Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Abstract

Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10(-8)) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

Figure 1

Manhattan plot of the primary meta-analysis of all migraine (59,674 cases vs. 316,078 controls). Each marker was tested for association using an additive genetic model by logistic regression adjusted for sex. A fixed-effects meta-analysis was then used to combine the association statistics from all 22 clinic and population-based studies. The horizontal axis shows the chromosomal position and the vertical axis shows the significance of tested markers from logistic regression. Markers that reach genome-wide significance (P < 5 × 10⁻⁸) at previously known and newly identified loci are highlighted according to the color legend.

Figure 2

Gene expression enrichment of genes from the migraine loci in GTEx tissues. Expression data from 1,641 samples was obtained using RNAseq for 42 tissues and three cell lines from the GTEx consortium. Enrichment P-values were assessed empirically for each tissue using a permutation procedure (100,000 replicates) and the red vertical line shows the significance threshold after adjusting for multiple testing by Bonferroni correction (see Online Methods).

Figure 3

Gene expression enrichment of genes from the migraine loci in 209 tissue/cell type annotations by DEPICT. Expression data was obtained from 37,427 human microarray samples and then genes in the migraine loci were assessed for high expression in each of the annotation categories. Enrichment P-values were determined by comparing the expression pattern from the migraine loci to 500 randomly generated loci and the false discovery rate (horizontal dashed line) was estimated to control for multiple testing (see Online Methods). A full list of these enrichment results are provided in Supplementary Table 20.

Figure 4

Enrichment of the migraine loci in sets of tissue-specific enhancers. We mapped credible sets from the migraine loci to sets of enhancers under active expression in 56 tissues and cell lines (identified by H3K27ac histone marks from the Roadmap Epigenomics and ENCODE projects). Enrichment P-values were assessed empirically by randomly generating a background set of matched loci for comparison (10,000 replicates) and the vertical dotted line is the significance threshold after adjusting for 56 separate tests by Bonferroni correction (see Online Methods).

Figure 5

DEPICT network of the reconstituted gene sets that were significantly enriched (false discovery rate < 0.05) for genes at the migraine loci (Online Methods). Enriched gene sets are represented as nodes with pairwise overlap denoted by the width of the connecting lines and empirical enrichment P-value is indicated by color intensity (darker is more significant). The 67 significantly enriched gene sets were clustered by similarity into 10 group nodes as shown in (a) where each group node is named after the most representative gene set in the group. (b) Shows one example of gene sets that were clustered within the now expanded ITGB1 PPI group. A full list of the 67 significantly enriched reconstituted gene sets can be found in Supplementary Table 23.