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. 2020 Aug:92:153.e1-153.e5.
doi: 10.1016/j.neurobiolaging.2020.04.011. Epub 2020 Apr 18.

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Collaborators, Affiliations

Analysis of shared common genetic risk between amyotrophic lateral sclerosis and epilepsy

Dick Schijven et al. Neurobiol Aging. 2020 Aug.

Abstract

Because hyper-excitability has been shown to be a shared pathophysiological mechanism, we used the latest and largest genome-wide studies in amyotrophic lateral sclerosis (n = 36,052) and epilepsy (n = 38,349) to determine genetic overlap between these conditions. First, we showed no significant genetic correlation, also when binned on minor allele frequency. Second, we confirmed the absence of polygenic overlap using genomic risk score analysis. Finally, we did not identify pleiotropic variants in meta-analyses of the 2 diseases. Our findings indicate that amyotrophic lateral sclerosis and epilepsy do not share common genetic risk, showing that hyper-excitability in both disorders has distinct origins.

Keywords: ALS; Epilepsy; Genetic correlation.

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Figures

Fig. 1.
Fig. 1.
Genetic correlation between ALS and epilepsy. Genetic correlation between ALS and epilepsy (including focal and generalized subtypes) (y-axis) was estimated based on all SNPs in the MAF range 0.01–0.5 (GCTA-All) and on SNPs in 5 MAF bins and using GCTA-GREML (x-axis). Furthermore, LDSC was used to estimate genetic correlation (All-LDSC). Error bars indicate 95% confidence intervals. Abbreviations: ALS, amyotrophic lateral sclerosis; GCTA, Genome-wide Complex Trait Analysis; GREML, genetic restricted maximum likelihood; LD, linkage disequilibrium; LDSC, linkage disequilibrium score regression; MAF, minor allele frequency; SNP, single-nucleotide polymorphism.
Fig. 2.
Fig. 2.
GRS analysis results. Twelve GRSs were calculated per individual in the target dataset and tested for association with the target disease using logistic regression (x-axis). (A) Epilepsy GWAS results were used as discovery datasets, and ALS was used as the target dataset. (B) ALS GWAS results were used as the discovery dataset, and epilepsy and subtypes were used as target datasets. Odds ratios reflect the amount by which the odds of ALS (in A) or epilepsy (in B) changes per SD increase in GRS (all GRS were scaled around mean 0 with SD 1). Error bars indicate 95% confidence intervals. The p-value threshold for significant GRS association was Bonferroni-corrected for 6 analyses times 12 PT (p < 6.94 × 10−4). Detailed results are shown in Supplementary Table 3. Abbreviations: ALS, amyotrophic lateral sclerosis; GRS, genomic risk score; GWAS, genome-wide association study; SD, standard deviation.
Fig. 3.
Fig. 3.
Association results of ALS epilepsy meta-analyses. Manhattan plots show association −log10-converted p-values (y-axis) of meta-analyzed SNPs against their relative position in the genome (x-axis). Diamonds indicate lead SNPs of loci reaching genome-wide significance, those marked red indicate pleiotropic loci, and those marked gray indicate loci with a stronger association in the single-phenotype GWAS of ALS or epilepsy compared to the meta-analysis. (A) Result for ALS-epilepsy (41,228 controls; 26,634 cases), with a pleiotropic genome-wide significant association (rs61779331, p = 3.2 × 10−8, OR = 1.02) near the gene BMP8A. (B) Result for ALS-focal epilepsy (41,228 controls; 21,598 cases). (C) Result for ALS-generalized epilepsy (41,228 controls; 15,808 cases). See Supplementary Table 4A for detailed statistics of lead SNPs. Abbreviations: ALS, amyotrophic lateral sclerosis; GWAS, genome-wide association study; OR, odds ratio; SNP, single-nucleotide polymorphism.

References

    1. The International League Against Epilepsy Consortium on Complex Epilepsies, 2018. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat. Commun 9, 5269. - PMC - PubMed
    1. van Rheenen W, Shatunov A, Dekker AM, McLaughlin RL, Diekstra FP, Pulit SL, van der Spek RA, Võsa U, de Jong S, Robinson MR, Yang J, Fogh I, van Doormaal PT, Tazelaar GH, 2016. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nat. Genet 48, 1043–1048. - PMC - PubMed

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