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Examining the Causal Inference of Leptin and Soluble Plasma Leptin Receptor Levels on Schizophrenia: A Mendelian Randomization Study

ABSTRACT: Background: Observational studies that have supported the role of the leptin level in schizophrenia (SCZ) risk are conflicting. Therefore, we performed a two-sample Mendelian randomization (MR) analysis to investigate whether the circulating leptin and soluble plasma leptin receptor (sOB-R) levels play a causal role in SCZ risk. Methods: We first selected five independent single-nucleotide polymorphisms (SNPs) associated with the circulating leptin level and three independent SNPs associated with the sOB-R level from two genome-wide association studies (GWASs) of European individuals. Then, we extracted their associations with SCZ using a large-scale GWAS that consisted of 40,675 patients with SCZ and 64,643 controls of European ancestry. We performed an MR analysis using the inverse variance-weighted (IVW) method to examine the causal effect of leptin on SCZ risk. Moreover, we performed sensitivity analyses to verify our MR results using the weighted median and MR-Egger methods. Results: According to the IVW method, genetically predicted circulating leptin levels were not associated with SCZ risk (OR = 1.98, for per 1-SD unit increase in leptin level; 95% CI, 0.87–4.53; p = 0.10). In addition, the sOB-R level showed no causal effect on the SCZ risk using IVW (OR = 0.98 for per 1-SD unit increase in sOB-R level; 95% CI, 0.97–1.00; p = 0.06). Our sensitivity analysis results confirmed our MR findings. Conclusions: By estimating the causal effect of leptin on SCZ risk using the MR methods, we identified no effect of genetically predicted circulating leptin or the sOB-R level on SCZ. As such, our study suggests that leptin might not be a risk factor for SCZ.

SUBMITTER: Chen G

PROVIDER: S-EPMC8578685 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundCross-sectional observational studies have reported obesity and cardiometabolic co-morbidities as important predictors of coronavirus disease 2019 (COVID-19) hospitalization. The causal impact of these risk factors is unknown at present.MethodsWe conducted multivariable logistic regression to evaluate the observational associations between obesity traits (body mass index [BMI], waist circumference [WC]), quantitative cardiometabolic parameters (systolic blood pressure [SBP], serum glucose, serum glycated hemoglobin [HbA1c], low-density lipoprotein [LDL] cholesterol, high-density lipoprotein [HDL] cholesterol and triglycerides [TG]) and SARS-CoV-2 positivity in the UK Biobank cohort. One-sample MR was performed by using the genetic risk scores of obesity and cardiometabolic traits constructed from independent datasets and the genotype and phenotype data from the UK Biobank. Two-sample MR was performed using the summary statistics from COVID-19 host genetics initiative. Cox proportional hazard models were fitted to assess the risk conferred by different genetic quintiles of causative exposure traits.ResultsThe study comprised 1,211 European participants who were tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and 387,079 participants who were either untested or tested negative between 16 March 2020 to 31 May 2020. Observationally, higher BMI, WC, HbA1c and lower HDL-cholesterol were associated with higher odds of COVID-19 infection. One-sample MR analyses found causal associations between higher genetically determined BMI and LDL cholesterol and increased risk of COVID-19 (odds ratio [OR]: 1.15, confidence interval [CI]: 1.05-1.26 and OR: 1.58, CI: 1.21-2.06, per 1 standard deviation increment in BMI and LDL cholesterol respectively). Two-sample MR produced concordant results. Cox models indicated that individuals in the higher genetic risk score quintiles of BMI and LDL were more predisposed to COVID-19 (hazard ratio [HR]: 1.24, CI: 1.03-1.49 and HR: 1.37, CI: 1.14-1.65, for the top vs the bottom quintile for BMI and LDL cholesterol, respectively).ConclusionWe identified causal associations between BMI, LDL cholesterol and susceptibility to COVID-19. In particular, individuals in higher genetic risk categories were predisposed to SARS-CoV-2 infection. These findings support the integration of BMI into the risk assessment of COVID-19 and allude to a potential role of lipid modification in the prevention and treatment.

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Examining the Causal Inference of Leptin and Soluble Plasma Leptin Receptor Levels on Schizophrenia: A Mendelian Randomization Study

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