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Background <p>Parkinson’s disease (PD) is a progressive neurodegenerative disorder with limited disease-modifying therapies. PANoptosis, an integrated form of programmed cell death involving apoptosis, pyroptosis, and necroptosis, has been implicated in neuroinflammation-related neurodegeneration. However, the roles of PANoptosis-related genes in PD remain unclear.</p> Methods <p>We performed two-sample Mendelian randomization (MR) using cis-eQTL instruments from the eQTLGen Consortium for 30 PANoptosis-related genes, with PD GWAS data from Nalls et al. 2019 as the outcome. Instrumental variables were selected using a hierarchical strategy, with genome-wide significant cis-eQTLs as primary instruments and a relaxed threshold applied only for genes with fewer than three independent SNPs. Sensitivity analyses included MR-Egger, weighted median, MR-PRESSO, MR-RAPS, and leave-one-out analyses. SMR/HEIDI testing and two-step MR mediation using 731 peripheral immune traits were also performed.</p> Results <p>Genetically predicted higher CXCL16 expression was associated with increased PD risk (OR = 1.115, 95% CI 1.060–1.173, <i>p</i> = 2.4 × 10<sup>−5</sup>), while higher FADD expression was associated with reduced PD risk (OR = 0.861, 95% CI 0.790–0.939, <i>p</i> = 7.1 × 10<sup>−4</sup>). CASP1 and IFI27 were nominally significant and considered exploratory. Sensitivity analyses were directionally consistent, although MR-Egger estimates were imprecise. SMR/HEIDI supported CXCL16. Exploratory mediation analysis identified 63/66 candidate immune mediators after FDR correction.</p> Conclusion <p>These findings provide MR-based genetic evidence linking CXCL16 expression to PD risk, with exploratory mediation through peripheral immune phenotypes. The CXCL16–immune cell–PD axis warrants further experimental validation.</p> Graphical abstract <p></p>

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Genetically predicted CXCL16 expression is associated with Parkinson’s disease risk and peripheral immune cell dysregulation: a two-sample mendelian randomization study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月30日

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  • Zhou Li,
  • Rong Yang,
  • Hao Feng,
  • Mou Sun,
  • Hongjun Liu

摘要

Background

Parkinson’s disease (PD) is a progressive neurodegenerative disorder with limited disease-modifying therapies. PANoptosis, an integrated form of programmed cell death involving apoptosis, pyroptosis, and necroptosis, has been implicated in neuroinflammation-related neurodegeneration. However, the roles of PANoptosis-related genes in PD remain unclear.

Methods

We performed two-sample Mendelian randomization (MR) using cis-eQTL instruments from the eQTLGen Consortium for 30 PANoptosis-related genes, with PD GWAS data from Nalls et al. 2019 as the outcome. Instrumental variables were selected using a hierarchical strategy, with genome-wide significant cis-eQTLs as primary instruments and a relaxed threshold applied only for genes with fewer than three independent SNPs. Sensitivity analyses included MR-Egger, weighted median, MR-PRESSO, MR-RAPS, and leave-one-out analyses. SMR/HEIDI testing and two-step MR mediation using 731 peripheral immune traits were also performed.

Results

Genetically predicted higher CXCL16 expression was associated with increased PD risk (OR = 1.115, 95% CI 1.060–1.173, p = 2.4 × 10−5), while higher FADD expression was associated with reduced PD risk (OR = 0.861, 95% CI 0.790–0.939, p = 7.1 × 10−4). CASP1 and IFI27 were nominally significant and considered exploratory. Sensitivity analyses were directionally consistent, although MR-Egger estimates were imprecise. SMR/HEIDI supported CXCL16. Exploratory mediation analysis identified 63/66 candidate immune mediators after FDR correction.

Conclusion

These findings provide MR-based genetic evidence linking CXCL16 expression to PD risk, with exploratory mediation through peripheral immune phenotypes. The CXCL16–immune cell–PD axis warrants further experimental validation.

Graphical abstract