Integration of common, rare, and structural variation to define the genetic architecture of neuropsychiatric disorders

Abstract Neuropsychiatric disorders (NPDs), including autism spectrum disorder (ASD), epilepsy, and schizophrenia, are collectively common conditions in the human population. Many studies have shown that NPDs have a significant genetic component, reaching upwards of 80-90% heritability, and include common and rare genetic variation

acting additively. However, much of this heritability remains unexplained by studies to date, which have largely focused on inspecting isolated slices of the human genetic variation spectrum, focusing on gene discovery within one specific NPD. This K01 proposes to provide extensive training and conduct in-depth analyses using an

integrative approach to statistical analyses that accounts for the complete spectrum of human genetic variation across multiple NPDs. Such an approach will not only increase the power to uncover gene associations but will also fill much-needed gaps in our understanding of the shared and distinct genetic architecture of NPDs.

In Aim 1 of this K01 proposal, I will receive extensive training in cross-NPD genetics, and will apply a rare variant association framework to ASD, epilepsy, and schizophrenia for joint NPD gene discovery. For Aim 2, I will learn new skills from leading experts in genetic association methods of common and noncoding variation for NPDs.

Finally, for Aim 3 of my proposal, I will combine my newly acquired expertise from Aim 1 and Aim 2 to develop frameworks and methods that will account for variants ranging from common to rare, from single-nucleotide to structural, and from coding to noncoding across NPD phenotypes to better define the complete genetic

architecture of these complex neurological phenotypes. For this proposal, my mentors and I have developed a comprehensive training plan to continue my transition to independence that will enable me to develop a research program at the forefront of neuropsychiatric genetics. My academic background consists of my undergraduate training in statistics at Duke University and a PhD in

biostatistics from Johns Hopkins University. My postdoctoral training at the Center of Genomic Medicine (CGM) and Department of Neurology at Massachusetts General Hospital (MGH) and at the Broad Institute has greatly advanced my expertise in the genetics of complex disorders, especially ASD, and have cultivated my interest in

studying NPDs. The overarching goal of this career program is to expand my understanding of NPD biology beyond ASD and to develop expertise in the modeling of common and noncoding variation. My mentors (Primary: Dr. Talkowski, Secondary: Dr. Mark Daly) and advisory team (Drs. Kathryn Roeder, Alicia Martin, Elise Robinson,

and Jordan Smoller) will supervise my scientific progress and collaboratively provide mentorship for soft skills development, including the responsible conduct of research, lab management, result communication, and grant writing. This tremendous mentorship team and the cutting-edge training environment of this proposal will catalyze

my transition to an independent research career studying NPD genetics.