Genome-wide association study highlights novel loci and hiding heritability for amyotrophic lateral sclerosis in 740,868 individuals
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Genome-wide association studies (GWAS) have identified several amyotrophic lateral sclerosis (ALS) risk loci, however only explained a small proportion of ALS variance. We consider that GWAS sample sizes and rare variants may explain the hiding heritability. Here, we collected six publicly available biobanks/cohorts, and conducted the largest multi-ancestry ALS GWAS meta-analysis in 740,868 participants (31,254 ALS and 709,614 controls) from European, East Asian, and African ancestries using genetic variants with the minor allele frequency of 0.01%. We identified 36 loci (22 new) explaining 26% of ALS variance. We integrated ALS GWAS with multi-omics data, and identified 321 risk genes. Using bulk tissue and single-nucleus RNA-seq, we demonstrated significantly differential expression of 218 genes including 21 GWAS loci. Drug-gene interaction analysis identified 4 genes as the potential therapeutic targets for ALS. Collectively, our findings highlight the hiding heritability of ALS and provide valuable insights into the potential underlying mechanisms of ALS.
