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[Preprint]. 2025 Aug 25:2024.07.09.602755. Originally published 2024 Jul 9. [Version 3] doi: 10.1101/2024.07.09.602755

Figure 2. Neuronal MPRA-QTLs largely validate brain eQTLs across inflammatory exposures, related to SI Fig. 17, SI Data 2.16.

Figure 2.

(A) Upset plot of the overlapping MPRA-QTLs by condition and direction of effect when compared to baseline (vehicle). Within MPRA-QTLs, stable-QTLs generally had increased transcriptional activity with the reference allele. (B) Cue-responsiveness often affects the “top” significant QTL at a GWAS locus. While the majority (43 out of 113) of GWAS loci represented had at least one MPRA-QTL in each condition, MPRA-QTLs uniquely mapped to 14 loci at baseline (vehicle), 5 loci for IL-6, and 8 loci for IFNα. (C) Genome-wide significant GWAS loci with one or more MPRA-QTL across conditions. (D) (i) Representative stable MPRA-QTL: rs61826812 on chromosome 1, with decreased activity with the presence of the alternative allele across all conditions (within condition Wilcoxon Rank Sum test (ref-vs-alt): Base p=6×10−04, IL-6 p=4.3×10−05, IFNα p=9.9×10−06). (ii-iii) Representative dynamic MPRA-QTLs: rs73088223 on chr 3 (ii), with increased activity with the alternative allele (p=0.0011) following exposure to IL-6 and rs117843471 on chr 22 (iii) with significant down regulation with the alternative allele following exposure to IFNα (p=7.1×10−06). (E) At the single cell level, most MPRA-QTLs overlapped with excitatory neuronal QTLs83, as anticipated. (F) Of the 544 bi-allelic variants tested, 23%, 47%, and 17% percent overlapped with significant (Bonferroni or FDR<=0.05) (i) adult cortical excitatory neuronal83, (ii) adult brain77, and (iii) fetal brain (12–19 PCW82) eQTLs, respectively. The concordance of allelic effects (ref-v-alt) was tested across all MPRA bi-allelic variants overlapping with brain eQTLs (cream bar), MPRA-QTLs at a qStorey<=0.05 threshold (teal bar), and MPRA-QTLs at pFDR<=0.1 threshold. The magnitude of effect of these concordant MPRA-QTLs was also significantly correlated with eQTL betas (SI Data 2.16): MPRA-QTLs qStorey <=0.05: (Excitatory: r=0.5–0.71; DLPFC: r=0.64–0.66; Fetal PFC: r=0.71–0.82)].