GWAS-Based Neurovascular Etiology of Migraine and its Associated Risk of Ischemic Stroke

About This Grant

Migraine is a unique and severe form of headache. It is also common, experienced by up to 30% of women with age-related prevalence 2-3x higher than men, and is a leading cause of disability worldwide. Migraine has a broadly neurovascular pathophysiology that may be treated by recently introduced drugs targeting the calcitonin gene-related peptide (CGRP), the CGRP receptor, or the serotonin receptor (HTRA11F). However, these drugs remain ineffective or contraindicated for many migraine sufferers, highlighting the need for additional therapeutics. Disability due to migraine is compounded by an approximate 1.5-fold elevated risk of ischemic stroke that is further elevated among individuals who experience migraine with aura, a form of migraine typically experienced as a reversible visual disturbance preceding the headache. The cause of such strokes is unknown but may involve intrinsic properties of the vasculature and/or microembolism. Both the identification of critically needed new therapeutic targets and a better understanding of the elevated ischemic stroke risk would be advanced by addressing gaps in knowledge about the pathophysiology of migraine susceptibility. The International Headache Genetics Consortium (IHGC) recently (in 2022) reported a new genome-wide association study (GWAS) that identifies 123 susceptibility loci for migraine with a strong aggregate signal related to vascular biology and also evidence of neurological functions. Here, we propose computational and experimental approaches to investigate specific causal mechanisms of migraine related to the genetic signals in this GWAS as well as in a proposed new genetic analysis of ischemic stroke among individuals with migraine. In Specific Aim 1, we will perform the new GWAS of ischemic stroke among individuals with migraine using existing large cohorts and biobanks to identify key risk loci and therefore genes underlying these events. In Specific Aim 2, we will investigate the impact of loci in the IHGC 2022 migraine and Specific Aim 1 GWAS’s on patterns of coordinately regulated, cell-specific transcription (“programs”) using two approaches: 1) Newly available computational methods that leverage public single cell expression data, and 2) a recently proven experimental strategy that perturbs the RNA expression at the GWAS loci in vascular endothelial and smooth muscle cells. Specific Aim 3, we would use computational and experimental approaches first to investigate overlap of targets of recent CGRP and ditan therapies with inferred transcriptional programs or biological pathways of migraine and strokes to better understand the mechanisms of these new drugs. Then, we will use similar methods to investigate whether existing drugs may be candidates for reducing the burden of migraine or stroke through repurposing. Thus, we propose three independent but complementary Specific Aims to advance mechanistic understanding of the pathophysiology of migraine and the associated risk of ischemic stroke, toward elucidating the action of existing treatments and potentially identifying novel therapeutic approaches.