Emily Olfson, M.D., Ph.D.
Fellow In ADHD
Thomas V. Fernandez, M.D.
Whole-Exome Sequencing Study of Parent-Child Trios with ADHD
Attention-deficit/hyperactivity disorder (ADHD) is among the most heritable of psychiatric disorders, so identifying genes contributing to ADHD risk is a key step towards understanding this disease process and improving treatments. However, decades of candidate gene studies have not identified reproducible findings, and only recently has a large genomewide association study (GWAS) identified the first genome-wide significant common variants with low effect. Similar to other childhood neuropsychiatric conditions, it is likely that rare inherited and de novo (spontaneous) genetic variants of larger effect also play an important role. In recent years, great progress has been made in identifying high-confidence risk genes by sequencing parent-child trios. Therefore, an important next step in the field of ADHD is to investigate whether sequencing of parent-child trios can similarly shed light on the underlying neurobiology of this condition. The overall objective of this fellowship application is to address this gap in the field by using whole-exome sequencing of parent-child trios to identify ADHD risk genes and important biologic processes. Our central hypothesis is that, similar to related conditions, de novo genetic variants that are predicted to be damaging to a gene will be seen more frequently in ADHD parent-child trios than in control trios. This finding will be harnessed to identify high-confidence risk genes, biologic pathways, gene networks, and spatiotemporal expression patterns. This hypothesis has been formulated based on our preliminary results from sequencing 76 parentchild trios impacted by ADHD, along with work conducted by my primary research mentor, Dr. Thomas Fernandez, which demonstrates an enrichment of de novo likely-damaging variants in other related childhood-onset neuropsychiatric conditions, including obsessive-compulsive disorder, Tourette’s disorder, and motor stereotypes. The rationale for the proposed research is that finding critical risk genes, biological pathways, gene networks, brain regions, and vulnerable developmental time periods will provide points of traction for mechanistic studies in model systems, ultimately leading to novel therapeutics.