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Identification of Novel Risk Loci with Shared Effects on Alcoholism, Heroin and Methamphetamine Dependence

39 Pages Posted: 28 Jan 2019

See all articles by Yan Sun

Yan Sun

Peking University - National Institute on Drug Dependence

Suhua Chang

Peking University - Institute of Mental Health

Zhen Liu

Peking University - National Institute on Drug Dependence

Libo Zhang

Peking University - National Institute on Drug Dependence

Fan Wang

Xinjiang Medical University

Weihua Yue

Peking University - National Clinical Research Center for Mental Disorders

Hongqiang Sun

Peking University - National Clinical Research Center for Mental Disorders

Zhaojun Ni

Peking University - National Clinical Research Center for Mental Disorders

Xiangwen Chang

Peking University - National Institute on Drug Dependence

Yibin Zhang

Peking University - National Institute on Drug Dependence

Yang Chen

Peking University - National Institute on Drug Dependence

Lin Lu

Peking University - National Institute on Drug Dependence

Jie Shi

Peking University - National Institute on Drug Dependence; Beijing Key Laboratory on Drug Dependence Research

More...

Abstract

Background: Different substances dependences have similar effects on reward pathway and molecular adaptations, but little is known about their shared genetic factors. We aimed to identify the common risk genetic variants of major substance dependences.  

Methods: We first conducted a combined genome-wide association analysis in 3296 substance patients (521 alcoholic/1026 heroin/1749 methamphetamine) and 2859 healthy controls, then validated in an independent cohort (1954 patients and 1904 controls). The effects of loci on gene expression was examined by e-QTL using UK Brain Expression data. Association between polygenetic risk and heroin characterizes were analyzed by a linear regression model. Among the subset with magnetic resonance imaging data, the genetic effects on brain were analyzed. The genetic modulation on addiction behaviors were assessed both in self-administration and daily administration rats of heroin and methamphetamine.  

Findings: We identified and confirmed three novel loci that was associated with the common risk of heroin, methamphetamine addiction and alcoholism at genome-wide significant level: ANKS1B rs2133896 (Pmeta=3.60×10-9 ), AGBL4 rs147247472 (Pmeta=3.40×10-12) and CTNNA2 rs10196867 (Pmeta=4.73×10-9 ). Rs2133896 in ANKS1B was associated with gene expression of ANKS1B, and has effects on the use frequency, gray matter of the left calcarine and white matter of the right superior longitudinal fasciculus of heroin dependence. Besides, the reduced anks1b expression in the ventral tegmental area increased addiction vulnerability for heroin and methamphetamine in self-administration rat models.  

Interpretation: Our findings could shed light on the root cause for substance dependence and be helpful for the development of cost-effective prevention strategies for general addiction disorders.  

Funding Statement: This work was supported by grants from the National Basic Research Program of China (No. 2015CB553503), the National Natural Science Foundation of China (No. U180220091, 81821092, 81601165), the National Key Research and Development Program of China (No. 2017YFC0803608 and No. 2017YFC0803609), Beijing Municipal Science & Technology Commission (Z181100001518005), and Youth Elite Scientists Sponsorship Program by CASR (No. CSTQT2017002).

Declaration of Interests: The authors declare no competing financial interests.

Ethics Approval Statement: This study was approved by the Peking University Institutional Review Board and was performed in accordance with the relevant guidelines and regulations. All individuals signed a written informed consent form and were paid for their participation.

Keywords: genome-wide association study (GWAS); common genetic risk factors; alcoholism; heroin; methamphetamine; ANKS1B rs2133896; imaging; self-administration rat models

Suggested Citation

Sun, Yan and Chang, Suhua and Liu, Zhen and Zhang, Libo and Wang, Fan and Yue, Weihua and Sun, Hongqiang and Ni, Zhaojun and Chang, Xiangwen and Zhang, Yibin and Chen, Yang and Lu, Lin and Shi, Jie, Identification of Novel Risk Loci with Shared Effects on Alcoholism, Heroin and Methamphetamine Dependence (January 26, 2019). Available at SSRN: https://ssrn.com/abstract=3323117

Yan Sun

Peking University - National Institute on Drug Dependence

Beijing
China

Suhua Chang

Peking University - Institute of Mental Health

China

Zhen Liu

Peking University - National Institute on Drug Dependence

Beijing
China

Libo Zhang

Peking University - National Institute on Drug Dependence

Beijing
China

Fan Wang

Xinjiang Medical University

393 Xinyi Rd, Xinshi Qu
Wulumuqi Shi
Xinjiang Weiwuerzizhiqu, 830011
China

Weihua Yue

Peking University - National Clinical Research Center for Mental Disorders

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Hongqiang Sun

Peking University - National Clinical Research Center for Mental Disorders

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Zhaojun Ni

Peking University - National Clinical Research Center for Mental Disorders

No. 38 Xueyuan Road
Haidian District
Beijing, Beijing 100871
China

Xiangwen Chang

Peking University - National Institute on Drug Dependence

Beijing
China

Yibin Zhang

Peking University - National Institute on Drug Dependence

Beijing
China

Yang Chen

Peking University - National Institute on Drug Dependence

Beijing
China

Lin Lu

Peking University - National Institute on Drug Dependence

Beijing
China

Jie Shi (Contact Author)

Peking University - National Institute on Drug Dependence ( email )

Beijing
China

Beijing Key Laboratory on Drug Dependence Research ( email )

Beijing
China

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