Genetic variants in migraine: a field synopsis and systematic re-analysis of meta-analyses

DOI: https://doi.org/10.1186/s10194- 020- 01087- 5

Abstract-Summary Numerous genetic variants from meta-analyses of observational studies and GWAS were reported to be associated with migraine susceptibility.

We performed this field synopsis and re-analysis study to evaluate the notewor-

thiness using a Bayesian approach in hope of finding true associations.

Relevant meta-analyses from observational studies and GWAS examining cor- relation between all genetic variants and migraine risk were included in our study by a PubMed search.

Using noteworthy variants, GO enrichment analysis were conducted through

DAVID online tool.

As for 8 significant genetic variants from observational studies, none of which

showed noteworthy at prior probability of 0.001.

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2 Mechanisms

Out of 47 significant genetic variants in GWAS, 36 were noteworthy at prior

probability of 0.000001 via FPRP or BFDP.

We have identified several noteworthy variants for migraine susceptibility in this

field synopsis.

Introduction Except for the common risk factors such as obesity, medication overuse, poor sleep, caffeine and stressful life events, the genetic factors for migraine susceptibility was drawing more and more attention [101, 102].

Numerous genetic polymorphisms from meta-analyses of observational studies

and GWAS were reported to be associated with migraine susceptibility [103].

In this field synopsis, we summarized and re-analyzed all significant genetic variants from meta-analyses of observational studies and GWAS, then assessed their noteworthiness using Bayesian procedures including false-positive rate prob- ability (FPRP) and Bayesian false discovery probability (BFDP) and discussed pos- sible molecular mechanisms for migraine occurrence.

Methods Studies were all selected according to the following criteria: (1) meta-analysis design study; (2) evaluating the association between genetic polymorphisms and migraine risk; (3) raw data available including odds ratios (ORs), 95% confidence intervals (CIs) or other information necessary for FPRP and BFDP calculation; (4) studies published in English.

For the statistically significant SNPs (95% CI that excluded 1 and p-value which was lower than 5 × 10− 8 for meta-analysis of GWAS or 0.05 for observational stud- ies), we calculated FPRP by using the Excel spreadsheet offered by Wacholder (http://jncicancerspectum.oupjournals.org/jnci/content/vol96/issue6) [104].

We used the minor allelic frequency (MAF) to calculated the population attribut- able risk (PAR) and further estimated the Joint PAR% for the SNPs showing note- worthiness during the computing of BFDP (BFDP < 0.8) or FPRP (FPRP < 0.2) at a prior probability of 10− 6 assumed for GWAS SNPs and 10− 3 for candidate SNPs at a statistical power to detect the OR of 1.5.

Results At a prior probability of 0.05, we identified the genetic variants, MTHFR/rs1801133, noteworthy via FPRP estimation with a statistical power to detect OR of 1.2.

When it comes to the re-analysis at a prior probability of 0.001, no noteworthy relationship between genetic variants and migraine risk could be detected via FPRP and BFDP.

In the migraine with aura subgroup, only 1 (TNF-α/rs1800629) and 3 (MTHFR/ rs1801133, ESR1/rs1801132 and TNF-α/rs1800629) genetic variants was notewor- thy in FPRP at the prior probability of 0.05 with a statistical power to detect an OR of 1.2 and 1.5, respectively.

Of the re-analyses, 32 and 26 SNPs were found to be noteworthy via FPRP esti- mation at the statistical power to detect the OR of 1.2 with the prior probability of 0.001 and 0.000001.

2.1 Genetics

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Discussion A growing number of meta-analyses from observational studies and GWAS were performed and further identified numerous significant genetic variants, which dis- played important insights into the mechanisms underlying migraine development.

We found several significant pathways (cell-cell signaling, inositol phosphate- mediated signaling, positive regulation of cytosolic calcium ion concentration, inte- gral component of plasma membrane and adult heart development, etc ) and 5 hub genes (MEF2D, TSPAN2, PHACTR1, TRPM8 and PRDM16) which were consid- ered to play vital roles in migraine occurrence.

PLCE1 and NMUR2, whose variants showed noteworthy association with migraine susceptibility, were found to be involved in two pathways called “positive regulation of cytosolic calcium ion concentration” and “inositol phosphate- mediated signaling” detected in our study.

Within the hub genes detected in our study, TRPM8 gene was found to play an

important role in the pathophysiology of migraine.

Conclusion The current findings susceptibility.

identify several noteworthy variants for migraine

We hope this field synopsis and systematic re-analysis would help identify novel

genetic biomarkers and potential therapeutic target for migraine.

Acknowledgement A machine generated summary based on the work of Zhao, Yating; Zhu, Ruixia; Xiao, Tongling; Liu, Xu. 2020 in The Journal of Headache and Pain.

Searching for Predictors of Migraine Chronification: a Pilot Study of 1911A>G Polymorphism of TRPV1 Gene in Episodic Versus Chronic Migraine