The morphometry of left cuneus mediating the genetic regulation on working memory

Working memory is a basic human cognitive function. However, the genetic signatures and their biological pathway remain poorly understood. In the present study, we tried to clarify this issue by exploring the potential associations and pathways among genetic variants, brain morphometry and working memory performance. We first carried out association analyses between 2-back accuracy and 212 image-derived phenotypes from 1141 Human Connectome Project (HCP) subjects using a linear mixed model (LMM). We found a significantly positive correlation between the left cuneus volume and 2-back accuracy (T = 3.615, p = 3.150e-4, Cohen's d = 0.226, corrected using family-wise error [FWE] method). Based on the LMM-based genome-wide association study (GWAS) on the HCP dataset and UK Biobank 33 k GWAS summary statistics, we identified eight independent single nucleotide polymorphisms (SNPs) that were reliably associated with left cuneus volume in both UKB and HCP dataset. Within the eight SNPs, we found a negative correlation between the rs76119478 polymorphism and 2-back accuracy accuracy (T = -2.045, p = .041, Cohen's d = -0.129). Finally, an LMM-based mediation analysis elucidated a significant effect of left cuneus volume in mediating rs76119478 polymorphism on the 2-back accuracy (indirect effect = -0.007, 95% BCa CI = [-0.045, -0.003]). These results were also replicated in a subgroup of Caucasians in the HCP population. Further fine mapping demonstrated that rs76119478 maps on intergene CTD-2315A10.2 adjacent to protein-encoding gene DAAM1, and is significantly associated with L3HYPDH mRNA expression. Our study suggested this new variant rs76119478 may regulate the working memory through exerting influence on the left cuneus volume.