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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\u2010back accuracy and 212 image\u2010derived 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\u2010back accuracy (<jats:italic>T<\/jats:italic>\u00a0=\u00a03.615, <jats:italic>p<\/jats:italic>\u00a0=\u00a03.150e\u22124, Cohen's <jats:italic>d<\/jats:italic>\u00a0=\u00a00.226, corrected using family\u2010wise error [FWE] method). Based on the LMM\u2010based genome\u2010wide association study (GWAS) on the HCP dataset and UK Biobank 33\u2009k 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\u2010back accuracy accuracy (<jats:italic>T<\/jats:italic>\u00a0=\u00a0\u22122.045, <jats:italic>p<\/jats:italic>\u00a0=\u00a0.041, Cohen's <jats:italic>d<\/jats:italic>\u00a0=\u00a0\u22120.129). Finally, an LMM\u2010based mediation analysis elucidated a significant effect of left cuneus volume in mediating rs76119478 polymorphism on the 2\u2010back accuracy (indirect effect\u00a0=\u00a0\u22120.007, 95% BCa CI\u00a0=\u00a0[\u22120.045, \u22120.003]). These results were also replicated in a subgroup of Caucasians in the HCP population. Further fine mapping demonstrated that rs76119478 maps on intergene CTD\u20102315A10.2 adjacent to protein\u2010encoding 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.<\/jats:p>","DOI":"10.1002\/hbm.25446","type":"journal-article","created":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T17:05:23Z","timestamp":1620061523000},"page":"3470-3480","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["The morphometry of left cuneus mediating the genetic regulation on working memory"],"prefix":"10.1002","volume":"42","author":[{"given":"Xiaoxi","family":"He","sequence":"first","affiliation":[{"name":"Department of Radiology Tianjin Medical University Cancer Institute and Hospital  Tianjin China"},{"name":"National Clinical Research Center for Cancer  Tianjin China"},{"name":"Key Laboratory of Cancer Prevention and Therapy  Tianjin China"},{"name":"Tianjin's Clinical Research Center for Cancer  Tianjin China"},{"name":"Department of Radiology and Tianjin 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