Dataset Information

Cluster Headache Genomewide 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.

SUBMITTER: Winsvold BS

PROVIDER: S-EPMC10952302 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Publications

Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor.

Winsvold Bendik S BS Harder Aster V E AVE Ran Caroline C Chalmer Mona A MA Dalmasso Maria Carolina MC Ferkingstad Egil E Tripathi Kumar Parijat KP Bacchelli Elena E Børte Sigrid S Fourier Carmen C Petersen Anja S AS Vijfhuizen Lisanne S LS Magnusson Sigurdur H SH O'Connor Emer E Bjornsdottir Gyda G Häppölä Paavo P Wang Yen-Feng YF Callesen Ida I Kelderman Tim T Gallardo Victor J VJ de Boer Irene I Olofsgård Felicia Jennysdotter FJ Heinze Katja K Lund Nunu N Thomas Laurent F LF Hsu Chia-Lin CL Pirinen Matti M Hautakangas Heidi H Ribasés Marta M Guerzoni Simona S Sivakumar Prasanth P Yip Janice J Heinze Axel A Küçükali Fahri F Ostrowski Sisse R SR Pedersen Ole B OB Kristoffersen Espen S ES Martinsen Amy E AE Artigas María S MS Lagrata Susie S Cainazzo Maria Michela MM Adebimpe Joycee J Quinn Olivia O Göbel Carl C Cirkel Anna A Volk Alexander E AE Heilmann-Heimbach Stefanie S Skogholt Anne Heidi AH Gabrielsen Maiken E ME Wilbrink Leopoldine A LA Danno Daisuke D Mehta Dwij D Guðbjartsson Daníel F DF Rosendaal Frits R FR Willems van Dijk Ko K Fronczek Rolf R Wagner Michael M Scherer Martin M Göbel Hartmut H Sleegers Kristel K Sveinsson Olafur A OA Pani Luca L Zoli Michele M Ramos-Quiroga Josep A JA Dardiotis Efthimios E Steinberg Anna A Riedel-Heller Steffi S Sjöstrand Christina C Thorgeirsson Thorgeir E TE Stefansson Hreinn H Southgate Laura L Trembath Richard C RC Vandrovcova Jana J Noordam Raymond R Paemeleire Koen K Stefansson Kari K Fann Cathy Shen-Jang CS Waldenlind Elisabet E Tronvik Erling E Jensen Rigmor H RH Chen Shih-Pin SP Houlden Henry H Terwindt Gisela M GM Kubisch Christian C Maestrini Elena E Vikelis Michail M Pozo-Rosich Patricia P Belin Andrea C AC Matharu Manjit M van den Maagdenberg Arn M J M AMJM Hansen Thomas F TF Ramirez Alfredo A Zwart John-Anker JA

Annals of neurology 20230807 4

<h4>Objective</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 37486023

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Project description:Approximately 4% of English-speaking children are affected by specific language impairment (SLI), a disorder in the development of language skills despite adequate opportunity and normal intelligence. Several studies have indicated the importance of genetic factors in SLI; a positive family history confers an increased risk of development, and concordance in monozygotic twins consistently exceeds that in dizygotic twins. However, like many behavioral traits, SLI is assumed to be genetically complex, with several loci contributing to the overall risk. We have compiled 98 families drawn from epidemiological and clinical populations, all with probands whose standard language scores fall > or =1.5 SD below the mean for their age. Systematic genomewide quantitative-trait-locus analysis of three language-related measures (i.e., the Clinical Evaluation of Language Fundamentals-Revised [CELF-R] receptive and expressive scales and the nonword repetition [NWR] test) yielded two regions, one on chromosome 16 and one on 19, that both had maximum LOD scores of 3.55. Simulations suggest that, of these two multipoint results, the NWR linkage to chromosome 16q is the most significant, with empirical P values reaching 10(-5), under both Haseman-Elston (HE) analysis (LOD score 3.55; P=.00003) and variance-components (VC) analysis (LOD score 2.57; P=.00008). Single-point analyses provided further support for involvement of this locus, with three markers, under the peak of linkage, yielding LOD scores >1.9. The 19q locus was linked to the CELF-R expressive-language score and exceeds the threshold for suggestive linkage under all types of analysis performed-multipoint HE analysis (LOD score 3.55; empirical P=.00004) and VC (LOD score 2.84; empirical P=.00027) and single-point HE analysis (LOD score 2.49) and VC (LOD score 2.22). Furthermore, both the clinical and epidemiological samples showed independent evidence of linkage on both chromosome 16q and chromosome 19q, indicating that these may represent universally important loci in SLI and, thus, general risk factors for language impairment.

Dataset Information

Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor.

Objective

Methods

Results

Interpretation

Publications

Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor.

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