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

Child and Adolescent Psychiatry and Mental Health

Research

Ting Yu¹  Zhiren Wang¹  Leilei Wang¹  Yunlong Tan¹  Xingguang Luo²  Xiaozhong Jing³  Reyisha Taximaimaiti³  Xiaoping Wang³  Xinqun Luo⁴  Yuping Cao⁵  Yu Chen⁶  Jaime S. Ide⁶  Chiang-Shan R. Li⁷  Xiandong Lin⁸  Jianming Zheng⁹  Wenhong Cheng^1,10  Yong Zhang^1,11  Jianying Xu^1,12 

[1] Beijing Huilongguan Hospital, Peking University Huilongguan Clinical School of Medicine, 100096, Beijing, China;Beijing Huilongguan Hospital, Peking University Huilongguan Clinical School of Medicine, 100096, Beijing, China;Department of Psychiatry, Yale University School of Medicine, 06510, New Haven, CT, USA;Department of Neurology, Shanghai First People’s Hospital, Shanghai Jiao Tong University, 200080, Shanghai, China;Department of Neurosurgery, The First Affiliated Hospital, Fujian Medical University, 350004, Fuzhou, Fujian, China;Department of Psychiatry, Second Xiangya Hospital, Central South University; China National Clinical Research Center On Mental Disorders, China National Technology Institute On Mental Disorders, 410011, Changsha, Hunan, China;Department of Psychiatry, Yale University School of Medicine, 06510, New Haven, CT, USA;Department of Psychiatry, Yale University School of Medicine, 06510, New Haven, CT, USA;Department of Neuroscience, Yale University School of Medicine, 06510, New Haven, CT, USA;Wu Tsai Institute, Yale University, 06510, New Haven, CT, USA;Laboratory of Radiation Oncology and Radiobiology, Fujian Medical University Cancer Hospital and Fujian Cancer Hospital, 350014, Fuzhou, China;National Medical Center for Infectious Diseases, Huashan Hospital, Fudan University School of Medicine, 200030, Shanghai, China;Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, 200030, Shanghai, China;Tianjin Mental Health Center, 300222, Tianjin, China;Zhuhai Center for Maternal and Child Health Care, 519000, Zhuhai, Guangdong, China;

关键词: KTN1;    ADHD;    ABCD;    Cortex;    Basal ganglia;    Gray matter volume (GMV);   

DOI  :  10.1186/s13034-022-00536-0

 received in 2022-10-14, accepted in 2022-11-23,  发布年份 2022

来源: Springer

【 摘 要 】

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-risk alleles significantly increased basal ganglia (2.8 × 10–22 ≤ p ≤ 0.040) and hippocampus (p = 0.010) GMVs but reduced amygdala GMV (p = 0.030) and TIV (0.010 < p ≤ 0.013). The ADHD-risk alleles also significantly reduced some cortical (right superior temporal pole, right rectus) and cerebellar but increased other cortical (0.007 ≤ p ≤ 0.050) GMVs. To conclude, we identified a set of replicable and functional risk KTN1 alleles for ADHD, specifically in males. KTN1 may play a critical role in the pathogenesis of ADHD, and the reduction of specific cortical and subcortical, including amygdalar but not basal ganglia or hippocampal, GMVs may serve as a neural marker of the genetic effects.

【 授权许可】

CC BY   
© The Author(s) 2023