Identifying novel genes for amyotrophic lateral sclerosis by integrating human brain proteomes with genome-wide association data

Background Genome-Wide Association Studies (GWAS) have identified numerous risk genes for Amyotrophic Lateral Sclerosis (ALS); however, the mechanisms by which these loci confer ALS risk are uncertain. This study aims to identify novel causal proteins in the brains of patients with ALS using an integrative analytical pipeline. Methods Using the datasets of Protein Quantitative Trait Loci (pQTL) (NpQTL1 = 376, NpQTL2 = 152), expression QTL (eQTL) (N = 452), and the largest ALS GWAS (NALS=27,205, NControls = 110,881), we performed a systematic analytical pipeline including Proteome-Wide Association Study (PWAS), Mendelian Randomization (MR), Bayesian colocalization, and Transcriptome-Wide Association Study (TWAS) to identify novel causal proteins for ALS in the brain. Results Using PWAS, we found that the altered protein abundance of 12 genes in the brain was associated with ALS. Three genes (SCFD1, SARM1 and CAMLG) were identified as lead causal genes for ALS with solid evidence (False discovery rate < 0.05, in MR analysis; PPH4 > 80% for Bayesian colocalization). Specifically, an increased abundance of SCFD1 and CAMLG led to an increased risk of ALS, whereas a higher abundance of SARM1 led to a decreased risk of developing ALS. TWAS showed that SCFD1 and CAMLG were related to ALS at the transcriptional level. Conclusions SCFD1, CAMLG, and SARM1 exhibited robust associations and causality with ALS. The study findings provide novel clues for identifying potential therapeutic targets in ALS. Further studies are required to explore the mechanisms underlying the identified genes..

Medienart:

E-Artikel

Erscheinungsjahr:

2023

Erschienen:

2023

Enthalten in:

Zur Gesamtaufnahme - volume:270

Enthalten in:

Journal of neurology - 270(2023), 8 vom: 06. Mai, Seite 4013-4023

Sprache:

Englisch

Beteiligte Personen:

Gu, Xiao-Jing [VerfasserIn]
Su, Wei-Ming [VerfasserIn]
Dou, Meng [VerfasserIn]
Jiang, Zheng [VerfasserIn]
Duan, Qing-Qing [VerfasserIn]
Wang, Han [VerfasserIn]
Ren, Yan-Ling [VerfasserIn]
Cao, Bei [VerfasserIn]
Wang, Yi [VerfasserIn]
Chen, Yong-Ping [VerfasserIn]

Links:

Volltext [lizenzpflichtig]

Themen:

Amyotrophic lateral sclerosis
Mendelian randomization
QTL

RVK:

RVK Klassifikation

Anmerkungen:

© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany 2023. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

doi:

10.1007/s00415-023-11757-4

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

OLC2144441723

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