Common variants at 5q33.1 predispose to migraine in African-American children

Abstract

Background: Genome-wide association studies (GWASs) have identified multiple susceptibility loci for migraine in European adults. However, no large-scale genetic studies have been performed in children or African Americans with migraine.

Methods: We conducted a GWAS of 380 African-American children and 2129 ancestry-matched controls to identify variants associated with migraine. We then attempted to replicate our primary analysis in an independent cohort of 233 African-American patients and 4038 non-migraine control subjects.

Results: The results of this study indicate that common variants at 5q33.1 associated with migraine risk in African-American children (rs72793414, p=1.94×10^-9). The association was validated in an independent study (p=3.87×10^-3) for an overall meta-analysis p value of 3.81×10^-10. eQTL (Expression quantitative trait loci) analysis of the Genotype-Tissue Expression data also shows the genotypes of rs72793414 were strongly correlated with the mRNA expression levels of NMUR2 at 5q33.1. NMUR2 encodes a G protein-coupled receptor of neuromedin-U (NMU). NMU, a highly conserved neuropeptide, participates in diverse physiological processes of the central nervous system.

Conclusions: This study provides new insights into the genetic basis of childhood migraine and allow for precision therapeutic development strategies targeting migraine patients of African-American ancestry.

Keywords: genetics; genome-wide; neurology.

Figure 1

(a) Regional plot of the 5q33.1 locus, plotted are the significance of association (−log10-transformed P values) and the recombination rate. SNPs are colored to reflect pairwise LD (r²) with the most significantly associated imputed SNP. The most significant SNPs are marked in purple. (b) Box plot of NMUR2 mRNA expression levels in the frontal cortex of individuals with rs72793414 genotype GG (65 individuals), GA (23 individuals), AA (4 individuals).