Causal associations of intelligence with schizophrenia and bipolar disorder: A Mendelian randomization analysis

BACKGROUND: Intelligence is inversely associated with schizophrenia (SCZ) and bipolar disorder (BD); it remains unclear whether low intelligence is a cause or consequence. We investigated causal associations of intelligence with SCZ or BD risk and a shared risk between SCZ and BD and SCZ-specific risk. METHODS: To estimate putative causal associations, we performed multi-single nucleotide polymorphism (SNP) Mendelian randomization (MR) using generalized summary-data-based MR (GSMR). Summary-level datasets from five GWASs (intelligence, SCZ vs. control [CON], BD vs. CON, SCZ + BD vs. CON, and SCZ vs. BD; sample sizes of up to 269,867) were utilized. RESULTS: A strong bidirectional association between risks for SCZ and BD was observed (odds ratio; OR(SCZ → BD) = 1.47, p = 2.89 × 10(−41), OR(BD → SCZ) = 1.44, p = 1.85 × 10(−52)). Low intelligence was bidirectionally associated with a high risk for SCZ, with a stronger effect of intelligence on SCZ risk (OR(lower intelligence → SCZ) = 1.62, p = 3.23 × 10(−14)) than the reverse (OR(SCZ → lower intelligence) = 1.06, p = 3.70 × 10(−23)). Furthermore, low intelligence affected a shared risk between SCZ and BD (OR (lower intelligence → SCZ + BD) = 1.23, p = 3.41 × 10(−5)) and SCZ-specific risk (OR(lower intelligence → SCZvsBD) = 1.64, p = 9.72 × 10(−10)); the shared risk (OR(SCZ + BD → lower intelligence) = 1.04, p = 3.09 × 10(−14)) but not SCZ-specific risk (OR(SCZvsBD → lower intelligence) = 1.00, p = 0.88) weakly affected low intelligence. Conversely, there was no significant causal association between intelligence and BD risk (p > 0.05). CONCLUSIONS: These findings support observational studies showing that patients with SCZ display impairment in premorbid intelligence and intelligence decline. Moreover, a shared factor between SCZ and BD might contribute to impairment in premorbid intelligence and intelligence decline but SCZ-specific factors might be affected by impairment in premorbid intelligence. We suggest that patients with these genetic factors should be categorized as having a cognitive disorder SCZ or BD subtype.