Role of common and rare genetic variants in the aetiology of trigeminal neuralgia
Authors: Burchiel Kim J. , Korczeniewska Olga A. , Kuo Fengshen , Huang Ching-Yu , Seltzer Ze’ev , Diehl Scott R 
Published: July 2024

SummaryBackgroundTrigeminal neuralgia (TN) is characterized by repeated paroxysmal attacks of severe facial pain usually lasting 1-3 minutes. Lifetime prevalence is ca.3 per 1,000, more common in women, and with onset generally in middle age. Medications usually provide relief in the early stages of the disorder, but for many patients, severe drug side effects emerge and medically intractable pain returns, sometimes lasting for life. Some patients present with paroxysmal pain predominantly while others also experience substantial concomitant constant facial pain. Some patients have a history of a blood vessel compressing and damaging their trigeminal nerve (neurovascular compression, NVC). For these “classical” cases, surgery often provides complete or substantial pain relief for many years. “Idiopathic” cases without NVC or any other apparent cause also occur. NVC was previously observed to be less frequent in females who had early age of onset and these patients may constitute a unique subgroup. Our aim was to evaluate the role of inherited genetic variation in the aetiology of TN in patient subgroups based on age of onset, presence of NVC and sex.MethodsTo maximize aetiological homogeneity, only patients with predominantly paroxysmal pain and minimal concomitant continuous pain were included in the analysis. Conditions known to cause secondary TN such as tumors or multiple sclerosis were excluded. The GWAS analysis was based on 626 TN patients and 827 Control subjects of European ancestry recruited in Canada, the UK, and US. A Genome-Wide Association Study (GWAS) analysis was performed using Affymetrix’s Precision Medicine arrays yielding 7,781,254 biallelic DNA variants available after Quality Control (QC) and imputation. Rare damaging mutations in genes with functions relevant to the biology of TN were identified in Whole Genome Sequencing (WGS) genomic DNA of 100 patients using a novel strategy based on overlap of symptoms of TN with symptoms of known genetic disorders.FindingsThe GWAS analysis revealed associations at eight genome locations including nearLRP1B(P-value 6.3 X 10-15), a gene important for repair of myelin sheath injury that has been previously proposed as a target for the treatment of neuropathic pain. Associations were also found for the potassium channel geneKCNK10, and forCHL1, CUX1, SGMS1andZNF804Bgenes, all genes with neural functions potentially relevant to the aetiology of TN. In addition, high-risk genotypes at theCUX1andKCNK10genes exhibit significant interactions with patients’ sex and the presence or absence of NVC (P-values 0.005 and 0.017, respectively). Whole genome sequencing of 100 TN patients revealed mutations in ion channel genesTRPM4(six patients),SCN10AandSCNN1B(five patients),CACNA1F, CACNA1Sand SCN5A (four patients) andCACNA1H,SCN2AandSCN9A(three patients). Female patients with onset prior to age 46 had more mutated genes with myelin-related functions (P-value 0.004) and associated with epilepsy or seizure (P-value 0.03) than older onset females and males of any onset age.InterpretationRisk of TN in patients presenting with paroxysmal pain only is associated with both common genetic variants and with rare mutations. Some high-risk genotypes have significant interactions with sex and NVC. Evidence of the condition’s heterogeneous genetic aetiology should be considered when evaluating novel therapies.FundingGrants from the William H. and Leila A. Cilker Genetics Research Program of the Facial Pain Research Foundation, The Foundation of the University of Medicine and Dentistry of New Jersey, and Rutgers School of Dental Medicine, Rutgers Health, Rutgers – The State University of New JerseyContactScott R Diehl, PhD,scott.diehl@rutgers.edu, 973-972-7053