Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles

International Headache Genetics Consortium, HUNT All-in Headache, Danish Blood Donor Study Genomic Cohort

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Abstract

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.

Original languageEnglish
Pages (from-to)152-160
Number of pages9
JournalNature Genetics
Volume54
Issue number2
DOIs
Publication statusPublished - 1 Feb 2022

Bibliographical note

Funding Information:
We thank the study participants for their contribution to this research. We also thank the numerous individuals who contributed to sample collection, storage, handling, phenotyping and genotyping for each of the individual cohorts. We acknowledge the participants and investigators of the FinnGen study. This research has been conducted using the UK Biobank Resource under Application Number 22627. We are supported by following grants: the US National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health (NIH) (grant numbers R21NS09296 and R21NS104398 (D.I.C.)), the Finnish innovation fund Sitra and Finska L?kares?llskapet (E.W.), the Academy of Finland (grant nos. 288509, 312076, 336825 (M.P.)), the Sigrid Juselius Foundation (M.P. and S.R.), the Academy of Finland Center of Excellence in Complex Disease Genetics (grant no. 312062 (S.R.)), the Finnish Foundation for Cardiovascular Research (S.R.), University of Helsinki HiLIFE Fellow and Grand Challenge grants (S.R.), The Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594 (T.F.H. and K.B.)), CANDY foundation (CEHEAD) (T.F.H.), and the South-Eastern Norway Regional Health Authority (grant no. 2020034 (B.S.W.)). A list of study-specific acknowledgements and funding information can be found in the Supplementary Note.

Funding Information:
We thank the study participants for their contribution to this research. We also thank the numerous individuals who contributed to sample collection, storage, handling, phenotyping and genotyping for each of the individual cohorts. We acknowledge the participants and investigators of the FinnGen study. This research has been conducted using the UK Biobank Resource under Application Number 22627. We are supported by following grants: the US National Institute of Neurological Disorders and Stroke (NINDS) of the US National Institutes of Health (NIH) (grant numbers R21NS09296 and R21NS104398 (D.I.C.)), the Finnish innovation fund Sitra and Finska Läkaresällskapet (E.W.), the Academy of Finland (grant nos. 288509, 312076, 336825 (M.P.)), the Sigrid Juselius Foundation (M.P. and S.R.), the Academy of Finland Center of Excellence in Complex Disease Genetics (grant no. 312062 (S.R.)), the Finnish Foundation for Cardiovascular Research (S.R.), University of Helsinki HiLIFE Fellow and Grand Challenge grants (S.R.), The Novo Nordisk Foundation (NNF14CC0001 and NNF17OC0027594 (T.F.H. and K.B.)), CANDY foundation (CEHEAD) (T.F.H.), and the South-Eastern Norway Regional Health Authority (grant no. 2020034 (B.S.W.)). A list of study-specific acknowledgements and funding information can be found in the .

Publisher Copyright:
© 2022, The Author(s).

Other keywords

  • Migraine Disorders
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Migraine Disorders/genetics
  • Molecular Sequence Annotation
  • Genetic Loci
  • Case-Control Studies
  • Central Nervous System/metabolism
  • Migraine with Aura/genetics
  • Alleles
  • Polymorphism, Single Nucleotide
  • Cardiovascular System/metabolism
  • Quantitative Trait Loci

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