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

• DOI: 10.1186/s13034-022-00536-0
• Publication Date: 2023-01-06T17:02:57Z
• Authors: Xingguang Luo; 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
• Keywords: Genotype; Cognitive Neuroscience; RC435-571; Analysis of Brain Functional Connectivity Networks; Pediatrics; Molecular Mechanisms of Neurodegenerative Diseases; Gene; Gray matter volume (GMV); RJ1-570; Attention deficit hyperactivity disorder; Cellular and Molecular Neuroscience; 03 medical and health sciences; 0302 clinical medicine; Health Sciences; Genetics; ADHD; Psychology; Attention-Deficit/Hyperactivity Disorder; Biology; Internal medicine; KTN1; Allele; Single-nucleotide polymorphism; Psychiatry; Research; Cohort; Life Sciences; FOS: Psychology; Psychiatry and Mental health; FOS: Biological sciences; Cortex; Basal ganglia; Medicine; ABCD; Neuroscience

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 ADHD risk. In this study, we aimed identify sex-specific, replicable risk alleles for explore their regulatory effects on mRNA expression GMVs. We examined a total 1020 SNPs in one discovery sample (ABCD cohort: 5573 males 5082 females) three independent replication European samples (Samples #1 #2 each 802/122 472/141 male/female offspring ADHD; Sample #3 14,154/4945 17,948/16,246 healthy males/females) associations within sex. the ADHD-risk two brain cohorts (n = 348), intracranial volume (TIV) 46 18,713) ABCD cohort, as well seven structures 50 38,258) 118 regions cohort. found that four variants regulated same direction effect across (0.003 ≤ p 0.041), but none females. All decreased all (1.2 × 10 –5 0.039). increased basal ganglia (2.8 –22 0.040) hippocampus (p 0.010) reduced amygdala GMV 0.030) TIV (0.010 < 0.013). also some (right superior temporal pole, right rectus) cerebellar other (0.007 0.050) To conclude, identified set functional ADHD, specifically males. may play critical role pathogenesis specific subcortical, including amygdalar not or hippocampal, serve neural marker genetic effects.