Genome-wide association analysis identifies susceptibility loci for migraine without aura

Abstract

Migraine without aura is the most common form of migraine, characterized by recurrent disabling headache and associated autonomic symptoms. To identify common genetic variants associated with this migraine type, we analyzed genome-wide association data of 2,326 clinic-based German and Dutch individuals with migraine without aura and 4,580 population-matched controls. We selected SNPs from 12 loci with 2 or more SNPs associated with P values of <1 × 10(-5) for replication testing in 2,508 individuals with migraine without aura and 2,652 controls. SNPs at two of these loci showed convincing replication: at 1q22 (in MEF2D; replication P = 4.9 × 10(-4); combined P = 7.06 × 10(-11)) and at 3p24 (near TGFBR2; replication P = 1.0 × 10(-4); combined P = 1.17 × 10(-9)). In addition, SNPs at the PHACTR1 and ASTN2 loci showed suggestive evidence of replication (P = 0.01; combined P = 3.20 × 10(-8) and P = 0.02; combined P = 3.86 × 10(-8), respectively). We also replicated associations at two previously reported migraine loci in or near TRPM8 and LRP1. This study identifies the first susceptibility loci for migraine without aura, thereby expanding our knowledge of this debilitating neurological disorder.

Figure 1. Regional and forest plots for the novel migraine loci

Regional association plots (generated using LocusZoom (see Web resources)) are shown for the four novel migraine loci together with a forest plot for the SNP with highest association for the respective locus (with the number of cases for each sample indicated) (a-d). Each regional plot shows the chromosomal position (NCBI build 36) of SNPs in the specific region against the –log₁₀ P-values. The SNP with the highest association signal in each locus is represented as a purple diamond; the additional SNPs are color-coded according to the extent of LD with that SNP. Estimated recombination rates (cM/Mb) from HapMap CEU release 22 are shown as light blue lines. Forest plots are shown for: rs3790455 (MEF2D) (a), rs7640543 (TGFBR2) (b), rs9349379 (PHACTR1) (c), and rs6478241 (ASTN2) (d). Black squares represent the odds ratios for the individual cohorts; the horizontal lines represent the 95% confidence intervals. Numbers in parentheses indicate the number of cases in each cohort.

Figure 2. Regional and forest plots for the previously reported migraine loci that replicate in the current MO study

Regional association plots (generated using LocusZoom (see Web resources)) are shown for the two previously reported migraine loci that significantly replicated in the current study as well as forest plots for the SNP with highest association in these loci (with the number of cases for each sample indicated) (a and b). Each regional plot shows the chromosomal position (NCBI build 36) of SNPs in the specific region against the –log₁₀ P-values. SNP with the highest association signal in each locus is represented as a purple diamond; the additional SNPs are color-coded according to the extent of LD with this SNP. Estimated recombination rates (cM/Mb) from HapMap CEU release 22 are shown as light blue lines. Forest plots are shown for: rs10166942 (TRPM8) (a) and rs11127113 (LRP1) (b). Black squares represent the odds ratio for the individual cohorts; the horizontal lines represent the 95% confidence intervals. Numbers in parentheses indicate the number of cases in each cohort.