| Summary: | Abstract Introduction Past research has suggested that reading disability is a complex disorder involving genetic and environment contributions, as well as gene–gene and gene–environment interaction, but to date little is known about the underlying mechanisms. Method Using the Avon Longitudinal Study of Parents and Children, we assessed the contributions of genetic, demographic, and environmental variables on case–control status using machine learning. We investigated the functional interactions between genes using pathway and network analysis. Results Our results support a systems approach to studying the etiology of reading disability with many genes (e.g., RAPGEF2, KIAA0319, DLC1) and biological pathways (e.g., neuron migration, positive regulation of dendrite regulation, nervous system development) interacting with each other. We found that single nucleotide variants within genes often had opposite effects and that enriched biological pathways were mediated by neuron migration. We also identified behavioral (i.e., receptive language, nonverbal intelligence, and vocabulary), demographic (i.e., mother's highest education), and environmental (i.e., birthweight) factors that influenced case–control status when accounting for genetic information. Discussion The behavioral and demographic factors were suggested to be protective against reading disability status, while birthweight conveyed risk. We provided supporting evidence that reading disability has a complex biological and environmental etiology and that there may be a shared genetic and neurobiological architecture for reading (dis)ability.
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