TY - JOUR

T1 - Functional gene networks reveal distinct mechanisms segregating in migraine families

AU - Rasmussen, Andreas H.

AU - Kogelman, Lisette J. A.

AU - Kristensen, David M.

AU - Chalmer, Mona Ameri

AU - Olesen, Jes

AU - Hansen, Thomas Folkmann

PY - 2020

Y1 - 2020

N2 - Migraine is the most common neurological disorder worldwide and it has been shown to have complex polygenic origins with a heritability of estimated 40-70%. Both common and rare genetic variants are believed to underlie the pathophysiology of the prevalent types of migraine, migraine with typical aura and migraine without aura. However, only common variants have been identified so far. Here we identify for the first time a gene module with rare mutations through a systems genetics approach integrating RNA sequencing data from brain and vascular tissues likely to be involved in migraine pathology in combination with whole genome sequencing of 117 migraine families. We found a gene module in the visual cortex, based on single nuclei RNA sequencing data, that had increased rare mutations in the migraine families and replicated this in a second independent cohort of 1930 patients. This module was mainly expressed by interneurons, pyramidal CA1, and pyramidal SS cells, and pathway analysis showed association with hormonal signalling (thyrotropin-releasing hormone receptor and oxytocin receptor signalling pathways), Alzheimer's disease pathway, serotonin receptor pathway and general heterotrimeric G-protein signalling pathways. Our results demonstrate that rare functional gene variants are strongly implicated in the pathophysiology of migraine. Furthermore, we anticipate that the results can be used to explain the critical mechanisms behind migraine and potentially improving the treatment regime for migraine patients.

AB - Migraine is the most common neurological disorder worldwide and it has been shown to have complex polygenic origins with a heritability of estimated 40-70%. Both common and rare genetic variants are believed to underlie the pathophysiology of the prevalent types of migraine, migraine with typical aura and migraine without aura. However, only common variants have been identified so far. Here we identify for the first time a gene module with rare mutations through a systems genetics approach integrating RNA sequencing data from brain and vascular tissues likely to be involved in migraine pathology in combination with whole genome sequencing of 117 migraine families. We found a gene module in the visual cortex, based on single nuclei RNA sequencing data, that had increased rare mutations in the migraine families and replicated this in a second independent cohort of 1930 patients. This module was mainly expressed by interneurons, pyramidal CA1, and pyramidal SS cells, and pathway analysis showed association with hormonal signalling (thyrotropin-releasing hormone receptor and oxytocin receptor signalling pathways), Alzheimer's disease pathway, serotonin receptor pathway and general heterotrimeric G-protein signalling pathways. Our results demonstrate that rare functional gene variants are strongly implicated in the pathophysiology of migraine. Furthermore, we anticipate that the results can be used to explain the critical mechanisms behind migraine and potentially improving the treatment regime for migraine patients.

KW - complex trait

KW - gene-gene interaction

KW - genetic network

KW - transcriptomics

KW - migraine

KW - CORTICAL SPREADING DEPRESSION

KW - SEROTONIN TRANSPORTER GENE

KW - RECEPTOR ANTAGONISTS

KW - HEMIPLEGIC MIGRAINE

KW - OXYTOCIN

KW - GLUTAMATE

KW - PLASMA

KW - RAT

KW - POLYMORPHISMS

KW - ASSOCIATION

U2 - 10.1093/brain/awaa242

DO - 10.1093/brain/awaa242

M3 - Journal article

C2 - 32968778

VL - 143

SP - 2945

EP - 2956

JO - Brain

JF - Brain

SN - 0006-8950

ER -