Mendelian randomization study of the relationship between blood and urine biomarkers and schizophrenia in the UK Biobank cohort

Bolun Cheng; Yunfeng Bai; Li Liu; Peilin Meng; Shiqiang Cheng; Xuena Yang; Chuyu Pan; Wenming Wei; Huan Liu; Yumeng Jia; Yan Wen; Feng Zhang

doi:10.1038/s43856-024-00467-1

Mendelian randomization study of the relationship between blood and urine biomarkers and schizophrenia in the UK Biobank cohort

Commun Med (Lond). 2024 Mar 7;4(1):40. doi: 10.1038/s43856-024-00467-1.

Authors

Bolun Cheng^#^{1 2 3}, Yunfeng Bai^#⁴, Li Liu^{1 2 3}, Peilin Meng^{1 2 3}, Shiqiang Cheng^{1 2 3}, Xuena Yang^{1 2 3}, Chuyu Pan^{1 2 3}, Wenming Wei^{1 2 3}, Huan Liu^{1 2 3}, Yumeng Jia^{1 2 3}, Yan Wen^{1 2 3}, Feng Zhang^{5 6 7}

Affiliations

¹ Key Laboratory of Trace Elements and Endemic Diseases (Xi'an Jiaotong University), National Health and Family Planning Commission, 710061, Xi'an, China.
² Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, 710061, Xi'an, China.
³ Collaborative Innovation Center of Endemic Disease and Health Promotion for Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, 710061, Xi'an, China.
⁴ School of Public Health, Shaanxi University of Chinese Medicine, 712046, Xianyang, China.
⁵ Key Laboratory of Trace Elements and Endemic Diseases (Xi'an Jiaotong University), National Health and Family Planning Commission, 710061, Xi'an, China. fzhxjtu@mail.xjtu.edu.cn.
⁶ Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education, 710061, Xi'an, China. fzhxjtu@mail.xjtu.edu.cn.
⁷ Collaborative Innovation Center of Endemic Disease and Health Promotion for Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, 710061, Xi'an, China. fzhxjtu@mail.xjtu.edu.cn.

^# Contributed equally.

Abstract

Background: The identification of suitable biomarkers is of crucial clinical importance for the early diagnosis of treatment-resistant schizophrenia (TRS). This study aims to comprehensively analyze the association between TRS and blood and urine biomarkers.

Methods: Candidate TRS-related single nucleotide polymorphisms (SNPs) were obtained from a recent genome-wide association study. The UK Biobank cohort, comprising 376,807 subjects with blood and urine biomarker testing data, was used to calculate the polygenic risk score (PRS) for TRS. Pearson correlation analyses were performed to evaluate the correlation between TRS PRS and each of the biomarkers, using calculated TRS PRS as the instrumental variables. Bidirectional two-sample Mendelian randomization (MR) was used to assess potential causal associations between candidate biomarkers with TRS.

Results: Here we identify a significant association between TRS PRS and phosphate (r = 0.007, P = 1.96 × 10^-4). Sex subgroup analyses identify seven and three candidate biomarkers associated with TRS PRS in male and female participants, respectively. For example, total protein and phosphate for males, creatinine and phosphate for females. Bidirectional two-sample MR analyses indicate that TRS is negatively associated with cholesterol (estimate = -0.363, P = 0.008). Conversely, TRS is positively associated with total protein (estimate = 0.137, P = 0.027), mean corpuscular volume (estimate = 0.032, P = 2.25 × 10^-5), and mean corpuscular hemoglobin (estimate = 0.018, P = 0.007).

Conclusions: Our findings provide insights into the roles of blood and urine biomarkers in the early detection and treatment of TRS.

Plain language summary

People with schizophrenia experience periods of time during which they misperceive reality. Some people with schizophrenia do not respond well to the usual drugs that are used to relieve their symptoms. This type of schizophrenia is known as treatment-resistant schizophrenia (TRS). We looked at differences in the genes (inherited characteristics), blood and urine of a group of people in the UK with schizophrenia to see if people with TRS have particular characteristics that would enable them to be distinguished from patients with schizophrenia who tend to respond to usual treatment. We found several differences in the blood that could be used to predict which people might get TRS, including some that were specific to men or women. These discoveries are important because they can help doctors identify people who are more likely to develop TRS earlier, enabling them to avoid using treatments that might not work well for them.