
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.01.610696
preprint
1
Article
A Deep Dive into Statistical Modeling of RNA Splicing QTLs Reveals New Variants that Explain Neurodegenerative Disease
Wang David http://orcid.org/0000-0002-1566-5123

Gazzara Matthew R. http://orcid.org/0000-0001-7710-4551

Jewell San http://orcid.org/0000-0002-6494-8015

Wales-McGrath Benjamin http://orcid.org/0009-0006-4184-7875

Brown Christopher D.
Choi Peter S. http://orcid.org/0000-0002-2820-3032

Barash Yoseph http://orcid.org/0000-0003-3005-5048

03 9 2024
2024.09.01.610696https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.09.01.610696
nihpp-2024.09.01.610696.pdf
Abstract

Genome-wide association studies (GWAS) have identified thousands of putative disease causing variants with unknown regulatory effects. Efforts to connect these variants with splicing quantitative trait loci (sQTLs) have provided functional insights, yet sQTLs reported by existing methods cannot explain many GWAS signals. We show current sQTL modeling approaches can be improved by considering alternative splicing representation, model calibration, and covariate integration. We then introduce MAJIQTL, a new pipeline for sQTL discovery. MAJIQTL includes two new statistical methods: a weighted multiple testing approach for sGene discovery and a model for sQTL effect size inference to improve variant prioritization. By applying MAJIQTL to GTEx, we find significantly more sGenes harboring sQTLs with functional significance. Notably, our analysis implicates the novel variant rs582283 in Alzheimer’s disease. Using antisense oligonucleotides, we validate this variant’s effect by blocking the implicated YBX3 binding site, leading to exon skipping in the gene MS4A3.
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pmc
