128 Genome-wide Association Study Reveals Genetic Risk Factors for Trigeminal Neuralgia

Abstract

INTRODUCTION: Trigeminal neuralgia (TN) is a debilitating neuropathic pain disease. While many clinical risk factors have been associated with TN, the genetic basis is largely unknown and no genome-wide association studies (GWAS) have been performed. Here we perform the first GWAS for TN and conduct a fixed-effect meta-analysis including 1,188 TN cases from BioVU, FinnGen, and the UK Biobank. METHODS: Age, sex, and five genotype-based principal components were used as covariates in logistic regression models to identify TN-associated single nucleotide polymorphisms (SNPs). Fixed-effect meta-analysis was performed using METAL. Genome-wide significance was defined as p < 5.0 x 10-8. Linkage disequilibrium (LD, r2) was determined using the LD matrix tool. RESULTS: We identify an intergenic locus on chromosome 1p22.2 flanked by ZNF326 and SNORD3G containing 5 SNPs (rs77449572, rs543311093, rs35117749, rs71666259, and rs116010656) reaching genome-wide significance (p < 5.0 x 10-8), with the SNP rs77449572 as the sentinel variant (p = 1.72 x 10-9). A number of SNPs in the locus are in moderate LD, as highlighted by the heatmap of r2 values. Haploreg analysis identifies rs77449572 which overlaps an enhancer element in cortex-derived neurospheres. In addition, rs71666259 and rs116010656 overlap enhancer elements in embryonic stem cells (HUES48), suggesting potential functional consequences of this locus. We also identify a second locus on chromosome 5q35.1 containing sentinel variant rs62376947 reaching genome-wide significance (p = 2.49 x 10-8). As the Q-Q plot confirms, there is no global inflation in the test statistic (no early separation of the expected from the observed), suggesting that population stratification has been adequately accounted for. The LocusZoom plots show the magnitude of the genome-wide significant associations in the 1p22.2 locus and the 5q35.1 locus. CONCLUSION: To our knowledge, we perform the first GWAS of TN, identifying risk loci reaching genome-wide significance.