A novel risk variant block across introns 36–45 of CACNA1C for schizophrenia: a cohort-wise replication and cerebral region-wide validation study

Author:

Guo Xiaoyun1,Wang Shibin1,Lin Xiandong2,Wang Zuxing3,Dou Yikai45,Cao Yuping6,Zhang Yong7,Luo Xinqun8,Kang Longli9,Yu Ting10,Wang Zhiren10,Tan Yunlong10,Gao Shenshen11,Zheng Hangxiao1,Zhao Fen1,Wang Huifen1,Wang Kesheng12,Xie Fan1,Chen Wenzhong1,Luo Xinguang1013

Affiliation:

1. Department of Psychiatry, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai

2. Laboratory of Radiation Oncology and Radiobiology, Department of Radiation Oncology, Fujian Provincial Cancer Hospital, The Teaching Hospital of Fujian Medical University, Fuzhou, Fujian

3. Department of Psychiatry, Sichuan Provincial Center for Mental Health, Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital

4. Department of Psychiatry, Mental Health Center and Psychiatric Laboratory, the State Key Laboratory of Biotherapy, West China Hospital of Sichuan University

5. Huaxi Brain Research Center, Department of Psychiatry, West China Hospital of Sichuan University, Chengdu

6. Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, Hunan

7. Department of Psychiatry, Tianjin Mental Health Center, Tianjin

8. Department of Clinical Medicine, College of Integrated Traditional Chinese and Western Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian

9. Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Diseases of Tibet Autonomous Region, Department of Genetics, Xizang Minzu University School of Medicine, Xiangyang, Shaanxi

10. Department of Biological Psychiatry, Beijing Huilongguan Hospital, Peking University Huilongguan School of Clinical Medicine, Beijing

11. Department of Clinical Research, Shanghai Shenkang Hospital Development Center established the Clinical Research and Development Center of Shanghai Municipal Hospitals, Shanghai, China

12. Department of Family and Community Health, School of Nursing, Health Sciences Center, West Virginia University, Morgantown, West Virginia and

13. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA

Abstract

Objectives Numerous genome-wide association studies have identified CACNA1C as one of the top risk genes for schizophrenia. As a necessary post-genome-wide association study (GWAS) follow-up, here, we focused on this risk gene, carefully investigated its novel risk variants for schizophrenia, and explored their potential functions. Methods We analyzed four independent samples (including three European and one African-American) comprising 5648 cases and 6936 healthy subjects to identify replicable single nucleotide polymorphism-schizophrenia associations. The potential regulatory effects of schizophrenia-risk alleles on CACNA1C mRNA expression in 16 brain regions (n = 348), gray matter volumes (GMVs) of five subcortical structures (n = 34 431), and surface areas and thickness of 34 cortical regions (n = 36 936) were also examined. Results A novel 17-variant block across introns 36–45 of CACNA1C was significantly associated with schizophrenia in the same effect direction across at least two independent samples (1.8 × 10−4 ≤ P ≤ 0.049). Most risk variants within this block showed significant associations with CACNA1C mRNA expression (1.6 × 10−3 ≤ P ≤ 0.050), GMVs of subcortical structures (0.016 ≤ P ≤ 0.048), cortical surface areas (0.010 ≤ P ≤ 0.050), and thickness (0.004 ≤ P ≤ 0.050) in multiple brain regions. Conclusion We have identified a novel and functional risk variant block at CACNA1C for schizophrenia, providing further evidence for the important role of this gene in the pathogenesis of schizophrenia.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Biological Psychiatry,Psychiatry and Mental health,Genetics (clinical),Genetics

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