Genetic signatures underlining circulating lipids display causal effects on schizophrenia

Schizophrenia (SZ) is a serious mental illness with unclear pathophysiologic mechanisms. Although some studies have found evidence of altered circulating lipid metabolites in patients with SZ, the causative relationship between the two remains unclear. Based on publicly summarized-level GWAS data, we investigated the bidirectional causative relationship between SZ (53,386 cases and 77,258 controls) and 233 traits describing circulating metabolites (136,016 participants) using a two-sample Mendelian randomization (MR) technique. For each outcome, we estimated causal effects of each exposure using the inverse variance weighted (IVW), MR-Egger, and weighted median methods, while sensitivity was gauged using the MR-Egger intercept and Cochran's Q test. Two circulating lipid metabolites (the ratio of triglycerides to total lipids in very small VLDL (OR [95% CI] = 1.07 [1.01-1.13]) and the ratio of omega-3 fatty acids to total fatty acids (OR [95% CI] = 1.11 [1.01-1.22])) emerged as risk factors for SZ, while five metabolites demonstrated protective effects against SZ (ORs ranging from 0.88 to 0.92). In reverse analysis, SZ were nominally associated with the levels of 52 circulating lipid metabolites. After multiple corrections, SZ still had weak but significant causal effects on seven of these metabolites (OR range from 0.97 to 1.02). The overall causal effects of the lipid metabolites (absolute beta = 0.035 ± 0.026) on SZ were larger than the reverse (absolute beta = 0.009 ± 0.006, p < 0.001). The causal effects of circulating lipid metabolites on the development of SZ imply that targeted dietary interventions may play an important role in its prevention and treatment.