Abstract
Epilepsy (EP) and congenital heart disease (CHD) are two apparently unrelated diseases that nevertheless display substantial mutual comorbidity. Thus, while congenital heart defects are associated with an elevated risk of developing epilepsy, the incidence of epilepsy in CHD patients correlates with CHD severity. Although genetic determinants have been postulated to underlie the comorbidity of EP and CHD, the precise genetic etiology is unknown. We performed variant and gene association analyses on EP and CHD patients separately, using whole exomes of genetically identified Europeans from the UK Biobank and Mount Sinai BioMe Biobank. We prioritized biologically plausible candidate genes and investigated the enriched pathways and other identified comorbidities by biological proximity calculation, pathway analyses, and gene-level phenome-wide association studies. Our variant- and gene-level results point to the Voltage-Gated Calcium Channels (VGCC) pathway as being a unifying framework for EP and CHD comorbidity. Additionally, pathway-level analyses indicated that the functions of disease-associated genes partially overlap between the two disease entities. Finally, phenome-wide association analyses of prioritized candidate genes revealed that cerebral blood flow and ulcerative colitis constitute the two main traits associated with both EP and CHD.
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This study was conducted using the UK Biobank Resource under Application 53074. The whole exome datasets are accessible upon approval of application. The BioMe biobank whole exome datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Abbreviations
- EP:
-
Epilepsy
- CHD:
-
Congenital heart disease
- NDD:
-
Neurodevelopmental disorders
- VEP:
-
Variant effect predictor
- MSC:
-
Mutation significance cutoff
- CADD:
-
Combined annotation dependent depletion
- PCA:
-
Principal component analysis
- IPA:
-
Ingenuity pathway analysis
- HGMD:
-
The human gene mutation database
- HGC:
-
The human gene connectome
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Acknowledgements
The authors would like to thank Ron Do and Ghislain Rocheleau for kindly providing guidance on statistical methods for pleiotropic variants.
Funding
This study was supported by the fund of the Sichuan University Innovation Spark under Project No. 2018SCUH0059.
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Conceptualization: LC, YW, BD, and SH. Methodology: YW, CSB, and YI. Data management and investigation: YW, YI, and PDS. Visualization: YW and CSB. Writing—original draft: YW, BD, and CSB. Writing—review and editing: LC, YI, and DNC.
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439_2022_2502_MOESM1_ESM.docx
Supplementary file1 Supplementary file 1: Fig. S1. The GWAS analyses results for EP and CHD. Fig. S2. The IPA-derived phenotypes associated with the top genes derived from SKAT-O analyses. Fig. S3. The variant level phenome-wide association analysis for the risk variants of both CHD and EP. The top 50 were displayed in the figure. Fig. S4. LocusZoom plot of rs148994715 for their LD information in the European population. Fig. S5. LocusZoom plot of rs57732048 for their LD information in the European population. (DOCX 1567 KB)
439_2022_2502_MOESM2_ESM.xlsx
Supplementary file2 Supplementary file 2: Table S1. SKAT-O analysis on epilepsy using high impact rare variants. Table S2. SKAT-O analysis on congenital heart disease using high impact rare variants. Table S3. Phenotype enrichment for the 12 samples having epilepsy and congenital heart disease using UK Biobank exomes. Table S4. SKAT-O analysis on epilepsy using BioMe exomes. Table S5. SKAT-O analysis on congenital heart disease using BioMe exomes. Table S6. Merged P values for EP SKAT-O analyses and CHD SKAT-O analyses using different Biobanks. Table S7. IPA canonical pathways among 134 candidate genes in CHD. Table S8. IPA canonical pathways among 143 candidate genes in EP. Table S9. InnateDB GO analysis among 134 candidate genes in CHD. Table S10. InnateDB GO analysis among 143 candidate genes in EP. Table S11. InnateDB Pathway Analysis among combined 272 candidate genes. Table S12. Human gene connectome (HGC) analyses on candidate genes. (XLSX 3161 KB)
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Wu, Y., Bayrak, C.S., Dong, B. et al. Identifying shared genetic factors underlying epilepsy and congenital heart disease in Europeans. Hum Genet 142, 275–288 (2023). https://doi.org/10.1007/s00439-022-02502-4
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DOI: https://doi.org/10.1007/s00439-022-02502-4