Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Abstract

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice.

Fig. 1. Genome-wide meta-analysis identifies 25 CNVs associated with seizure disorders.

Miami plot of the meta-analysis of the CNV genome-wide association analyses of (1) 16,109 individuals with clinically validated epilepsy vs. 8545 controls and (2) 10,590 individuals with seizure disorders vs. 483,779 controls. Dots represent -log₁₀ of the meta-analysis P-values (P_DEL and P_DUP for deletions and duplications, respectively) of the cohort-specific Fisher exact tests for the enrichment of CNVs in cases vs. controls for each a 200 kb sliding window. Genomic regions that surpassed the Bonferroni-corrected threshold for significance (red line, α = 3.74 × 10⁻⁶) were annotated with the genomic band containing the signal. Deletions (top) and duplications (mirrored) are shown.

Fig. 2. Genotype-first phenomic analysis in 10,880 individuals with detailed clinical data.

For each CNV, the proportion of carriers and non-carriers annotated with each HPO concept is plotted. Those above the diagonal were enriched among carriers, and those below were depleted. Odds ratios are represented by dot size. The selected phenotypes labeled were prioritized according to statistical evidence and clinical breadth. Full results for all associations reaching unadjusted P < 0.05 are provided in Supplementary Data 3. SUDEP sudden unexpected death in epilepsy, CNS central nervous system, EEG electroencephalogram.

Fig. 3. Summary clinical signatures of CNVs in a deeply phenotyped epilepsy cohort.

The percentage of carriers of the CNV with each broad phenotype is shown by the height of bars arranged on a polar axis, with two-sided 95% confidence interval error bars for these percentages derived from the binomial distribution using stats::binom.test(). For reference, dots indicate the percentage of the entire Phenomic cohort of 10,880 people with each broad phenotype (representing the prior probability of a person having the phenotype without genetic stratification). The binomial distribution two-sided 95% confidence intervals for a cohort size of 10,880 are no wider than 1.9% (not shown for clarity). “Craniofacial or skeletal dysmorphism” includes individuals with either “Abnormality of the head [HP:0000234]” (which excludes isolated brain structural abnormalities) or “Abnormal skeletal morphology [HP:0011842]”. “Motor, movement or muscular disorder” includes individuals with any of “Abnormal central motor function [HP:0011442]”, “Abnormality of movement [HP:0100022]” or “Abnormality of the musculature [HP:0003011]”, but not “Motor delay [HP:0001270]”, which is included in “Neurodevelopmental abnormality”. While “Neurodevelopmental abnormality” includes those with “Intellectual disability”, the latter is shown additionally as it is a neurodevelopmental outcome with particularly important socioeconomically important consequences. EEG electroencephalogram. Further CNV profiles are shown in Supplementary Fig. 2.