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

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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.

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Data Availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China [81922059]; and the Fundamental Research Funds for the Central Universities [xzy022019006]. We would like to thank the authors who generously shared their data as well as all study participants.

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  1. Ping Li and Shiqiang Cheng have contributed equally to this work.

Authors and Affiliations

  1. Division of Spine Surgery, Department of Orthopaedics, Nanfang Hospital, Southern Medical University, No. 1838, North Guangzhou Avenue, Baiyun District, Guangzhou, Guangdong, 510515, People’s Republic of China

    Ping Li, Xiuhua Wu, Zucheng Huang, Congrui Liao & Zhongmin Zhang

  2. School of Public Health, Health Science Center, Xi’an Jiaotong University, No. 76 Yan Ta West Road, Yanta District, Xi’an, Shaanxi, 710061, People’s Republic of China

    Shiqiang Cheng, Yan Wen, Bolun Cheng, Li Liu & Feng Zhang

  3. Department of Orthopaedics, the Third Affiliated Hospital of Southern Medical University, No.183, West Zhongshan Avenue, Tianhe District, Guangzhou, Guangdong, 510630, People’s Republic of China

    Xiang Ao

  4. Department of Outpatient, Air Force Hospital of Southern Theater Command, No. 801, East Dongfeng Avenue, Yuexiu District, Guangzhou, Guangdong, 510062, People’s Republic of China

    Shaen Li

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  1. Ping Li
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Contributions

FZ and ZMZ take responsibility for the integrity of the work as a whole, from inception to the finished manuscript. ZMZ gave the conception, design and some critical suggestion to this study. PL, SQC, BLC, and LL performed all analysis. XHW, XA, ZCH, CRL, and SEL partially performed some experiments. PL and SQC convinced the project and wrote the manuscript.

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Correspondence to Feng Zhang or Zhongmin Zhang.

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Li, P., Cheng, S., Wen, Y. et al. Identifying Candidate Genes Associated with Sporadic Amyotrophic Lateral Sclerosis via Integrative Analysis of Transcriptome-Wide Association Study and Messenger RNA Expression Profile. Cell Mol Neurobiol 43, 327–338 (2023). https://doi.org/10.1007/s10571-021-01186-0

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