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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.

SUBMITTER: van den Maagdenberg AMJM

PROVIDER: S-EPMC6734558 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Novel hypotheses emerging from GWAS in migraine?

van den Maagdenberg Arn M J M AMJM Nyholt Dale R DR Anttila Verneri V

The journal of headache and pain 20190111 1

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 S ...[more]

PMID: 30634909

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Project description:BACKGROUND:There are now over 2000 loci in the human genome where genome wide association studies (GWAS) have found one or more SNPs to be associated with altered risk of a complex trait disease. At each of these loci, there must be some molecular level mechanism relevant to the disease. What are these mechanisms and how do they contribute to disease? RESULTS:Here we consider the roles of three primary mechanism classes: changes that directly alter protein function (missense SNPs), changes that alter transcript abundance as a consequence of variants close-by in sequence, and changes that affect splicing. Missense SNPs are divided into those predicted to have a high impact on in vivo protein function, and those with a low impact. Splicing is divided into SNPs with a direct impact on splice sites, and those with a predicted effect on auxiliary splicing signals. The analysis was based on associations found for seven complex trait diseases in the classic Wellcome Trust Case Control Consortium (WTCCC1) GWA study and subsequent studies and meta-analyses, collected from the GWAS catalog. Linkage disequilibrium information was used to identify possible candidate SNPs for involvement in disease mechanism in each of the 356 loci associated with these seven diseases. With the parameters used, we find that 76% of loci have at least of these mechanisms. Overall, except for the low incidence of direct impact on splice sites, the mechanisms are found at similar frequencies, with changes in transcript abundance the most common. But the distribution of mechanisms over diseases varies markedly, as does the fraction of loci with assigned mechanisms. Many of the implicated proteins have previously been suggested as relevant, but the specific mechanism assignments are new. In addition, a number of new disease relevant proteins are proposed. CONCLUSIONS:The high fraction of GWAS loci with proposed mechanisms suggests that these classes of mechanism play a major role. Other mechanism types, such as variants affecting expression of genes remote in the DNA sequence, will contribute in other loci. Each of the identified putative mechanisms provides a hypothesis for further investigation.

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Novel hypotheses emerging from GWAS in migraine?

Publications

Novel hypotheses emerging from GWAS in migraine?

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