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A significant, functional and replicable risk KTN1 variant block for schizophrenia

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作者：
Mao Qiao[1] * ; Lin Xiandong[2] * ; Yin Qin[3] * ; Liu Ping[1] ; Zhang Yong[4] ; Qu Shihao[5] ; Xu Jianying[5] ; Cheng Wenhong[6] ; Luo Xinqun[7] ; Kang Longli[8] ; Taximaimaiti Reyisha[9] ; Zheng Chengchou[10] ; Zhang Huihao[11] ; Wang Xiaoping[17] ; Ren Honggang[12] ; Cao Yuping[13] ; Lin Jie[14,15] ; Luo Xingguang[16] ;
机构： [1]Department of Psychosomatic Medicine, People's Hospital of Deyang City, Deyang, 618000, Sichuan, China. [2]Laboratory of Radiation Oncology and Radiobiology, Fujian Provincial Cancer Hospital, the Teaching Hospital of Fujian Medical University, Fuzhou, 350014, Fujian, China. [3]Department of Respiratory and Critical Care Medicine, Hubei Provincial Hospital of Integrated Chinese and Western Medicine, Wuhan, 430000, Hubei, China. [4]Tianjin Mental Health Center, Tianjin, 300222, China. [5]Zhuhai Center for Maternal and Child Health Care, Zhuhai, Guangdong, 519001, China. [6]Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200030, China. [7]Department of Neurosurgery, The First Hospital, Fujian Medical University, Fuzhou, 350004, Fujian, China. [8]Key Laboratory for Molecular Genetic Mechanisms and Intervention Research On High Altitude Diseases of Tibet Autonomous Region, Xizang Minzu University School of Medicine, Xiangyang, 712082, Shaanxi, China. [9]Department of Neurology, Shanghai Tongren Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China. [10]Minqing Psychiatric Hospital, Minqing, 350800, Fujian, China. [11]The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350001, China. [12]Department of Neurology, The 1st People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 201620, USA. [13]Department of Internal Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [14]Department of Psychiatry, Second Xiangya Hospital, Central South University, China National Clinical Research Center On Mental Disorders, China National Technology Institute On Mental Disorders, Changsha, 410011, Hunan, China. caoyp001@csu.edu.cn. [15]Fujian Center for Disease Control and Prevention, Fuzhou, 350012, Fujian, China. 108912906@qq.com. [16]Fujian Institute of Preventive Medicine, Fuzhou, 350012, Fujian, China. 108912906@qq.com. [17]Beijing Huilongguan Hospital, Peking University Huilongguan School of Clinical Medicine, Beijing, 100096, China. Xingguang.Luo@yale.edu.
出处：
DOI： 10.1038/s41598-023-27448-z
ISSN：

摘要：
Cortical and subcortical structural alteration has been extensively reported in schizophrenia, including the unusual expansion of gray matter volumes (GMVs) of basal ganglia (BG), especially putamen. Previous genome-wide association studies pinpointed kinectin 1 gene (KTN1) as the most significant gene regulating the GMV of putamen. In this study, the role of KTN1 variants in risk and pathogenesis of schizophrenia was explored. A dense set of SNPs (n = 849) covering entire KTN1 was analyzed in three independent European- or African-American samples (n = 6704) and one mixed European and Asian Psychiatric Genomics Consortium sample (n = 56,418 cases vs. 78,818 controls), to identify replicable SNP-schizophrenia associations. The regulatory effects of schizophrenia-associated variants on the KTN1 mRNA expression in 16 cortical or subcortical regions in two European cohorts (n = 138 and 210, respectively), the total intracranial volume (ICV) in 46 European cohorts (n = 18,713), the GMVs of seven subcortical structures in 50 European cohorts (n = 38,258), and the surface areas (SA) and thickness (TH) of whole cortex and 34 cortical regions in 50 European cohorts (n = 33,992) and eight non-European cohorts (n = 2944) were carefully explored. We found that across entire KTN1, only 26 SNPs within the same block (r2 > 0.85) were associated with schizophrenia across ≥ 2 independent samples (7.5 × 10-5 ≤ p ≤ 0.048). The schizophrenia-risk alleles, which increased significantly risk for schizophrenia in Europeans (q < 0.05), were all minor alleles (f < 0.5), consistently increased (1) the KTN1 mRNA expression in 12 brain regions significantly (5.9 × 10-12 ≤ p ≤ 0.050; q < 0.05), (2) the ICV significantly (6.1 × 10-4 ≤ p ≤ 0.008; q < 0.05), (3) the SA of whole (9.6 × 10-3 ≤ p ≤ 0.047) and two regional cortices potentially (2.5 × 10-3 ≤ p ≤ 0.042; q > 0.05), and (4) the TH of eight regional cortices potentially (0.006 ≤ p ≤ 0.050; q > 0.05), and consistently decreased (1) the BG GMVs significantly (1.8 × 10-19 ≤ p ≤ 0.050; q < 0.05), especially putamen GMV (1.8 × 10-19 ≤ p ≤ 1.0 × 10-4; q < 0.05, (2) the SA of four regional cortices potentially (0.010 ≤ p ≤ 0.048), and (3) the TH of four regional cortices potentially (0.015 ≤ p ≤ 0.049) in Europeans. We concluded that we identified a significant, functional, and robust risk variant block covering entire KTN1 that might play a critical role in the risk and pathogenesis of schizophrenia.© 2023. The Author(s).

