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. 2023 Jan;43(1):327-338.
doi: 10.1007/s10571-021-01186-0. Epub 2022 Jan 17.

Identifying Candidate Genes Associated with Sporadic Amyotrophic Lateral Sclerosis via Integrative Analysis of Transcriptome-Wide Association Study and Messenger RNA Expression Profile

Ping Li  1 , Shiqiang Cheng  2 , Yan Wen  2 , Bolun Cheng  2 , Li Liu  2 , Xiuhua Wu  1 , Xiang Ao  3 , Zucheng Huang  1 , Congrui Liao  1 , Shaen Li  4 , Feng Zhang  5 , Zhongmin Zhang  6
Affiliations

Identifying Candidate Genes Associated with Sporadic Amyotrophic Lateral Sclerosis via Integrative Analysis of Transcriptome-Wide Association Study and Messenger RNA Expression Profile

Ping Li et al. Cell Mol Neurobiol. 2023 Jan.

Abstract

Amyotrophic lateral sclerosis, a fatal neurodegeneration disease affecting motor neurons in the brain and spinal cord, is difficult to diagnose and treat. The objective of this study is to identify novel candidate genes related to ALS. Transcriptome-wide association study of ALS was conducted by integrating the genome-wide association study summary data (including 1234 ALS patients and 2850 controls) and pre-computed gene expression weights of different tissues. The ALS-associated genes identified by TWAS were further compared with the differentially expressed genes detected by the mRNA expression profiles of the sporadic ALS. Functional enrichment and annotation analysis of identified genes were performed by an R package and the functional mapping and annotation software. TWAS identified 761 significant genes (PTWAS < 0.05), 627 Gene ontology terms, and 8 Kyoto Encyclopedia of Genes and Genomes pathways for ALS, such as C9orf72, with three expression quantitative trait loci were found significantly: rs2453554 (PTWAS CBRS = 4.68 × 10-10, PTWAS CBRS = 2.54 × 10-9), rs10967976 (PTWAS CBRS = 7.85 × 10-10, PTWAS CBRS = 8.91 × 10-9, PTWAS CBRS = 1.49 × 10-7, PTWAS CBRS = 5.59 × 10-7), rs3849946 (PTWAS CBRS = 7.69 × 10-4, PTWAS YBL = 4.02 × 10-2), Mitochondrion (Padj = 4.22 × 10-16), and Cell cycle (Padj = 2.04 × 10-3). Moreover, 107 common genes, 4 KEGG pathways and 41 GO terms were detected by integrating mRNA expression profiles of sALS, such as CPVL (FC = 2.06, PmRNA = 6.99 × 10-6, PTWAS CBR = 2.88 × 10-2, PTWAS CBR = 4.37 × 10-2), Pyrimidine Metabolism (Padj = 2.43 × 10-2), and Cell Activation (Padj = 5.54 × 10-3). Multiple candidate genes and pathways were detected for ALS. Our findings may provide novel clues for understanding the genetic mechanism of ALS.

Keywords: Amyotrophic lateral sclerosis (ALS); Sporadic Amyotrophic lateral sclerosis (sALS); Transcriptome-wide association study (TWAS); mRNA expression profile.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The significant genes and SNPs identified by TWAS for ALS. A and B Are the venn diagram and table of the number of genes identified from the four tissues of ALS by TWAS. CBRS, CBR, NBL, and YBL stand for brain RAN-seq splicing, brain RNA-seq, peripheral blood, and whole blood, respectively. (C) is the manhattan plot of the significant SNPs of ALS identified by TWAS
Fig. 2
Fig. 2
The top 20 enriched GO terms of ALS
Fig. 3
Fig. 3
The volcano plot of the 107 common genes for sALS
Fig. 4
Fig. 4
The heatmap of the 107 common genes for sALS
See this image and copyright information in PMC

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