Project Grant F31MH141823

ILLUMINATING THE ROLE OF STRUCTURAL VARIANTS IN THE GENETIC ARCHITECTURE OF AUTISM SPECTRUM DISORDER - ABSTRACT AUTISM SPECTRUM DISORDER (ASD) IS A HIGHLY HERITABLE NEURODEVELOPMENTAL DISORDER AFFECTING APPROXIMATELY 2.3% OF CHILDREN IN THE UNITED STATES. WHILE MUCH OF THE GENETIC RISK FOR ASD HAS BEEN FOUND TO RESULT FROM SMALL ADDITIVE EFFECTS OF COMMON VARIANTS ACROSS THE GENOME, RARE AND DE NOVO VARIANTS ALSO SIGNIFICANTLY CONTRIBUTE TO RISK IN MANY CASES. THESE PREVIOUS INSIGHTS INTO THE GENETICS OF ASD HAVE MOSTLY ARISEN FROM STUDIES LIMITED TO SINGLE NUCLEOTIDE VARIANTS AND SMALL INSERTIONS AND DELETIONS. CONSEQUENTLY, STRUCTURAL VARIANTS (SVS) REPRESENT A LARGELY UNTAPPED RESERVOIR OF VARIATION WITH HIGH RELATIVE RISK THAT CAN PROVIDE NOVEL INSIGHTS INTO THE GENETIC RISK FACTORS OF ASD. MOREOVER, A TECHNICAL REVOLUTION IS EMERGING IN GENOMICS FROM LONG READ WHOLE GENOME SEQUENCING (LRWGS), WHICH ENABLES NEAR COMPLETE GENETIC VARIATION ASCERTAINMENT BUT REMAINS LIMITED TO SMALL COHORTS AND ESOTERIC ANALYTIC METHODS. RECENTLY DEVELOPED PANGENOME-BASED TOOLS SUCH AS KAGE CAN TRANSLATE THESE DISCOVERIES TO THE SCALE OF ASD ASSOCIATION STUDIES BY GENOTYPING SVS FROM LRWGS HAPLOTYPES INTO SHORT READ WGS (SRWGS) SAMPLES, ALTHOUGH PREVIOUS STUDIES HAVE NOT YET COMPLETED THE SUBSTANTIAL RESEARCH AND BENCHMARKING REQUIRED TO ACHIEVE THIS GOAL. IN THIS FELLOWSHIP, I WILL LEVERAGE STATE-OF-THE-ART SV DISCOVERY PIPELINES AND CALLSETS TO INTEGRATE NOVEL CLASSES OF GENETIC VARIATION INTO ASD ASSOCIATION ANALYSES. IN AIM 1, I WILL USE SRWGS TO GENOTYPE ALL CLASSES OF SVS INTO OVER 12,000 ASD FAMILIES, UNCOVER NOVEL ASD RISK GENES, AND IDENTIFY COMPONENTS OF ASD GENETIC RISK SHARED WITH OTHER NEUROPSYCHIATRIC DISORDERS. AND IN AIM 2, I WILL COMPREHENSIVELY BENCHMARK THE PERFORMANCE OF KAGE BEFORE USING THIS TOOL TO GENOTYPE LRWGS SVS INTO OVER 40,000 SRWGS ASD CASE AND CONTROL SAMPLES AND EXAMINE HOW THESE NEWLY ACCESSIBLE CLASSES OF GENETIC VARIATION CONTRIBUTE TO ASD RISK. COLLECTIVELY, THESE ANALYSES AIM TO PROVIDE NOVEL INSIGHTS INTO THE GENETIC ARCHITECTURE OF ASD WHILE ALSO ESTABLISHING THE FIRST THOROUGHLY BENCHMARKED, SCALABLE APPROACH FOR GENOTYPING LRWGS-DERIVED SVS INTO SRWGS COHORTS. FINALLY, IN PARALLEL WITH THESE RESEARCH GOALS, AN OUTSTANDING TEAM OF FIVE MENTORS ACROSS MULTIPLE DISCIPLINES, CAREER STAGES, AND INSTITUTIONS WILL CONTRIBUTE DIDACTIC TRAINING, HANDS-ON RESEARCH SUPPORT, CAREER ADVICE, AND REGULAR PRESENTATION OPPORTUNITIES THROUGHOUT THIS FELLOWSHIP TO SUPPORT MY PH.D. TRAINING IN BIOINFORMATICS, STATISTICAL GENETICS, SV GENOTYPING, AND THE BIOLOGICAL MECHANISMS OF ASD.