DDR1-WWC1 complex is associated with human cognition

The WWC1 (KIBRA) gene has been repeatedly implicated in cognitive performance, with carriers of the favorable allele showing enhanced episodic memory, spatial ability, and achievements in chess and STEM fields. However, gene-level associations do not reveal the underlying biological mechanisms. Here, we applied a modern proteomic assay coupled with an AI-based protein complex quantification method to elucidate the protein interaction phenotype involving WWC1 in a Scottish cohort (Viking Genes; N = 200). Although the bulk plasma level of WWC1 was not significantly associated with cognitive g factor, several WWC1-containing protein complexes, including the DDR1-WWC1 and the DDR1-PRKCZ-WWC1 complex scores, demonstrated significant associations with cognitive performance. In particular, one standard deviation increase in the normalized DDR1-WWC1 complex score corresponded to about 14% decrease in cognitive g factor (P = 0.024), even with educational attainment adjusted. These findings validate previous genetic studies and highlight the importance of protein-protein interactions in mediating the cognitive effects of WWC1.