Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor
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Cluster Headache Genomewide 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; Olofsgård, Felicia Jennysdotter; 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.
In: Annals of Neurology, Vol. 94, No. 4, 2023, p. 713-726.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Cluster Headache Genomewide 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 - Olofsgård, Felicia Jennysdotter
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
N1 - Publisher Copyright: © 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2023
Y1 - 2023
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.
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.
U2 - 10.1002/ana.26743
DO - 10.1002/ana.26743
M3 - Journal article
C2 - 37486023
AN - SCOPUS:85167330217
VL - 94
SP - 713
EP - 726
JO - Annals of Neurology
JF - Annals of Neurology
SN - 0364-5134
IS - 4
ER -
ID: 365706251