New and sex-specific migraine susceptibility loci identified from a multiethnic genome-wide meta-analysis

DOI: https://doi.org/10.1038/s42003- 021- 02356- y

Abstract-Summary Migraine is a common disabling primary headache disorder that is ranked as the most common neurological cause of disability worldwide.

Migraine heritability is estimated to up to 57%, yet much of the genetic risk

remains unaccounted for, especially in non-European ancestry populations.

To elucidate the etiology of this common disorder, we conduct a multiethnic genome-wide association meta-analysis of migraine, combining results from the GERA and UK Biobank cohorts, followed by a European-ancestry meta-analysis using public summary statistics.

We report 79 loci associated with migraine, of which 45 were novel. Extended: Migraine is a common disabling disorder that can be accompanied by a wide range of symptoms of varying intensity, including headache pain that is often one-sided, and accompanied by nausea, sound and light sensitivity, and disturbed vision [85–87].

Although these findings will help to better understand the etiology of migraine susceptibility, additional genetic studies are needed to validate these associations in more large cohorts.

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2 Mechanisms

Introduction Decade, genome-wide association studies (GWASs) have reported 42 genetic loci associated with migraine at genome-wide significance [58–89].

The most recent large genetic study of migraine was conducted by the International Headache Genetics Consortium (IHGC), by combining 22 European ancestry GWASs in a meta-analysis, they identified 38 loci, including 28 novel loci awaiting independent replication [58].

No studies have yet conducted a genetic analysis of migraine in large and ethni-

cally diverse cohorts.

We present a large and ethnically diverse human genetic study of migraine, including, for the first time to our knowledge, East Asian, African American, and Hispanic/Latino adult individuals.

Results To prioritize variants within the 22 loci identified in the combined multiethnic (GERA + UKB) meta-analysis and within the 73 loci identified in the combined (GERA + UKB + IHGC) European-specific meta-analysis, we applied a Bayesian approach (CAVIARBF) [90].

To identify additional genes associated with migraine at a gene level, we con- ducted a gene-based association analysis using the functional mapping and annota- tion of genetic associations (FUMA) [91] integrative tool using the combined multiethnic GWAS meta-analysis (GERA + UKB) results.

To prioritize genes within the 73 loci identified in the combined (GERA + UKB + IHGC) European-specific meta-analysis, we used the DEPICT [92] integra- tive tool.

Genome-wide genetic correlations of migraine were calculated with a total of 772 complex traits and diseases by comparing allelic effects using a LDSC with the European-specific migraine meta-analysis (GERA + UKB) summary statistics (Methods).

Discussion We identified a new region associated with migraine at 17q21 and our DEPICT gene analysis prioritized three members of the Antp homeobox family genes (i.e., HOXB2, HOXB3, and HOXB6) at this region that encode proteins with a homeo- box DNA-binding domain.

Our study also reported, for the first time to our knowledge, sex-specific loci

associated with migraine susceptibility in women but not in men.

Among the sex-specific loci associated with migraine susceptibility in women but not in men, less is known about the role of the identified CPS1 and SLC25A21 in regard to the biologic pathways underlying migraine.

Our multiethnic meta-analysis results identified variants in CALCB associated

with migraine susceptibility.

Although these findings will help to better understand the etiology of migraine susceptibility, additional genetic studies are needed to validate these associations in more large cohorts.

2.1 Genetics

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Methods To prioritize genes and biological pathways, and highlight gene-set and tissue/cell enrichments within the 22 migraine-associated loci identified in the combined mul- tiethnic (GERA + UKB) meta-analysis, we used the FUMA [91] integrative tool.

For the MAGMA gene-based association analysis conducted on the combined (GERA + UKB) meta-analysis results, the p value adjusted for Bonferroni correc- tion was set as p < 2.51 × 10−6 (0.05/19,933 genes tested).

To prioritize genes and biological pathways, and highlight gene-set and tissue/ cell enrichments within the 73 migraine-associated loci identified in the combined (GERA + UKB + IHGC) European meta-analysis, we used the following integrative tool: DEPICT [92].

All independent genome-wide significant genetic variants (p < 5.0 × 10−8) served as input, and as the reference panel, we used 10,000 random samples from GERA non-Hispanic white ethnic group.

Acknowledgement A machine generated summary based on the work of Choquet, Hélène; Yin, Jie; Jacobson, Alice S.; Horton, Brandon H.; Hoffmann, Thomas J.; Jorgenson, Eric; Avins, Andrew L.; Pressman, Alice R. 2021 in Communications Biology.

TRPM8 genetic variant is associated with chronic migraine and allodynia