Novel Genes Associated with Working Memory Are Identified by Combining Connectome, Transcriptome, and Genome

Working memory (WM) plays a crucial role in human cognition. Previous candidate and genome-wide association studies have reported many genetic variations associated with WM. However, little research has examined genetic basis of WM by using transcriptome, even though it reflects gene function more directly than does the genome. Here we propose a new approach to exploring the genetic mechanisms of WM by integrating connectome, transcriptome, and genome data in a high-quality dataset comprising 481 Chinese healthy adults. First, relevance vector regression was used to define WM-related brain regions. Second, genes differentially expressed within these regions were identified using the Allen Human Brain Atlas (AHBA) dataset. Finally, two independent datasets were used to validate these genes' contributions to WM. With this method, we identified 24 novel genes and 20 of them were confirmed in the large-scale datasets of ABCD and UK Biobank. These novel genes were enriched in the cellular component of collagen-containing extracellular matrix and the CCL18 signaling pathway. Our method offers an effective approach to integrating multimodal gene discovery and demonstrates the superiority of expression data. This new method and the newly identified genes deserve more attention in the future.