Male-specific, replicable and functional roles of genetic variants and cerebral gray matter volumes in ADHD: a gene-wide association study across KTN1 and a region-wide functional validation across brain

作者：Xingguang Luο, Xiandong Lin, Jaime S. Ide, Xinqun Luo, Yong Zhang, Jianying Xu, Leilei Wang, Yu Chen, Wenhong Cheng, Jianming Zheng, Zhiren Wang, Ting Yu, Reyisha Taximaimaiti, Xiaozhong Jing, Xiaoping Wang, Yuping Cao, Yunlong Tan, Chiang‐Shan R. Li · 发表于：Child and Adolescent Psychiatry and Mental Health · 年份：2023 · DOI：10.1186/s13034-022-00536-0 · 被引用次数：4 · 研究领域：Attention Deficit Hyperactivity Disorder、Functional Brain Connectivity Studies、Genetic Neurodegenerative Diseases

Abstract Attention deficit hyperactivity disorder (ADHD) is associated with reduction of cortical and subcortical gray matter volumes (GMVs). The kinectin 1 gene ( KTN1 ) has recently been reported to significantly regulate GMVs and ADHD risk. In this study, we aimed to identify sex-specific, replicable risk KTN1 alleles for ADHD and to explore their regulatory effects on mRNA expression and cortical and subcortical GMVs. We examined a total of 1020 KTN1 SNPs in one discovery sample (ABCD cohort: 5573 males and 5082 females) and three independent replication European samples (Samples #1 and #2 each with 802/122 and 472/141 male/female offspring with ADHD; and Sample #3 with 14,154/4945 ADHD and 17,948/16,246 healthy males/females) to identify replicable associations within each sex. We examined the regulatory effects of ADHD-risk alleles on the KTN1 mRNA expression in two European brain cohorts (n = 348), total intracranial volume (TIV) in 46 European cohorts (n = 18,713) and the ABCD cohort, as well as the GMVs of seven subcortical structures in 50 European cohorts (n = 38,258) and of 118 cortical and subcortical regions in the ABCD cohort. We found that four KTN1 variants significantly regulated the risk of ADHD with the same direction of effect in males across discovery and replication samples (0.003 ≤ p ≤ 0.041), but none in females. All four ADHD-risk alleles significantly decreased KTN1 mRNA expression in all brain regions examined (1.2 × 10 –5 ≤ p ≤ 0.039). The ADHD-ri...