Abstract
ABSTRACTMany psychiatric and neurological disorders show significant heritability, indicating strong genetic influence. In parallel, dynamic functional network connectivity (dFNC) measures functional temporal coupling between brain networks in a time-varying manner and has proven to identify disease-related changes in the brain. However, it remains largely unclear how genetic risk contributes to brain dysconnectivity that further manifests into clinical symptoms. The current work aimed to address this gap by proposing a novel joint ICA (jICA)-based “dynamic fusion” framework to identify dynamically tuned SNP manifolds by linking static SNPs to dynamic functional information of the brain. The sliding window approach was utilized to estimate four dFNC states and compute subject-level state-specific dFNC features. Each state of dFNC features were then combined with 12946 SZ risk SNPs for jICA decomposition, resulting in four parallel fusions in 32861 European ancestry individuals within the UK Biobank cohort. The identified joint SNP-dFNC components were further validated for SZ relevance in an aggregated SZ cohort, and compared for across-state similarity to indicate level of dynamism. The results supported that dynamic fusion yielded “static” and “dynamic” components (i.e., high and low across-state similarity, respectively) for SNP and dFNC modalities. As expected, the SNP components presented a mixture of static and dynamic manifolds, with the latter largely driven by fusion with dFNC. We also showed that some of the dynamic SNP manifolds uniquely elicited by fusion with state-specific dFNC features complemented each other in terms of biological interpretation. This dynamic fusion framework thus allows expanding the SNP modality to manifolds in the time dimension, which provides a unique lens to elicit unique SNP correlates of dFNC otherwise unseen, promising additional insights on how genetic risk links to disease-related dysconnectivity.
Publisher
Cold Spring Harbor Laboratory