Causal Inference of Genetic Variants and Genes in Amyotrophic Lateral Sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal progressive multisystem disorder with limited therapeutic options. Although genome-wide association studies (GWASs) have revealed multiple ALS susceptibility loci, the exact identities of causal variants, genes, cell types, tissues, and their functional roles in the development of ALS remain largely unknown. Here, we reported a comprehensive post-GWAS analysis of the recent large ALS GWAS (n = 80,610), including functional mapping and annotation (FUMA), transcriptome-wide association study (TWAS), colocalization (COLOC), and summary data-based Mendelian randomization analyses (SMR) in extensive multi-omics datasets. Gene property analysis highlighted inhibitory neuron 6, oligodendrocytes, and GABAergic neurons (Gad1/Gad2) as functional cell types of ALS and confirmed cerebellum and cerebellar hemisphere as functional tissues of ALS. Functional annotation detected the presence of multiple deleterious variants at three loci (9p21.2, 12q13.3, and 12q14.2) and highlighted a list of SNPs that are potentially functional. TWAS, COLOC, and SMR identified 43 genes at 24 loci, including 23 novel genes and 10 novel loci, showing significant evidence of causality. Integrating multiple lines of evidence, we further proposed that rs2453555 at 9p21.2 and rs229243 at 14q12 functionally contribute to the development of ALS by regulating the expression of C9orf72 in pituitary and SCFD1 in skeletal muscle, respectively. Together, these results advance our understanding of the biological etiology of ALS, feed into new therapies, and provide a guide for subsequent functional experiments.

TBK1, a prioritized drug repurposing target for amyotrophic lateral sclerosis: evidence from druggable genome Mendelian randomization and pharmacological verification in vitro

“…Secondly, we meticulously selected multiple tissue datasets with the largest sample size and rigorously conducted verifications using various instrumental variable selection criteria, thereby enhancing the credibility of our findings. Furthermore, our study also validated partial findings from previous research, such as TBK1 [13], a druggable target identified in our study; however, it was not reported as a prioritized drug target for ALS in other studies [23,[88][89][90]. Additionally, we have made novel discoveries by identifying new druggable genes in blood samples, brain tissue, and spinal cord (e.g., TNFSF12, TNFSF13, and RESP18), which offer promising avenues for future investigation of ALS drugs.…”

Brain Catalog: a comprehensive resource for the genetic landscape of brain-related traits

“…Interestingly, in the rs2453555_C9orf72 locus, although the candidate consensus SNP was determined as rs143956135, a nearby SNP, rs2453555, was also reported by one method (PolyFun + SuSiE) with a high posterior probability (PP = 0.9). Furthermore, COLOC analysis revealed that rs2453555 showed significant colocalization signals with eQTL (PP4 = 0.81, PP4/PP3 = 5.8) or sQTL in brain (PP4 = 0.97, PP4/PP3 = 30.7) (Figure 3B , Supplementary Table S6 ), which was in line with our previous study ( 50 ).…”

“…By using three TWAS methods (S-PrediXcan, UTMOST and JTI), we identified a total of 102 genes significantly associated with ALS by at least two methods (FDR < 0.05), of which 19 were reported in recent GWAS and post-GWAS studies ( 46 , 50 , 51 ) ( Supplementary Table S4 ), leaving a large number of newly identified candidate genes for ALS. By using the SMR analysis, we tested the exposure measurements from six types of cis-xQTLs and identified a total of 84 genes with significant evidence that likely mediated the genetic associations (FDR < 0.05 and HEIDI > 0.05).…”

Cerebellum in Alzheimer's disease and other neurodegenerative diseases: an emerging research frontier

“…283 The cerebellum in ALS also has exhibited oxidative stress abnormalities, 284 mitochondrial damage, 285 neurotransmitters and receptors changes, 277 and gene changes (Figure 3). 286,287 Structural and functional imaging studies have revealed structural and functional alterations in the cerebellum of ALS patients. 288 Several studies have demonstrated cerebellar atrophy in ALS, 257,289,290 affecting both cerebellar grey matter, [291][292][293][294] and cerebellar white matter.…”

“…The cerebellum in ALS also has exhibited oxidative stress abnormalities, 284 mitochondrial damage, 285 neurotransmitters and receptors changes, 277 and gene changes (Figure 3). 286,287 …”