Identification of Novel Risk Loci with Shared Effects on Alcoholism, Heroin and Methamphetamine Dependence
39 Pages Posted: 28 Jan 2019More...
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
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