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Genome-wide association study implicates lipid pathway dysfunction in antipsychotic-induced weight gain: multi-ancestry validation

Molecular Psychiatry (2024)Cite this article

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Abstract

Antipsychotic-induced weight gain (AIWG) is a common side effect of antipsychotic medication and may contribute to diabetes and coronary heart disease. To expand the unclear genetic mechanism underlying AIWG, we conducted a two-stage genome-wide association study in Han Chinese patients with schizophrenia. The study included a discovery cohort of 1936 patients and a validation cohort of 534 patients, with an additional 630 multi-ancestry patients from the CATIE study for external validation. We applied Mendelian randomization (MR) analysis to investigate the relationship between AIWG and antipsychotic-induced lipid changes. Our results identified two novel genome-wide significant loci associated with AIWG: rs10422861 in PEPD (P = 1.373 × 10–9) and rs3824417 in PTPRD (P = 3.348 × 10–9) in Chinese Han samples. The association of rs10422861 was validated in the European samples. Fine-mapping and functional annotation revealed that PEPD and PTPRD are potentially causal genes for AIWG, with their proteins being prospective therapeutic targets. Colocalization analysis suggested that AIWG and type 2 diabetes (T2D) shared a causal variant in PEPD. Polygenic risk scores (PRSs) for AIWG and T2D significantly predicted AIWG in multi-ancestry samples. Furthermore, MR revealed a risky causal effect of genetically predicted changes in low-density lipoprotein cholesterol (P = 7.58 × 10−4) and triglycerides (P = 2.06 × 10−3) caused by acute-phase of antipsychotic treatment on AIWG, which had not been previously reported. Our model, incorporating antipsychotic-induced lipid changes, PRSs, and clinical predictors, significantly predicted BMI percentage change after 6-month antipsychotic treatment (AUC = 0.79, R2 = 0.332). Our results highlight that the mechanism of AIWG involves lipid pathway dysfunction and may share a genetic basis with T2D through PEPD. Overall, this study provides new insights into the pathogenesis of AIWG and contributes to personalized treatment of schizophrenia.

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Fig. 1: Identification of PEPD and PTPRD SNPs associated with antipsychotic-induced weight gain (AIWG).
Fig. 2: Polygenic risk score (PRS) and lipid profile predictors for antipsychotic-induced weight gain (AIWG).
Fig. 3: Exploring precision psychiatry approaches for antipsychotic-induced weight gain (AIWG): prediction model and drug candidate targets.

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Data availability

NIMH REPOSITORY & GENOMICS RESOURCE approved the individual data from the CATIE study to the present study (https://www.nimhgenetics.org/, Requested ID: 63084551a4921). GWAS summary data on the association between SNPs and East Asian T2D was retrieved from the website https://blog.nus.edu.sg/agen/summary-statistics/t2d-2020. Summary statistics for the 912,253 SNP-protein expression pairs in the ROSMAP pQTL dataset are based on data obtained from the AD Knowledge Portal (https://adknowledgeportal.org), which can be found at https://www.synapse.org/#!Synapse:syn23191787. The other datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (81825009, 82330042, 82301687, 81901358); National Key R&D Program of China (2023YFE0119400, 2021YFF1201103); Fundamental Research Funds for the Central Universities (Peking University Medicine Fund for world’s leading discipline or discipline cluster development, BMU2022DJXK007); Chinese Academy of Medical Sciences Research Unit (2019-I2M-5-006, 2021-I2M-C&T-B-099), Collaborative Research Fund of Chinese Institute for Brain Research Beijing (grant 2020-NKX-XM-12); Major science and technology projects of Henan Province (201300310200); Natural Science Foundation of Shandong Province (ZR2019BH001 and ZR2021YQ55), and Young Taishan Scholars of Shandong Province (tsqn201909146). We thank all subjects who participated in our study. We also thank the assistance from the Chinese Antipsychotics Pharmacogenomics Consortium and the research assistant from Peking University Sixth Hospital (Xuan Lu).

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  1. These authors contributed equally: Yundan Liao, Hao Yu.

Authors and Affiliations

  1. Peking University Sixth Hospital, Peking University Institute of Mental Health, Beijing, 100191, China

    Yundan Liao, Yuyanan Zhang, Zhe Lu, Yaoyao Sun, Liangkun Guo, Jing Guo, Zhewei Kang, Xiaoyang Feng, Tianlan Lu, Hao Yan, Dai Zhang & Weihua Yue

  2. National Clinical Research Center for Mental Disorders (Peking University Sixth Hospital), Beijing, 100191, China

    Yundan Liao, Yuyanan Zhang, Zhe Lu, Yaoyao Sun, Liangkun Guo, Jing Guo, Zhewei Kang, Xiaoyang Feng, Tianlan Lu, Hao Yan, Dai Zhang & Weihua Yue

  3. NHC Key Laboratory of Mental Health (Peking University), Beijing, 100191, China

    Yundan Liao, Yuyanan Zhang, Zhe Lu, Yaoyao Sun, Liangkun Guo, Jing Guo, Zhewei Kang, Xiaoyang Feng, Tianlan Lu, Hao Yan, Dai Zhang & Weihua Yue

  4. Department of Psychiatry, Jining Medical University, Jining, Shandong, 272067, China

    Hao Yu

  5. No.5 Hospital, Tangshan, Hebei, 063000, China

    Yutao Sun

  6. The Second Affiliated Hospital of Jining Medical College, Jining, 272051, China

    Guishan Wang & Zhonghua Su

  7. The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453002, Henan, China

    Yongfeng Yang, Wenqiang Li & Luxian Lv

  8. Chinese Institute for Brain Research, Beijing, 102206, China

    Dai Zhang & Weihua Yue

  9. Institute for Brain Research and Rehabilitation (IBRR), Guangdong Key Laboratory of Mental Health and Cognitive Science, South China Normal University, Guangzhou, 510631, China

    Dai Zhang

  10. PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, 100871, China

    Weihua Yue

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  1. Yundan Liao
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Contributions

WY, YL, and HYu conceived and designed the project. YL and HYu contributed to the analysis and interpretation of data and wrote the manuscript. YL, HYu, and YZ did the statistical analyses and prepared the tables and figures. ZL, YaoS, LG, JG, ZK, and XF verified the results. WY, YZ, and DZ edited the manuscript and provided supervision. TL, YY, WL, LL, and HYa contributed to the data acquisition. YuS, GW, and ZS made the further interpretation of data. All authors contributed to drafting the work or critically revising it for important intellectual content and made substantial contributions to the concept and design of the study and data acquisition, analysis, and interpretation.

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Correspondence to Yuyanan Zhang or Weihua Yue.

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Liao, Y., Yu, H., Zhang, Y. et al. Genome-wide association study implicates lipid pathway dysfunction in antipsychotic-induced weight gain: multi-ancestry validation. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02447-2

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  • DOI: https://doi.org/10.1038/s41380-024-02447-2

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