Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache

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...

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Vydané v:	Annals of neurology Ročník 90; číslo 2; s. 203 - 216
Hlavní autori:	Harder, Aster V.E., Winsvold, Bendik S., Noordam, Raymond, Vijfhuizen, Lisanne S., Børte, Sigrid, Kogelman, Lisette J.A., Boer, Irene, Tronvik, Erling, Rosendaal, Frits R., Willems van Dijk, Ko, O'Connor, Emer, Fourier, Carmen, Thomas, Laurent F., Kristoffersen, Espen S., Fronczek, Rolf, Pozo‐Rosich, Patricia, Jensen, Rigmor H., Ferrari, Michel D., Hansen, Thomas F., Zwart, John‐Anker, Terwindt, Gisela M., Maagdenberg, Arn M.J.M
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	Hoboken, USA John Wiley & Sons, Inc 01.08.2021 Wiley Subscription Services, Inc
Predmet:	Blood cells Clusters Confidence intervals Epidemiology Gene expression Gene mapping Gene sequencing Genetic disorders Genetic diversity Genetic variance Headache Headaches Linkage disequilibrium Loci Migraine Population studies Ribonucleic acid Risk RNA Single-nucleotide polymorphism Statistical analysis Tissue analysis
ISSN:	0364-5134, 1531-8249, 1531-8249
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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
AbstractList	ObjectiveIdentifying common genetic variants that confer genetic risk for cluster headache.MethodsWe 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.ResultsAn 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.InterpretationThis 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 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 Identifying common genetic variants that confer genetic risk for cluster headache.OBJECTIVEIdentifying common genetic variants that confer genetic risk for cluster headache.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.METHODSWe 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.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.RESULTSAn 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.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.INTERPRETATIONThis 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.
Author	Terwindt, Gisela M. Zwart, John‐Anker Harder, Aster V.E. Fourier, Carmen Jensen, Rigmor H. Børte, Sigrid Maagdenberg, Arn M.J.M Tronvik, Erling Fronczek, Rolf Rosendaal, Frits R. Hansen, Thomas F. Noordam, Raymond Vijfhuizen, Lisanne S. Willems van Dijk, Ko Ferrari, Michel D. O'Connor, Emer Winsvold, Bendik S. Kristoffersen, Espen S. Pozo‐Rosich, Patricia Kogelman, Lisette J.A. Boer, Irene Thomas, Laurent F.
AuthorAffiliation	12 Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center Leiden The Netherlands 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 9 Department of Neuromedicine and Movement Science Norwegian University of Science and Technology Trondheim Norway 13 Department of Internal Medicine, Division of Endocrinology Leiden University Medical Center Leiden The Netherlands 3 Department of Research, Innovation and Education, Division of Clinical Neuroscience Oslo University Hospital Oslo Norway 22 Department of Neurology Akershus University Hospital Lørenskog Norway 20 Clinic of Laboratory Medicine St. Olavs Hospital Trondheim Norway 23 Headache Research Group, Vall d'Hebron Institute of Research (VHIR) Universitat Autònoma de Barcelona Barcelona Spain 4 K.G. Jebsen Center for Genetic Epidemiology, Departmen
AuthorAffiliation_xml	– name: 1 Department of Neurology Leiden University Medical Center Leiden The Netherlands – name: 15 Neurogenetics Laboratory, Institute of Neurology University College London London UK – name: 18 Department of Clinical and Molecular Medicine Norwegian University of Science and Technology Trondheim Norway – name: 3 Department of Research, Innovation and Education, Division of Clinical Neuroscience Oslo University Hospital Oslo Norway – name: 19 BioCore ‐ Bioinformatics Core Facility Norwegian University of Science and Technology Trondheim Norway – name: 23 Headache Research Group, Vall d'Hebron Institute of Research (VHIR) Universitat Autònoma de Barcelona Barcelona Spain – name: 5 Department of Neurology Oslo University Hospital Oslo Norway – name: 7 Institute of Clinical Medicine, Faculty of Medicine University of Oslo Oslo Norway – name: 11 Department of Clinical Epidemiology Leiden University Medical Center Leiden The Netherlands – name: 21 Department of General Practice, HELSAM University of Oslo Oslo Norway – name: 12 Einthoven Laboratory for Experimental Vascular Medicine Leiden University Medical Center Leiden The Netherlands – name: 16 Headache and Facial Pain Group The National Hospital for Neurology and Neurosurgery London UK – name: 22 Department of Neurology Akershus University Hospital Lørenskog Norway – name: 20 Clinic of Laboratory Medicine St. Olavs Hospital Trondheim Norway – name: 14 Department of Neuromuscular Diseases, Institute of Neurology University College London London UK – name: 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 – name: 8 Department of Neurology Danish Headache Center, Rigshospitalet Glostrup Denmark – name: 13 Department of Internal Medicine, Division of Endocrinology Leiden University Medical Center Leiden The Netherlands – name: 17 Department of Neuroscience Karolinska Institutet Stockholm Sweden – name: 10 National Advisory Unit on Headaches, Department of Neurology and Clinical Neurophysiology St. Olav's Hospital Trondheim Norway – name: 6 Department of Internal Medicine, Section of Gerontology and Geriatrics Leiden University Medical Center Leiden The Netherlands – name: 9 Department of Neuromedicine and Movement Science Norwegian University of Science and Technology Trondheim Norway – name: 2 Department of Human Genetics Leiden University Medical Center Leiden The Netherlands – name: 24 España Unidad de Cefalea, Servicio de Neurología Hospital Universitari Vall d'Hebron Barcelona Spain
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Notes	J.A.Z., G.M.T., and A.M.J.M.vdM. contributed equally to this work and should be considered co‐last authors. A.V.E.H., B.S.W., and R.N. contributed equally to this work and should be considered co‐first authors. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
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Snippet	Objective Identifying common genetic variants that confer genetic risk for cluster headache. Methods We conducted a case–control study in the Dutch Leiden... ObjectiveIdentifying common genetic variants that confer genetic risk for cluster headache.MethodsWe conducted a case–control study in the Dutch Leiden... Identifying common genetic variants that confer genetic risk for cluster headache.OBJECTIVEIdentifying common genetic variants that confer genetic risk for...
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SubjectTerms	Blood cells Clusters Confidence intervals Epidemiology Gene expression Gene mapping Gene sequencing Genetic disorders Genetic diversity Genetic variance Headache Headaches Linkage disequilibrium Loci Migraine Population studies Ribonucleic acid Risk RNA Single-nucleotide polymorphism Statistical analysis Tissue analysis
Title	Genetic Susceptibility Loci in Genomewide Association Study of Cluster Headache
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