Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache

Aster V E Harder; Bendik S Winsvold; Raymond Noordam; Lisanne S Vijfhuizen; Sigrid Børte; Lisette J A Kogelman; Irene de Boer; Erling Tronvik; Frits R Rosendaal; Ko Willems van Dijk; Emer O'Connor; Carmen Fourier; Laurent F Thomas; Espen S Kristoffersen; Cluster Headache Genetics Working Group; Rolf Fronczek; Patricia Pozo-Rosich; Rigmor H Jensen; Michel D Ferrari; Thomas F Hansen; John-Anker Zwart; Gisela M Terwindt; Arn M J M van den Maagdenberg

doi:10.1002/ana.26146

Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache

Ann Neurol. 2021 Aug;90(2):203-216. doi: 10.1002/ana.26146. Epub 2021 Jul 14.

Authors

Aster V E Harder^#^{1

2}, Bendik S Winsvold^#^{3

4

5}, Raymond Noordam^#⁶, Lisanne S Vijfhuizen², Sigrid Børte^{3

4

7}, Lisette J A Kogelman⁸, Irene de Boer¹, Erling Tronvik^{9

10}, Frits R Rosendaal¹¹, Ko Willems van Dijk^{2

12

13}, Emer O'Connor^{14

15

16}, Carmen Fourier¹⁷, Laurent F Thomas^{4

18

19

20}, Espen S Kristoffersen^{3

21

22}; Cluster Headache Genetics Working Group; Rolf Fronczek¹, Patricia Pozo-Rosich^{23

24}, Rigmor H Jensen⁸, Michel D Ferrari¹, Thomas F Hansen⁸, John-Anker Zwart^#^{3

4

7}, Gisela M Terwindt^#¹, Arn M J M van den Maagdenberg^#^{1

2}

Affiliations

¹ Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
² Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
³ Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.
⁴ K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway.
⁵ Department of Neurology, Oslo University Hospital, Oslo, Norway.
⁶ Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, The Netherlands.
⁷ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
⁸ Department of Neurology, Danish Headache Center, Rigshospitalet, Glostrup, Denmark.
⁹ Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway.
¹⁰ National Advisory Unit on Headaches, Department of Neurology and Clinical Neurophysiology, St. Olav's Hospital, Trondheim, Norway.
¹¹ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
¹² Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
¹³ Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands.
¹⁴ Department of Neuromuscular Diseases, Institute of Neurology, University College London, London, UK.
¹⁵ Neurogenetics Laboratory, Institute of Neurology, University College London, London, UK.
¹⁶ Headache and Facial Pain Group, The National Hospital for Neurology and Neurosurgery, London, UK.
¹⁷ Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
¹⁸ Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
¹⁹ BioCore - Bioinformatics Core Facility, Norwegian University of Science and Technology, Trondheim, Norway.
²⁰ Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim, Norway.
²¹ Department of General Practice, HELSAM, University of Oslo, Oslo, Norway.
²² Department of Neurology, Akershus University Hospital, Lørenskog, Norway.
²³ Headache Research Group, Vall d'Hebron Institute of Research (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.
²⁴ España Unidad de Cefalea, Servicio de Neurología, Hospital Universitari Vall d'Hebron, Barcelona, Spain.

^# Contributed equally.

Abstract

Objective: Identifying common genetic variants that confer genetic risk for cluster headache.

Methods: We conducted a case-control study in the Dutch Leiden University Cluster headache neuro-Analysis program (LUCA) study population (n = 840) and unselected controls from the Netherlands Epidemiology of Obesity Study (NEO; n = 1,457). Replication was performed in a Norwegian sample of 144 cases from the Trondheim Cluster headache sample and 1,800 controls from the Nord-Trøndelag Health Survey (HUNT). Gene set and tissue enrichment analyses, blood cell-derived RNA-sequencing of genes around the risk loci and linkage disequilibrium score regression were part of the downstream analyses.

Results: An association was found with cluster headache for 4 independent loci (r² < 0.1) with genomewide significance (p < 5 × 10^-8 ), rs11579212 (odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.33-1.72 near RP11-815 M8.1), rs6541998 (OR = 1.53, 95% CI = 1.37-1.74 near MERTK), rs10184573 (OR = 1.43, 95% CI = 1.26-1.61 near AC093590.1), and rs2499799 (OR = 0.62, 95% CI = 0.54-0.73 near UFL1/FHL5), collectively explaining 7.2% of the variance of cluster headache. SNPs rs11579212, rs10184573, and rs976357, as proxy SNP for rs2499799 (r² = 1.0), replicated in the Norwegian sample (p < 0.05). Gene-based mapping yielded ASZ1 as possible fifth locus. RNA-sequencing indicated differential expression of POLR1B and TMEM87B in cluster headache patients.

Interpretation: This genomewide association study (GWAS) identified and replicated genetic risk loci for cluster headache with effect sizes larger than those typically seen in complex genetic disorders. ANN NEUROL 2021;90:203-216.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Case-Control Studies
Cluster Headache / epidemiology*
Cluster Headache / genetics*
Female
Genetic Loci / genetics*
Genetic Predisposition to Disease / epidemiology*
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study / methods*
Humans
Male
Netherlands / epidemiology
Polymorphism, Single Nucleotide / genetics
Sequence Analysis, RNA / methods