基金：
We thank NIH GWAS Data Repository, the Contributing Investigator(s) who contributed the phenotype and genotype data from his/her original study (e.g., Drs. Suarez BK, Gejman PV, Manolio TA, Collins FS, Sanders AR, O’Donovan MC, Cloninger CR, Owen MJ, Sklar P, Stefansson H, Collier DA, Fromer M, Purcell SM, Kirov G, etc.), and the primary funding organization that supported the contributing study. Funding and other supports for phenotype and genotype data were provided through the National Institutes of Health (NIH) [R01 MH67257, R01 MH59588, R01 MH59571, R01 MH59565, R01 MH59587, R01 MH60870, R01 MH59566, R01 MH59586, R01 MH61675, R01 MH60879, R01 MH81800, U01 MH46276, U01 MH46289 U01 MH46318, U01 MH79469, and U01 MH79470], the Broad Institute (Fidelity Foundations, the Sylvan Herman Foundation and philanthropic gifts from Kent and Liz Dauten, Ted and Vada Stanley, and an anonymous donor to the Stanley Center for Psychiatric Research), Cardiff University (Medical Research Council (MRC) Centre (G0800509) and Program Grants (G0801418), the European Community’s Seventh Framework Programme (HEALTH-F2-2010-241909 (Project EU-GEI)), Icahn School of Medicine at Mount Sinai (Friedman Brain Institute, the Institute for Genomics and Multiscale Biology and National Institutes of Health grants R01HG005827 (SMP) and R01MH071681 (PS)), the Wellcome Trust Sanger Institute (The Wellcome Trust (WT089062 and WT098051)), the Janssen Research Foundation, and the Genetic Association Information Network (GAIN).
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外文
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出版当年[2022]版：
大类 | 3 区 综合性期刊
小类 | 3 区 综合性期刊
最新[2023]版：
大类 | 2 区 综合性期刊
小类 | 2 区 综合性期刊
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出版当年[2021]版：
Q2 MULTIDISCIPLINARY SCIENCES
最新[2023]版：
Q1 MULTIDISCIPLINARY SCIENCES

影响因子： 最新[2023版] 最新五年平均 出版当年[2021版] 出版当年五年平均 出版前一年[2020版] 出版后一年[2022版]

第一作者：
第一作者机构： [1]Department of Psychosomatic Medicine, People's Hospital of Deyang City, Deyang, 618000, Sichuan, China.
共同第一作者：
通讯作者：
通讯机构： [14]Department of Psychiatry, Second Xiangya Hospital, Central South University, China National Clinical Research Center On Mental Disorders, China National Technology Institute On Mental Disorders, Changsha, 410011, Hunan, China. caoyp001@csu.edu.cn. [15]Fujian Center for Disease Control and Prevention, Fuzhou, 350012, Fujian, China. 108912906@qq.com.
推荐引用方式(GB/T 7714)：
Mao Qiao,Lin Xiandong,Yin Qin,et al.A significant, functional and replicable risk KTN1 variant block for schizophrenia[J].SCIENTIFIC REPORTS.2023,13(1):doi:10.1038/s41598-023-27448-z.
APA：
Mao Qiao,Lin Xiandong,Yin Qin,Liu Ping,Zhang Yong...&Luo Xingguang.(2023).A significant, functional and replicable risk KTN1 variant block for schizophrenia.SCIENTIFIC REPORTS,13,(1)
MLA：
Mao Qiao,et al."A significant, functional and replicable risk KTN1 variant block for schizophrenia".SCIENTIFIC REPORTS 13..1(2023)

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