Novel hypotheses emerging from GWAS in migraine?

Abstract

Recent technical advances in genetics made large-scale genome-wide association studies (GWAS) in migraine feasible and have identified over 40 common DNA sequence variants that affect risk for migraine types. Most of the variants, which are all single nucleotide polymorphisms (SNPs), show robust association with migraine as evidenced by the fact that the vast majority replicate in subsequent independent studies. However, despite thorough bioinformatic efforts aimed at linking the migraine risk SNPs with genes and their molecular pathways, there remains quite some discussion as to how successful this endeavour has been, and their current practical use for the diagnosis and treatment of migraine patients. Although existing genetic information seems to favour involvement of vascular mechanisms, but also neuronal and other mechanisms such as metal ion homeostasis and neuronal migration, the complexity of the underlying genetic pathophysiology presents challenges to advancing genetic knowledge to clinical use. A major issue is to what extent one can rely on bioinformatics to pinpoint the actual disease genes, and from this the linked pathways. In this Commentary, we will provide an overview of findings from GWAS in migraine, current hypotheses of the disease pathways that emerged from these findings, and some of the major drawbacks of the approaches used to identify the genes and pathways. We argue that more functional research is urgently needed to turn the hypotheses that emerge from GWAS in migraine to clinically useful information.

Advances in genetics of migraine

“…Other SVDs that commonly feature migraine include syndromes such as retinal vasculopathy with cerebral leukodystrophy (RVCL; MIM #192315) caused by mutations in TREX1 [156, 157], and COL4A1 and COL4A2 -related disorders [158–160]. The exact mechanism through which vascular disorders lead to an increased prevalence of migraine is unknown [154], but they indicate that some genes with roles in vascular function are also implicated in migraine, something which has also become apparent in polygenic migraine from both epidemiological studies and GWAS [161, 162].…”

“…These studies are demanding as, although each variant may contribute to migraine susceptibility, it is neither necessary, nor sufficient, to cause it. Effect sizes for most loci are generally small (allelic odds ratio of 1.03–1.28), requiring genotyping of large numbers of individuals to robustly obtain results that pass significance thresholds [162]. Significant differences in allele frequencies of a SNP does not necessarily mean that the SNP is itself a susceptibility factor, but that a causal variant may be in linkage disequilibrium (LD) with it.…”

Metabolomics and 16S rRNA Gene Sequencing Analyses of Changes in the Intestinal Flora and Biomarkers Induced by Gastrodia-Uncaria Treatment in a Rat Model of Chronic Migraine

“…In CMG model rats, metagenomic data indicated an increased relative abundance of Prevotellaceae_ unclassified,Prevotella_1,Ruminococcaceae_norank,Bacteroides,Parasutterella,Bacteroidales_unclassified,Prevotellaceae_NK3B31_group,Ruminococcus_2,Gastranaerophilales_ norank,Rikenellaceae_RC9_gut_group,and Streptococcus, while decreases were observed in the relative abundance Lachnospiraceae_NK4A136_group,Desulfovibrio,Ruminiclostridium_6,Ruminiclostridium_9,Lachnoclostridium,Clostridiales_unclassified,Lachnospiraceae_ norank,Bilophila,Christensenellaceae_ norank,and Peptococcus. It has been reported that women with high intestinal levels of Prevotella_1 show more negative emotions, such as anxiety and pain (Tillisch et al, 2017), which is consistent with our results. Lack of Coprococcus is found in most patients with depression, reflecting a link between Coprococcus and brain disease (Valles-Colomer et al, 2019). Desulfovibrio is associated with amino acid breakdown and ammonia production (Eschenlauer et al, 2002).…”

Burden of migraine in Finland: multimorbidity and phenotypic disease networks in occupational healthcare

“…There are potential pathophysiological overlaps with migraine and neuroendocrineimmune-related skin disorders, in which also calcitonin gene related peptide (CGRP) has been suggested to play a role. Moreover, the role of vascular changes in rosacea and migraine are not fully understood but remain an interesting hypothesis also when reflecting on genetic studies [21,38,39].…”

“…Migraine is acknowledged as a complex genetic disorder that runs in families. Current evidence from genome-wide association studies mainly point at vascular function and metal ion channel activity involvement in the pathophysiology, whereas less genes linking to neuronal function and ion channel activity have been found [21].…”