Mendelian randomization suggests that head circumference, but not birth weight and length, associates with intelligence

Introduction: Birth parameters have long been reported to have a role in human intelligence. However, the causalities reported in previous observational studies were controversial. Our study aims to provide an unbiased investigation of the causal associations between birth parameters and human intelligence using the Mendelian randomization (MR) approach. Methods: Genetic instrumental variables for MR analyses were extracted from large genome-wide association studies of infant head circumference (N = 10,768), birth length (N = 28,489), and birth weight (N = 321,223). Data for intelligence were obtained from a meta-analysis of genome-wide association studies of 269,867 individuals of the European ancestry. Primary MR analysis was performed using the standard inverse-variance weighted method, and sensitivity analyses were performed using the weighted median, MR-Egger, and MR-PRESSO methods. Results: Using 10 single nucleotide polymorphisms as instrumental variables, we found that 1 standard deviation increase in infant head circumference was associated with 0.14-fold higher scores in intelligence tests (β = 0.14, 95% confidence interval: 0.09 to 0.18, P_IVW=2.05 × 10^–9). The causal relationship was robust when sensitivity analyses were performed. However, birth length and birth weight had no significant associations with intelligence. Conclusion: Our findings suggested infant head circumference, but not birth weight and length were associated with intelligence, which might indicate that brain development rather than general fetal growth was responsible for the development of intelligence.