PROJECT SUMMARY/ABSTRACT Dr. Colin Ellis is an Assistant Professor of Neurology at the University of Pennsylvania with clinical expertise in both epilepsy and genetics. His long-term goal as a physician-scientist is to translate genetic discoveries into clinically meaningful tools that improve the care of people with epilepsy across the lifespan. Epilepsy is a highly heritable disorder and often runs in families. Recent progress identifying the genes that cause epilepsy applies mostly to severe pediatric epilepsies with de novo (not inherited) mutations. Familial epilepsy presumably also has a genetic basis, yet most families with epilepsy do not have an identifiable single gene mutation. This proposal tests the hypothesis that familial epilepsy is caused by the aggregate effects of many variants (risk alleles) distributed across the genome. Experiments will apply polygenic risk analysis to a unique cohort of over 1,000 multiplex epilepsy families. The specific aims are (1) determine the genome-wide contribution of polygenic risk to familial epilepsies, (2) identify novel and candidate biological pathways that contribute to familial epilepsy, and (3) quantify the transmission of polygenic epilepsy risk within families using a novel analytic method. The results of this project will contribute to understanding the genetic basis of familial epilepsy, the biological pathways that are potential treatment targets, and the future development of clinical tools that use patients’ genetic data to improve the diagnosis and management of epilepsy. The proposal builds on Dr. Ellis’s prior research on the heritability of phenotypic traits within familial epilepsies, and extends that research into the analysis of genomic data. His training plan will develop his expertise in genomic research methods, statistical genetics, and bioinformatics. He will also gain training and skills in clinical trial design and implementation, positioning himself for the future clinical applications of this and other genetic research in his dedicated neurogenetics clinics. Dr. Ellis’s team of mentors and advisors at the University of Pennsylvania (Drs. Hakon Hakonarson, Laura Almasy, Kai Wang, and Brian Litt) provide specific expertise in his areas of skill development and strong track records of mentorship. He will also leverage his existing relationships with external advisors through the international Epi4K Consortium (Drs. Samuel Berkovic, Michael Epstein, and Ruth Ottman) who are among the world leaders in his field of epilepsy genetics research. Dr. Ellis’s clinical background in epilepsy and genetics, with the additional support of this career development award and his unique mentorship opportunities, will position him to succeed as an independent physician- scientist focused on using genetic discoveries to improve the lives of people with epilepsy.