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Elucidating the relationship between migraine risk and brain structure using genetic data

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  • Brittany L Mitchell
  • Santiago Diaz-Torres
  • Svetlana Bivol
  • Gabriel Cuellar-Partida
  • Zachary F Gerring
  • Nicholas G Martin
  • Sarah E Medland
  • Katrina L Grasby
  • Dale R Nyholt
  • Miguel E Rentería
  • International Headache Genetics Consortium
  • Jes Olesen (Medlem af forfattergruppering)
  • Thomas Folkmann Hansen (Medlem af forfattergruppering)
Vis graf over relationer

Migraine is a highly common and debilitating disorder that often affects individuals in their most productive years of life. Previous studies have identified both genetic variants and brain morphometry differences associated with migraine risk. However, the relationship between migraine and brain morphometry has not been examined on a genetic level, and the causal nature of the association between brain structure and migraine risk has not been determined. Using the largest available genome-wide association studies to date, we examined the genome-wide genetic overlap between migraine and intracranial volume, as well as the regional volumes of nine subcortical brain structures. We further focused the identification and biological annotation of genetic overlap between migraine and each brain structure on specific regions of the genome shared between migraine and brain structure. Finally, we examined whether the size of any of the examined brain regions causally increased migraine risk using a Mendelian randomization approach. We observed a significant genome-wide negative genetic correlation between migraine risk and intracranial volume (rG = -0.11, P = 1 × 10-3) but not with any subcortical region. However, we identified jointly associated regional genomic overlap between migraine and every brain structure. Gene enrichment in these shared genomic regions pointed to possible links with neuronal signalling and vascular regulation. Finally, we provide evidence of a possible causal relationship between smaller total brain, hippocampal and ventral diencephalon volume and increased migraine risk, as well as a causal relationship between increased risk of migraine and a larger volume of the amygdala. We leveraged the power of large genome-wide association studies to show evidence of shared genetic pathways that jointly influence migraine risk and several brain structures, suggesting that altered brain morphometry in individuals with high migraine risk may be genetically mediated. Further interrogation of these results showed support for the neurovascular hypothesis of migraine aetiology and shed light on potentially viable therapeutic targets.

OriginalsprogEngelsk
TidsskriftBrain
Vol/bind145
Udgave nummer9
Sider (fra-til)3214-3224
Antal sider11
ISSN0006-8950
DOI
StatusUdgivet - 14 sep. 2022

Bibliografisk note

© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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