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Generative prediction of causal gene sets responsible for complex traits

Kuznets-Speck, Benjamin1; Ogonor, Buduka1; Wytock, Thomas1; Motter, Adilson1

Published Apr 15, 2025 on Dryad. https://doi.org/10.5061/dryad.s4mw6m9hf

Data files

Apr 15, 2025 version files 1.96 GB

Abstract

The relationship between genotype and phenotype remains an outstanding question for organism-level traits because these traits are generally complex. The challenge arises from complex traits being determined by a combination of multiple genes (or loci), which leads to an explosion of possible genotype-phenotype mappings. The primary techniques to resolve these mappings are genome/transcriptome-wide association studies, which are limited by their lack of causal inference and statistical power.  Here, we develop an approach that leverages transcriptional data endowed with causal information and a generative machine learning model to strengthen statistical power.  Our implementation of the approach-- dubbed TWAVE---includes a variational autoencoder trained on human transcriptional data, which is incorporated into an optimization framework. TWAVE generates trait expression profiles, which we dimensionally reduce by identifying independently varying generalized pathways (eigengenes). We then conduct constrained optimization to find causal gene sets that are the gene perturbations whose measured transcriptomic responses best explain trait differences. By considering several complex traits, we show that the approach identifies causal genes that cannot be detected by the primary existing techniques. Moreover, the approach identifies complex diseases caused by distinct sets of genes, meaning that the disease is polygenic and exhibits distinct subtypes driven by different genotype-phenotype mappings.  We suggest that the approach will enable the design of tailored experiments to identify multi-genic targets to address complex diseases.