Population-specific differences in ClinVar pathogenic and likely pathogenic variants of epilepsy-associated genes between East Asian and non-finnish European populations: a nucleotide-resolved gnomAD v4.1.1 analysis
- 1Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Department of Neurology, Institute of Neuroscience, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
- 2Department of Neurology, Ganzhou Hospital-Nanfang Hospital, Southern Medical University (Ganzhou People’s Hospital), Ganzhou, China
Abstract
Pathogenic and likely pathogenic (P/LP) variants in ClinVar guide variant interpretation in clinical genetic testing, yet their population-specific frequency differences have not been systematically examined in epilepsy. We compiled 199 epilepsy-associated genes, extracted 46,746 unique P/LP variants from ClinVar, and retrieved allele frequencies from gnomAD v4.1.1 gene-level tables using nucleotide-resolved matching. Fisher’s exact test with Benjamini-Hochberg correction (q < 0.05) identified nine variants significantly enriched in East Asian (EAS) relative to non-Finnish European (NFE) populations, with odds ratios of 36.3–867.9. Eight additional low-frequency EAS signals met the same enrichment criterion with at least two EAS alleles and an uncorrected p < 0.01 and are reported as exploratory. Thirteen of the seventeen variants reside in seven autosomal recessive genes, namely, ALDH7A1, ST3GAL5, GOSR2, AARS1, BRAT1, WWOX, and UBA5. In parallel, an rsID-level workflow, the standard approach in database mining, yielded 60 candidate EAS-enriched variants. Nucleotide-resolved matching confirmed only fifteen of these and additionally recovered two signals the rsID workflow missed, a false-positive rate of 75.0%. These findings show that epilepsy P/LP variant frequencies differ substantially between EAS and NFE populations and concentrate in recessive genes with direct relevance to carrier screening. rsID-level ClinVar-gnomAD integration systematically overestimates population specificity, and nucleotide-resolved allele matching should become a standard step in population frequency analyses.
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BibTeX
@article{lai2026populationspecific,
title = {{Population-specific differences in ClinVar pathogenic and likely pathogenic variants of epilepsy-associated genes between East Asian and non-finnish European populations: a nucleotide-resolved gnomAD v4.1.1 analysis}},
author = {Jin-Xing Lai and Jin-Xing Lai and Ming-Feng He and Zhi-Cong Fan and Fu-Jiang Yan and Bao-Zhu Guan and Xiang-Hong Liu},
journal = {Frontiers in Genetics},
year = {2026},
month = oct,
doi = {10.3389/fgene.2026.1973684},
url = {https://doi.org/10.3389/fgene.2026.1973684},
note = {CC BY},
}
RIS
TY - JOUR
TI - Population-specific differences in ClinVar pathogenic and likely pathogenic variants of epilepsy-associated genes between East Asian and non-finnish European populations: a nucleotide-resolved gnomAD v4.1.1 analysis
AU - Jin-Xing Lai
AU - Jin-Xing Lai
AU - Ming-Feng He
AU - Zhi-Cong Fan
AU - Fu-Jiang Yan
AU - Bao-Zhu Guan
AU - Xiang-Hong Liu
PY - 2026
DA - 2026/10/23
JO - Frontiers in Genetics
DO - 10.3389/fgene.2026.1973684
UR - https://doi.org/10.3389/fgene.2026.1973684
AB - Pathogenic and likely pathogenic (P/LP) variants in ClinVar guide variant interpretation in clinical genetic testing, yet their population-specific frequency differences have not been systematically examined in epilepsy. We compiled 199 epilepsy-associated genes, extracted 46,746 unique P/LP variants from ClinVar, and retrieved allele frequencies from gnomAD v4.1.1 gene-level tables using nucleotide-resolved matching. Fisher’s exact test with Benjamini-Hochberg correction (q < 0.05) identified nine variants significantly enriched in East Asian (EAS) relative to non-Finnish European (NFE) populations, with odds ratios of 36.3–867.9. Eight additional low-frequency EAS signals met the same enrichment criterion with at least two EAS alleles and an uncorrected p < 0.01 and are reported as exploratory. Thirteen of the seventeen variants reside in seven autosomal recessive genes, namely, ALDH7A1, ST3GAL5, GOSR2, AARS1, BRAT1, WWOX, and UBA5. In parallel, an rsID-level workflow, the standard approach in database mining, yielded 60 candidate EAS-enriched variants. Nucleotide-resolved matching confirmed only fifteen of these and additionally recovered two signals the rsID workflow missed, a false-positive rate of 75.0%. These findings show that epilepsy P/LP variant frequencies differ substantially between EAS and NFE populations and concentrate in recessive genes with direct relevance to carrier screening. rsID-level ClinVar-gnomAD integration systematically overestimates population specificity, and nucleotide-resolved allele matching should become a standard step in population frequency analyses.
SN - 1664-8021
ER -