A biologically-informed polygenic score identifies endophenotypes and clinical conditions associated with the insulin receptor function on specific brain regions

Conventional polygenic scores derived from genome-wide association studies do not reflect gene networks that code for biological functions. We present an alternative approach creating a biologically informed polygenic score based on the insulin receptor (IR) gene networks in the mesocorticolimbic system and hippocampus that regulate reward sensitivity/inhibitory control and memory, respectively. Across multiple samples (n = 4300) our biologically-informed IR-PRS score showed better prediction of child impulsivity and cognitive performance, as well as risk for early addiction onset and Alzheimer9s disease in comparison to conventional polygenic scores for ADHD, addiction and dementia. This novel, biologically-informed approach enables the use of genomic datasets to probe relevant biological processes involved in neural function and disorders.