Genome-wide association study reveals genetic risk factors for trigeminal neuralgia

At, Hale; He, Jing; Akinnusotu, Oluwatoyin; Rl, Sale; Wang, J; Bastarache, Lisa; Gamazon, Eric R.

doi:10.1101/2021.02.08.21251349

Cited by 4 publications

(2 citation statements)

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“…14 Meta-analysis was performed using inverse-variance method and Cochran’s Q test (to estimate heterogeneity) with METAL. 15,16 Age, sex, and the first twenty principal components were included as covariates in logistic regression models to identify IA-associated SNPs as previously described. 17 Threshold for genome-wide significance was defined after Bonferroni correction for the total number of SNPs tested (p < 5.0×10 −8 ).…”

Section: Methodsmentioning

confidence: 99%

Integrative genomics analysis implicates decreased FGD6 expression underlying risk of intracranial aneurysm rupture

Hale

Jones

2022

Preprint

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Importance: The genetic determinants and mechanisms underlying intracranial aneurysm rupture (rIA) are largely unknown. Given the ~50% mortality rate of rIA, approaches to identify patients at high-risk will inform screening, diagnostic, and preventative measures. Objective: To identify and characterize the genetic basis of rIA. Design: We perform a genome-wide association study (GWAS) use functional genomics approaches to identify and characterize rIA-associated loci and genes. Setting: We perform a meta-analysis across 24 published GWAS of rIA. Participants: Our cohort contains 84,353 individuals (7,843 rIA cases and 76,510 controls). Main Outcome and Measure: Single nucleotide polymorphisms (SNP), gene-burden analysis, and functional genomics identify and characterize genetic risk factors for rIA. Results: We identify 5 independent genetic loci reaching genome-wide significance (p<5.0x10-8) for rIA including rs12310399 (FGD6, OR=1.16), which to our knowledge, has not been implicated in prior GWAS of (r)IA. We then quantified gene-level mutation-burden across ~20,000 genes, and only FGD6 (containing 21 rIA-associated SNPs) reached transcriptome-wide significance. Expression quantitative trait loci (eQTL) mapping indicates that rs12310399 causes decreased FGD6 gene expression in arterial tissue. Single-cell RNA sequencing of normal human cerebrovascular cells obtained during resection surgery identified high expression of FGD6 in 1 of 3 arterial lineages but absent in perivascular cells. Patients with a Mendelian disease caused by FGD6 mutations (Aarskog-Scott syndrome) have been diagnosed with rIA, among other features, providing direct causal evidence for FGD6 in rIA pathogenesis. Conclusions and Relevance: We identify and characterize a previously unknown risk loci for rIA containing FGD6. Variable expressivity of FDG6 causes a range of clinical features from Mendelian disease to sporadic rIA. Elucidation of high-risk genetic loci may instruct population-genetic screening and clinical-genetic testing strategies to identify patients predisposed to rIA.

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Section: Methodsmentioning

confidence: 99%

Integrative genomics analysis implicates decreased FGD6 expression underlying risk of intracranial aneurysm rupture

Hale

Jones

2022

Preprint

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“…GWAS meta-analysis was performed using METAL, an inverse-variance method that incorporates the Cochran's Q test to estimate heterogeneity. 22,23 Covariates for logistic regression models to identify IA-associated single-nucleotide polymorphisms (SNPs) included age, sex, and the first 5 principal components as previously described. 24 Genome-wide statistical significance was defined after Bonferroni correction for the total number of SNPs tested (P ≤ 5.0 × 10 À8 ) as previously described.…”

Section: Genome-wide Association Study Analysismentioning

confidence: 99%

Multinational Genome-Wide Association Study and Functional Genomics Analysis Implicates Decreased SIRT3 Expression Underlying Intracranial Aneurysm Risk

Hale

Jones

2022

Neurosurgery

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BACKGROUND:The genetic mechanisms regulating intracranial aneurysm (IA) formation and rupture are largely unknown. To identify germline-genetic risk factors for IA, we perform a multinational genome-wide association study (GWAS) of individuals from the United Kingdom, Finland, and Japan.OBJECTIVE:To identify a shared, multinational genetic basis of IA.METHODS:Using GWAS summary statistics from UK Biobank, FinnGen, and Biobank Japan, we perform a meta-analysis of IA, containing ruptured and unruptured IA cases. Logistic regression was used to identify IA-associated single-nucleotide polymorphisms. Effect size was calculated using the coefficient r, estimating the contribution of the single-nucleotide polymorphism to the genetic variance of the trait. Genome-wide significance was set at 5.0 × 10−8. Expression quantitative trait loci mapping and functional genomics approaches were used to infer mechanistic consequences of implicated variants.RESULTS:Our cohort contained 155 154 individuals (3132 IA cases and 152 022 controls). We identified 4 genetic loci reaching genome-wide: rs73392700 (SIRT3, effect size = 0.28, P = 4.3 × 10−12), rs58721068 (EDNRA, effect size = −0.20, P = 4.8 × 10−12), rs4977574 (AL359922.1, effect size = 0.18, P = 7.9 × 10−12), and rs11105337 (ATP2B1, effect size = −0.15, P = 3.4 × 10−8). Expression quantitative trait loci mapping suggests that rs73392700 has a large effect size on SIRT3 gene expression in arterial and muscle, but not neurological, tissues. Functional genomics analysis suggests that rs73392700 causes decreased SIRT3 gene expression.CONCLUSION:We perform a multinational GWAS of IA and identify 4 genetic risk loci, including 2 novel IA risk loci (SIRT3 and AL359922.1). Identification of high-risk genetic loci across ancestries will enable population-genetic screening approaches to identify patients with IA.

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Role of common and rare genetic variants in the aetiology of trigeminal neuralgia

Burchiel,

Korczeniewska,

Kuo

et al. 2024

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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

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Genome-wide association study reveals genetic risk factors for trigeminal neuralgia

Cited by 4 publications

References 38 publications

Integrative genomics analysis implicates decreased FGD6 expression underlying risk of intracranial aneurysm rupture

Integrative genomics analysis implicates decreased FGD6 expression underlying risk of intracranial aneurysm rupture

Multinational Genome-Wide Association Study and Functional Genomics Analysis Implicates Decreased SIRT3 Expression Underlying Intracranial Aneurysm Risk

Role of common and rare genetic variants in the aetiology of trigeminal neuralgia

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