Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study.

Abstract

BackgroundC-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal.Methods and findingsWe performed Mendelian randomization (MR) analyses using two genetic risk scores (GRSs) as instrumental variables (IVs). The first GRS consisted of four single nucleotide polymorphisms (SNPs) in the CRP gene (GRSCRP), and the second consisted of 18 SNPs that were significantly associated with CRP levels in the largest genome-wide association study (GWAS) to date (GRSGWAS). To optimize power, we used summary statistics from GWAS consortia and tested the association of these two GRSs with 32 complex somatic and psychiatric outcomes, with up to 123,865 participants per outcome from populations of European ancestry. We performed heterogeneity tests to disentangle the pleiotropic effect of IVs. A Bonferroni-corrected significance level of less than 0.0016 was considered statistically significant. An observed p-value equal to or less than 0.05 was considered nominally significant evidence for a potential causal association, yet to be confirmed. The strengths (F-statistics) of the IVs were 31.92-3,761.29 and 82.32-9,403.21 for GRSCRP and GRSGWAS, respectively. CRP GRSGWAS showed a statistically significant protective relationship of a 10% genetically elevated CRP level with the risk of schizophrenia (odds ratio [OR] 0.86 [95% CI 0.79-0.94]; p ConclusionsGenetically elevated CRP levels showed a significant potentially protective causal relationship with risk of schizophrenia. We observed nominal evidence at an observed p < 0.05 using either GRSCRP or GRSGWAS-with persistence after correction for heterogeneity-for a causal relationship of elevated CRP levels with psoriatic osteoarthritis, rheumatoid arthritis, knee osteoarthritis, systolic blood pressure, diastolic blood pressure, serum albumin, and bipolar disorder. These associations remain yet to be confirmed. We cannot verify any causal effect of CRP level on any of the other common somatic and neuropsychiatric outcomes investigated in the present study. This implies that interventions that lower CRP level are unlikely to result in decreased risk for the majority of common complex outcomes.