Genome-wide association studies (GWASs) generally focus on a single marker, which limits the elucidation of the genetic architecture of complex traits. Herein, we present a new computational framework, termed probabilistic natural mapping (PALM), for performing gene-level association tests. PALM robustly reveals the inherent genomic structures of genes and generates feature representations that can be seamlessly incorporated into conventional statistic tests. Our approach substantially improves the effectiveness of uncovering associations derived from a subgroup of variants with weak effects, which represents a known challenge associated with existing methods. We applied PALM in a gastric cancer GWAS and identified two additional gastric cancer-associated susceptibility genes, NOC3L and RUNDC2A. The robust susceptibility discoveries of PALM are widely supported by existing studies from other biological perspectives. PALM will be useful for further GWAS analytical strategies that use gene-level analyses.

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