Gut microbial diversity moderates polygenic risk of schizophrenia

Liyuan Zhang; Xiuxia Yuan; Xue Li; Xiaoyun Zhang; Yiqiao Mao; Shaohua Hu; Ole A Andreassen; Yunpeng Wang; Xueqin Song

doi:10.3389/fpsyt.2024.1275719

Gut microbial diversity moderates polygenic risk of schizophrenia

Front Psychiatry. 2024 Feb 1:15:1275719. doi: 10.3389/fpsyt.2024.1275719. eCollection 2024.

Authors

Liyuan Zhang^{1

2

3}, Xiuxia Yuan^{1

2

3}, Xue Li^{1

2

3}, Xiaoyun Zhang^{1

2

3}, Yiqiao Mao⁴, Shaohua Hu⁵, Ole A Andreassen⁶, Yunpeng Wang⁷, Xueqin Song^{1

2

3}

Affiliations

¹ Department of Psychiatry, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
² Henan International Joint Laboratory of Biological Psychiatry, Zhengzhou University, Zhengzhou, China.
³ Henan Psychiatric Transformation Research Key Laboratory, Zhengzhou University, Zhengzhou, China.
⁴ School of Information Engineering, Zhengzhou University, Zhengzhou, China.
⁵ Department of Psychiatry, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
⁶ Norwegian Centre for Mental Disorders Research (NORMENT), Institute of Clinical Medicine, Oslo University Hospital, University of Oslo, Oslo, Norway.
⁷ Centre for Lifespan Changes in Brain and Cognition (LCBC), Department of Psychology, University of Oslo, Oslo, Norway.

Abstract

Background: Schizophrenia (SCZ) is a heritable disorder with a polygenic architecture, and the gut microbiota seems to be involved in its development and outcome. In this study, we investigate the interplay between genetic risk and gut microbial markers.

Methods: We included 159 first-episode, drug-naïve SCZ patients and 86 healthy controls. The microbial composition of feces was characterized using the 16S rRNA sequencing platform, and five microbial α-diversity indices were estimated [Shannon, Simpson, Chao1, the Abundance-based Eoverage Estimator (ACE), and a phylogenetic diversity-based estimate (PD)]. Polygenic risk scores (PRS) for SCZ were constructed using data from large-scale genome-wide association studies. Effects of microbial α-diversity, microbial abundance, and PRS on SCZ were evaluated via generalized linear models.

Results: We confirmed that PRS was associated with SCZ (OR = 2.08, p = 1.22×10^-5) and that scores on the Shannon (OR = 0.29, p = 1.15×10^-8) and Simpson (OR = 0.29, p = 1.25×10^-8) indices were inversely associated with SCZ risk. We found significant interactions (p < 0.05) between PRS and α-diversity indices (Shannon, Simpson, and PD), with the effects of PRS being larger in those exhibiting higher diversity compared to those with lower diversity. Moreover, the PRS effects were larger in individuals with a high abundance of the genera Romboutsia, Streptococcus, and Anaerostipes than in those with low abundance (p < 0.05). All three of these genera showed protective effects against SCZ.

Conclusion: The current findings suggest an interplay between the gut microbiota and polygenic risk of SCZ that warrants replication in independent samples. Experimental studies are needed to determine the underpinning mechanisms.

Keywords: Romboutsia; microbiota; polygenic score; schizophrenia; α-diversity.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Natural Science Foundation of China (grant number 81971253 to XS), Zhong yuan Innovation Leading Talents of the Thousand Talents Plan (grant number 204200510019 to XS), Medical science and technology foundation of health and family planning commission of Henan province (grant number SBGJ201808 to XS), School and Hospital Co-incubation Funds of Zhengzhou University (grant number 2017-BSTDJJ-04 to XS), UiO:Life Science Convergence environment, University of Oslo, Norway (project 4MENT to YW and OA), and Research Council of Norway (grant number 223273 to OA; grant number 302854 to YW).