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Immune-Related Mendelian Randomization Signals for Anxiety Disorders Highlight the CD40 Locus on Chromosome 20
Luwei Wang1, Yifan Duan1, Bo Sun2
1School of Food Engineering, Yantai Engineering Research Center of Food Green Processing and Quality Control, Ludong University, Yantai 264025, China.
Background/Objectives:
Although genetic studies have linked immune phenotypes with anxiety, broad Mendelian randomization (MR) screens require explicit multiple-testing control. We reappraised 1753 reported immune-cell-trait-to-anxiety inverse-variance-weighted (IVW) association records available in the analysis tables and assessed the chromosome 20 signal that includes CD40.
Methods:
The reported records were derived from the 731-trait Sardinian flow-cytometry GWAS of Orrù et al. and were evaluated across one UK Biobank and three FinnGen anxiety phenotypes; outcome-specific Benjamini-Hochberg false-discovery-rate (FDR) correction was applied to the available analysis table. The leading locus was examined using bulk and single-cell expression quantitative trait locus annotations, two-sample MR, summary-data-based MR (SMR), HEIDI tests, and regional colocalization results.
Results:
Of 1753 tests, 120 were nominally significant, and 21 were retained after outcome-specific FDR correction (14 for UK Biobank anxiety and 7 for FinnGen all anxiety; none for generalized or phobic anxiety). B-cell and regulatory/CD4 T-cell traits were common among retained associations, and several B-cell traits mapped to variants at the CD40 locus. For FinnGen all anxiety disorders, monocyte instruments gave a positive estimate (beta = 0.00418, p = 9.25 × 10-4), whereas three naïve B-cell instruments gave a negative estimate (beta = -0.0520, p = 2.64 × 10-4). Monocyte SMR was null (p = 0.542). Naïve B-cell SMR was nominally significant (p = 0.00537), but HEIDI could not be calculated. Regional colocalization was weak in both cell contexts (PP.H4 = 0.0205 and 0.00272).
Conclusions:
The post-selection locus follow-up prioritizes a chromosome 20 immune locus but does not establish CD40-mediated regulation of anxiety. Because the upstream screen was not regenerated from source GWAS files and complete per-instrument F-statistics were unavailable, all findings are exploratory. CD40 remains a testable candidate for ancestry-matched fine-mapping and cell-state-specific validation.