Genetics: SUDS3

[Hutan]

DecodeMe Candidate Gene

In DecodeME, we attempted to link GWAS variants to target genes. Here we discuss the top two tiers of predicted linked genes that we are most confident about –‘Tier 1’ and ’Tier 2’.

We defined genes as Tier 1 genes if: (i) they are protein-coding genes, (ii) they have GTEx-v10 expression quantitative trait loci (eQTLs) lying within one of the FUMA-defined ME/CFS-associated intervals, and (iii) their expression and ME/CFS risk are predicted to share a single causal variant with a posterior probability for colocalisation (H4) of at least 75%. For this definition, we disregarded the histone genes in the chr6p22.2 HIST1 cluster, as their sequences and functions are highly redundant (1). This prioritisation step yielded 29 Tier 1 genes. For the intervals without Tier 1 genes, three Tier 2 genes were defined as the closest protein-coding genes without eQTL association: FBXL4 (chr6q16.1), OLFM4 (chr13q14.3), and CCPG1 (chr15q21.3).

CHROMOSOME 12 (GWAS-2)
Chr12 contained three Tier 1 genes.

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SUDS3 (Tier 1)

• Protein: SIN3A corepressor complex component, also known as SDS3. UniProt. GeneCards.
The allele that increases the risk of ME/CFS is associated with increased SUDS3 expression.7

• Molecular function: Regulatory protein that represses transcription and augments histone deacetylase activity of HDAC1 (UniProt). SUDS3 alters expression of the upstream kinase, ASK1, in the p38 MAPK pathway cascade (44).

• Cellular function: Chromatin remodeling and transcriptional regulation. Depletion of mouse Suds3 reveals an essential role in early lineage specification (45).

• Link to disease: Proposed to contribute to the microglial inflammatory response (44).

• Potential relevance to ME/CFS: Unclear, but potentially to neuroinflammation.

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References
7. Johnson BS, Farkas D, El-Mergawy R, Adair JA, Elhance A, Eltobgy M, et al. Targeted degradation of extracellular mitochondrial aspartyl-tRNA synthetase modulates immune responses. Nat Commun. 2024 Dec 1;15(1).

44. Shen J, Lai W, Li Z, Zhu W, Bai X, Yang Z, et al. SDS3 regulates microglial inflammation by modulating the expression of the upstream kinase ASK1 in the p38 MAPK signaling pathway. Inflamm Res. 2024 Sep;73(9):1547–64.
(note SDS3 is an earlier name for SUDS3)

45. Zhang K, Dai X, Wallingford MC, Mager J. Depletion of Suds3 reveals an essential role in early lineage specification. Dev Biol. 2013 Jan 15;373(2):359–72.