Assessing the association between global structural brain age and polygenic risk for schizophrenia in early adulthood: a recall-by-genotype study

Abstract

Neuroimaging studies consistently show advanced brain age in schizophrenia, suggesting that brain structure is often ‘older’ than expected at a given chronological age. Whether advanced brain age is linked to genetic liability for schizophrenia remains unclear. In this pre-registered secondary data analysis, we utilised a recall-by-genotype approach applied to a population-based subsample from the Avon Longitudinal Study of Parents and Children to assess brain age differences between young adults aged 21-24 years with relatively high (n=96) and low (n=93) polygenic risk for schizophrenia (SCZ-PRS). A global index of brain age (or brain-predicted age) was estimated using a publicly available machine learning model previously trained on a combination of region-wise gray-matter measures, including cortical thickness, surface area and subcortical volumes derived from T1-weighted magnetic resonance imaging (MRI) scans. We found no difference in mean brain PAD (the difference between brain-predicted age and chronological age) between the high- and low- SCZ-PRS groups, controlling for the effects of sex and age at time of scanning (b = - 0.21; 95% CI -2.00, 1.58; p = 0.82; Cohen’s d = - 0.03; partial R2 = 0.00029). These findings do not support an association between SCZ-PRS and brain-PAD based on global age-related structural brain patterns, suggesting that brain age may not be a vulnerability marker of common genetic risk for SCZ. Future studies with larger samples and multimodal brain age measures could further investigate global or localised effects of SCZ-PRS.