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Investigating the shared genetic architecture between schizophrenia and body mass index

Molecular Psychiatry volume 28, pages 2312–2319 (2023)Cite this article

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Abstract

Evidence for reciprocal comorbidity of schizophrenia (SCZ) and body mass index (BMI) has grown in recent years. However, little is known regarding the shared genetic architecture or causality underlying the phenotypic association between SCZ and BMI. Leveraging summary statistics from the hitherto largest genome-wide association study (GWAS) on each trait, we investigated the genetic overlap and causal associations of SCZ with BMI. Our study demonstrated a genetic correlation between SCZ and BMI, and the correlation was more evident in local genomic regions. The cross-trait meta-analysis identified 27 significant SNPs shared between SCZ and BMI, most of which had the same direction of influence on both diseases. Mendelian randomization analysis showed the causal association of SCZ with BMI, but not vice versa. Combining the gene expression information, we found that the genetic correlation between SCZ and BMI is enriched in six regions of brain, led by the brain frontal cortex. Additionally, 34 functional genes and 18 specific cell types were found to have an impact on both SCZ and BMI within these regions. Taken together, our comprehensive genome-wide cross-trait analysis suggests a shared genetic basis including pleiotropic loci, tissue enrichment, and shared function genes between SCZ and BMI. This work provides novel insights into the intrinsic genetic overlap of SCZ and BMI, and highlights new opportunities and avenues for future investigation.

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Fig. 1: Overview of results of shared genetic architecture between SCZ and BMI.
Fig. 2: Local genetic correlation between SCZ and BMI.
Fig. 3: Partitioned genetic correlation between SCZ and BMI.
Fig. 4: Bi-directional Mendelian Randomization (MR) analyses between SCZ and BMI.
Fig. 5: Tissue specific enrichment of SNP heritability for SCZ and BMI.
Fig. 6: Overlap of significant genes associated with both SCZ and BMI in SMR in enriched tissues.

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Code availability

LDSC, Partition heritability: https://github.com/bulik/ldsc; ρ-HESS: https://huwenboshi.github.io/hess/local_rhog/; MTAG: https://github.com/JonJala/mtag; CPASSOC: https://github.com/futurologist/UKB_phenotypes_and_scripts/; Colocalization: https://github.com/chr1swallace/coloc/; PLINK: https://www.cog-genomics.org/plink/1.9; TwoSampleMR: https://mrcieu.github.io/TwoSampleMR/; Multi-tissue enrichment: https://github.com/bulik/ldsc/wiki/Cell-type-specific-analyses/; SMR: https://cnsgenomics.com/software/smr/; MAGMA: https://ctg.cncr.nl/software/magma/; FUMA: https://fuma.ctglab.nl/celltype/.

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Acknowledgements

We are grateful to all investigators who shared genome-wide summary statistics. This work was supported by the National Natural Science Foundation of China (82170870 and 82120108008), Shanghai Ninth People’s Hospital affiliated to Shanghai Jiao Tong University School of Medicine (YBKA201909), Shanghai Municipal Human Resources and Social Security Bureau (2020074), Clinical Research Plan of Shanghai Hospital Development Center (SHDC2020CR4006), and Innovative Research Team of High-level Local Universities in Shanghai (SHSMU-ZDCX20212501). The funders played no role in the design or conduction of the study; in the collection, management, analysis, or interpretation of the data; or in the preparation, review, or approval of the article.

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  1. These authors contributed equally: Yuefeng Yu, Yanqi Fu, Yuetian Yu.

Authors and Affiliations

  1. Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China

    Yuefeng Yu, Yanqi Fu, Yuetian Yu, Ying Sun, Yuying Wang, Kun Zhang, Huixia Li, Hui Guo, Bin Wang, Ningjian Wang & Yingli Lu

  2. The 967th Hospital of Joint Logistic Support Force of PLA, Dalian, China

    Mengjun Tang

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Contributions

BW and NW contributed to the concept and design. YL contributed technical and material support. YY, YF, YY wrote the manuscript, researched data, and reviewed/edited the manuscript. All authors contributed to data acquisition and reviewed/edited the manuscript. BW, NW, and YL revised it critically for important intellectual content. All authors approved the final version of the article for submission.

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Correspondence to Bin Wang, Ningjian Wang or Yingli Lu.

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Yu, Y., Fu, Y., Yu, Y. et al. Investigating the shared genetic architecture between schizophrenia and body mass index. Mol Psychiatry 28, 2312–2319 (2023). https://doi.org/10.1038/s41380-023-02104-0

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