Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

Abstract

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 × 10⁻⁹, odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 × 10⁻¹¹ (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 × 10⁻⁵, permuted threshold for genome-wide significance 7.7 × 10⁻⁵. To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

Figure 1. Cochran-Mantel-Haenszel association results for combined analysis of the three study populations between 97.5 and 98.5 Mb on chromosome 8q22.1

Diamonds show position and p-value for each marker in the region, with colors representing extent of linkage disequilibrium (measured in r²) with marker rs1835740, and blue circles indicate locations and p-values of imputed markers. For rs1835740, p-values are shown for both the original genome-wide association study and the meta-analysis of all migraine samples in the study (denoted by asterisk). The blue graph shows the local recombination rate based on HapMap Phase II data. Red line denotes the threshold for genome-wide significance (p ≤ 5 × 10⁻⁸). Figure was generated using a modified version of the script available at broadinstitute.org/node/555.

Figure 2. Forest plot of migraine risk for individuals carrying the A allele of marker rs1835740 in each study population

For each dataset, the horizontal line indicates 95% confidence interval, and the number above the line indicates the point estimate of the odds ratio. MA only – patients whose attacks are always accompanied with aura, Both MA, MO – patients with attacks with and without aura, MO only – patients whose attacks never include aura.

Figure 3. A box-plot of the quantified expression values for MTDH/AEG-1 ordered based on sample genotype of rs1835740

Normalised expression levels in lymphoblastoid cell lines using Illumina's WG-6 v3 Expression BeadChip array are shown. In each group, the small pyramid indicates median value, the shaded area represents the lower and upper quartiles, and the crosses show the minimum and maximum values in the expression data.