Project 453997

If you've read a news article about the "largest genetic study" of a disease like depression or Alzheimer's disease, it was probably a genome-wide association study (GWAS). GWAS have found hundreds of genetic variants with higher frequencies in neuropsychiatric disease patients than healthy controls. Yet these variants are often difficult to interpret. Most lie outside the crucial 2% of the genome that encodes proteins, and it is rarely clear which causal genes underlie their disease effects. Fortunately, the UK Biobank, one of the world's largest biomedical research cohorts, is providing the means to address this research gap by performing "whole-exome sequencing" on their entire 500,000-person cohort, which allows detection of the full spectrum of protein-coding variants. First, I will leverage the unprecedented scale of this effort to discover rare, damaging "loss-of-function" (LOF) variants for 12 neuropsychiatric traits. I will focus on variants in "constrained" genes, leveraging my recent discovery that this strategy is extraordinarily effective at finding LOF variants with psychiatric consequences. LOF variants pinpoint causal genes more directly than GWAS, facilitating therapeutic translation. Second, I will derive personalized genetic risk scores for these 12 traits based on LOF variants. In conjunction with conventional genetic risk scores derived from GWAS, these scores will improve personalized risk prediction of specific neuropsychiatric illnesses. Third, I will test if LOF variants are associated with brain-region-specific structural changes on magnetic resonance imaging (MRI). These region-specific changes may be targetable by region-specific interventions like transcranial magnetic stimulation, a highly effective treatment for major depression. In sum, this project will leverage state-of-the-art datasets and techniques to aid personalized psychiatry and broaden our understanding of how genetic variation contributes to neuropsychiatric disease.