Simon Winther

Familial analysis reveals rare risk variants for migraine in regulatory regions

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Tanya Ramdal Techlo, Danish Headache Center, Department of Neurology, Rigshospitalet, Nordstjernevej 40, DK-2600, Glostrup, Denmark.
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  • Andreas Høiberg Rasmussen, Danish Headache Center, Department of Neurology, Rigshospitalet, Nordstjernevej 40, DK-2600, Glostrup, Denmark.
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  • Peter L Møller
  • Morten Bøttcher
  • Simon Winther
  • Olafur B Davidsson, Danish Headache Center, Department of Neurology, Rigshospitalet, Nordstjernevej 40, DK-2600, Glostrup, Denmark.
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  • Isa A Olofsson, Danish Headache Center, Department of Neurology, Rigshospitalet, Nordstjernevej 40, DK-2600, Glostrup, Denmark.
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  • Mona Ameri Chalmer, Danish Headache Center, Department of Neurology, Rigshospitalet, Nordstjernevej 40, DK-2600, Glostrup, Denmark.
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  • Lisette J A Kogelman, Danish Headache Center, Department of Neurology, Rigshospitalet, Nordstjernevej 40, DK-2600, Glostrup, Denmark.
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  • Mette Nyegaard
  • Jes Olesen, Danish Headache Center, Department of Neurology, Rigshospitalet, Nordstjernevej 40, DK-2600, Glostrup, Denmark.
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  • Thomas Folkmann Hansen, Danish Headache Center, Department of Neurology, Rigshospitalet, Nordstjernevej 40, DK-2600, Glostrup, Denmark. thomas.hansen@regionh.dk., Institute for Biological Psychiatry, Mental Health Center Sct. Hans, Roskilde, Denmark. thomas.hansen@regionh.dk., Novo Nordic Foundation Centre for Protein Research, Copenhagen University, Copenhagen, Denmark. thomas.hansen@regionh.dk.

The most recent genome-wide association study of migraine increased the total number of known migraine risk loci to 38. Still, most of the heritability of migraine remains unexplained, and it has been suggested that rare gene dysregulatory variants play an important role in migraine etiology. Addressing the missing heritability of migraine, we aim to fine-map signals from the known migraine risk loci to regulatory mechanisms and associate these to downstream genic targets. We analyzed a large cohort of whole-genome sequenced patients from extended migraine pedigrees (1040 individuals from 155 families). We test for association between rare variants segregating in regulatory regions with migraine. The findings were replicated in an independent case-control cohort (2027 migraineurs, 1650 controls). We report an increased burden of rare variants in one CpG island and three polycomb group response elements near four migraine risk loci. We found that the association is independent of the common risk variants in the loci. The regulatory regions are suggested to affect different genes than those originally tagged by the index SNPs of the migraine loci. Families with familial clustering of migraine have an increased burden of rare variants in regulatory regions near known migraine risk loci, with effects that are independent of the variants in the loci. The possible regulatory targets suggest different genes than those originally tagged by the index SNPs of the migraine loci.

Original languageEnglish
JournalNeurogenetics
Volume21
Issue3
Pages (from-to)149-157
ISSN1364-6745
DOIs
Publication statusPublished - 2020

    Research areas

  • Family study, Gene regulation, Genetics, Genome-wide, Migraine, Rare-variant association analysis, POPULATION, DEFICIT HYPERACTIVITY DISORDER, TENSION-TYPE HEADACHE, TRANSCRIPTION, IMPACT, DISEASE, GENES, TRAITS, CPG ISLANDS, POTASSIUM CHANNEL

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