{\aa}rd}, Felicia and Katja Heinze and Nunu Lund and Thomas, {Laurent F} and Chia-Lin Hsu and Matti Pirinen and Heidi Hautakangas and Marta Ribas{\'e}s and Simona Guerzoni and Prasanth Sivakumar and Janice Yip and Axel Heinze and Fahri K{\"u}{\c c}{\"u}kali and Ostrowski, {Sisse R} and Pedersen, {Ole B} and Kristoffersen, {Espen S} and Martinsen, {Amy E} and Artigas, {Mar{\'i}a S} and Susie Lagrata and Cainazzo, {Maria Michela} and Joycee Adebimpe and Olivia Quinn and Carl G{\"o}bel and Anna Cirkel and Volk, {Alexander E} and Stefanie Heilmann-Heimbach and Skogholt, {Anne Heidi} and Gabrielsen, {Maiken E} and Wilbrink, {Leopoldine A} and Daisuke Danno and Dwij Mehta and Gu{\dh}bjartsson, {Dan{\'i}el F} and Rosendaal, {Frits R} and {Willems van Dijk}, Ko and Rolf Fronczek and Michael Wagner and Martin Scherer and Hartmut G{\"o}bel and Kristel Sleegers and Sveinsson, {Olafur A} and Luca Pani and Michele Zoli and Ramos-Quiroga, {Josep A} and Efthimios Dardiotis and Anna Steinberg and Steffi Riedel-Heller and Christina Sj{\"o}strand and Thorgeirsson, {Thorgeir E} and Hreinn Stefansson and Laura Southgate and Trembath, {Richard C} and Jana Vandrovcova and Raymond Noordam and Koen Paemeleire and Kari Stefansson and Fann, {Cathy Shen-Jang} and Elisabet Waldenlind and Erling Tronvik and Jensen, {Rigmor H} and Shih-Pin Chen and Henry Houlden and Terwindt, {Gisela M} and Christian Kubisch and Elena Maestrini and Michail Vikelis and Patricia Pozo-Rosich and Belin, {Andrea C} and Manjit Matharu and {van den Maagdenberg}, {Arn M J M} and Hansen, {Thomas F} and Alfredo Ramirez and John-Anker Zwart and {HUNT All-In Headache, The International Headache Genetics Consortium, DBDS Genomic Consortium}",

year = "2023",

month = oct,

doi = "10.1002/ana.26743",

language = "English",

volume = "94",

pages = "713--726",

journal = "ANN NEUROL",

issn = "0364-5134",

publisher = "John Wiley and Sons Inc.",

number = "4",

}

RIS

TY - JOUR

T1 - Cluster headache genome-wide association study and meta-analysis identifies eight loci and implicates smoking as causal risk factor

AU - Winsvold, Bendik S

AU - Harder, Aster V E

AU - Ran, Caroline

AU - Chalmer, Mona A

AU - Dalmasso, Maria Carolina

AU - Ferkingstad, Egil

AU - Tripathi, Kumar Parijat

AU - Bacchelli, Elena

AU - Børte, Sigrid

AU - Fourier, Carmen

AU - Petersen, Anja S

AU - Vijfhuizen, Lisanne S

AU - Magnusson, Sigurdur H

AU - O'Connor, Emer

AU - Bjornsdottir, Gyda

AU - Häppölä, Paavo

AU - Wang, Yen-Feng

AU - Callesen, Ida

AU - Kelderman, Tim

AU - Gallardo, Victor J

AU - de Boer, Irene

AU - Jennysdotter Olofsgård, Felicia

AU - Heinze, Katja

AU - Lund, Nunu

AU - Thomas, Laurent F

AU - Hsu, Chia-Lin

AU - Pirinen, Matti

AU - Hautakangas, Heidi

AU - Ribasés, Marta

AU - Guerzoni, Simona

AU - Sivakumar, Prasanth

AU - Yip, Janice

AU - Heinze, Axel

AU - Küçükali, Fahri

AU - Ostrowski, Sisse R

AU - Pedersen, Ole B

AU - Kristoffersen, Espen S

AU - Martinsen, Amy E

AU - Artigas, María S

AU - Lagrata, Susie

AU - Cainazzo, Maria Michela

AU - Adebimpe, Joycee

AU - Quinn, Olivia

AU - Göbel, Carl

AU - Cirkel, Anna

AU - Volk, Alexander E

AU - Heilmann-Heimbach, Stefanie

AU - Skogholt, Anne Heidi

AU - Gabrielsen, Maiken E

AU - Wilbrink, Leopoldine A

AU - Danno, Daisuke

AU - Mehta, Dwij

AU - Guðbjartsson, Daníel F

AU - Rosendaal, Frits R

AU - Willems van Dijk, Ko

AU - Fronczek, Rolf

AU - Wagner, Michael

AU - Scherer, Martin

AU - Göbel, Hartmut

AU - Sleegers, Kristel

AU - Sveinsson, Olafur A

AU - Pani, Luca

AU - Zoli, Michele

AU - Ramos-Quiroga, Josep A

AU - Dardiotis, Efthimios

AU - Steinberg, Anna

AU - Riedel-Heller, Steffi

AU - Sjöstrand, Christina

AU - Thorgeirsson, Thorgeir E

AU - Stefansson, Hreinn

AU - Southgate, Laura

AU - Trembath, Richard C

AU - Vandrovcova, Jana

AU - Noordam, Raymond

AU - Paemeleire, Koen

AU - Stefansson, Kari

AU - Fann, Cathy Shen-Jang

AU - Waldenlind, Elisabet

AU - Tronvik, Erling

AU - Jensen, Rigmor H

AU - Chen, Shih-Pin

AU - Houlden, Henry

AU - Terwindt, Gisela M

AU - Kubisch, Christian

AU - Maestrini, Elena

AU - Vikelis, Michail

AU - Pozo-Rosich, Patricia

AU - Belin, Andrea C

AU - Matharu, Manjit

AU - van den Maagdenberg, Arn M J M

AU - Hansen, Thomas F

AU - Ramirez, Alfredo

AU - Zwart, John-Anker

AU - HUNT All-In Headache, The International Headache Genetics Consortium, DBDS Genomic Consortium

PY - 2023/10

Y1 - 2023/10

N2 - OBJECTIVE: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights.METHODS: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses.RESULTS: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine.INTERPRETATION: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023;94:713-726.

AB - OBJECTIVE: The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights.METHODS: A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses.RESULTS: The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine.INTERPRETATION: This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023;94:713-726.

U2 - 10.1002/ana.26743

DO - 10.1002/ana.26743

M3 - SCORING: Journal article

C2 - 37486023

VL - 94

SP - 713

EP - 726

JO - ANN NEUROL

JF - ANN NEUROL

SN - 0364-5134

IS - 4

ER -