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Identification of novel risk loci with shared effects on alcoholism, heroin, and methamphetamine dependence

Molecular Psychiatry volume 26, pages 1152–1161 (2021)Cite this article

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Abstract

Different substance dependences have common effects on reward pathway and molecular adaptations, however little is known regarding their shared genetic factors. We aimed to identify the risk genetic variants that are shared for substance dependence (SD). First, promising genome-wide significant loci were identified from 3296 patients (521 alcoholic/1026 heroin/1749 methamphetamine) vs 2859 healthy controls and independently replicated using 1954 patients vs 1904 controls. Second, the functional effects of promising variants on gene expression, addiction characteristics, brain structure (gray and white matter), and addiction behaviors in addiction animal models (chronic administration and self-administration) were assessed. In addition, we assessed the genetic correlation among the three SDs using LD score regression. We identified and replicated three novel loci that were associated with the common risk of heroin, methamphetamine addiction, and alcoholism: 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 ANKS1B gene expression and had effects on gray matter of the left calcarine and white matter of the right superior longitudinal fasciculus in heroin dependence. Overexpression of anks1b gene in the ventral tegmental area decreased addiction vulnerability for heroin and methamphetamine in self-administration rat models. Our findings could shed light on the root cause for substance dependence and will be helpful for the development of cost-effective prevention strategies for general addiction disorders.

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Acknowledgements

This work was supported by grants from the National Basic Research Program of China (2015CB553503), the National Natural Science Foundation of China (U180220091, 81821092, 81601165), the National Key Research and Development Program of China (2017YFC0803608, 2017YFC0803609, 2016YFC0800908), Beijing Municipal Science & Technology Commission (Z181100001518005 and Z161100002616006), and Youth Elite Scientists Sponsorship Program by CASR (CSTQT2017002). We are grateful to Beijing Compass Biotechnology Company for technical assistance with the microarray experiments.

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  1. These authors contributed equally: Yan Sun, Suhua Chang

Authors and Affiliations

  1. National Institute on Drug Dependence, Peking University, 100191, Beijing, China

    Yan Sun, Zhen Liu, Libo Zhang, Xiangwen Chang, Yibing Zhang, Yang Chen, Lin Lu & Jie Shi

  2. Peking University Sixth Hospital, Peking University Institute of Mental Health, NHC Key Laboratory of Mental Health (Peking University), National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Peking University, 100191, Beijing, China

    Suhua Chang, Weihua Yue, Hongqiang Sun, Zhaojun Ni & Lin Lu

  3. The Second Affiliated Hospital, Xinjiang Medical University, 830063, Urumqi, China

    Fan Wang

  4. Beijing Hui Long Guan Hospital, 100096, Beijing, China

    Fan Wang

  5. Beijing Compass Biotechnology Company, 102206, Beijing, China

    Jiqiang Liu

  6. Beijing Key Laboratory of Drug Dependence Research, Peking University, 100191, Beijing, China

    Jie Shi

  7. The State Key Laboratory of Natural and Biomimetic Drugs, Peking University, 100191, Beijing, China

    Jie Shi

  8. The Key Laboratory for Neuroscience of the Ministry of Education and Health, Peking University, 100191, Beijing, China

    Jie Shi

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Contributions

JS, YS, and SC designed the study and obtained financial support; YS, FW, WY, HS, ZN, and XC conducted cohort recruitment, collected biological samples, and phenotypic data. JL performed the genotype microarray experiments. SC and YS performed genetic data processing, statistical, and bioinformatics analysis. ZL performed the brain imaging analysis. LZ, YZ, and YC performed the animal and in vitro experiments. YS and SC drafted the manuscript. JS and LL supervised the experiments and data analysis. All authors critically reviewed the manuscript and approved the final version.

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Correspondence to Jie Shi.

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Sun, Y., Chang, S., Liu, Z. et al. Identification of novel risk loci with shared effects on alcoholism, heroin, and methamphetamine dependence. Mol Psychiatry 26, 1152–1161 (2021). https://doi.org/10.1038/s41380-019-0497-y

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