Evolutionary Roles of Homozygosity & Copy Number Variation in Mental Disorders

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DESCRIPTION (provided by applicant): The objective of this Mentored Research Scientist Development Award is to establish Dr. Matthew Keller as an independent investigator in psychiatric genetics. The application brings together advances from evolutionary genetics, statistical genetics, and psychiatry to build an interdisciplinary research program for understanding the genetic variation underlying mental disorders. Specifically, training and research focus on how copy number variants (CNVs) and extended homozygosity (EH) influence mental disorder risk. Efforts to link such variation to mental disorders are just beginning, and so there is a potential for making important contributions to this area of inquiry. Evolutionary genetics helps situate findings within a rich conceptual framework, linking them to a deep literature and suggesting several critical hypotheses. The training goal is to develop the skills needed to launch an independently funded, interdisciplinary research career. The training includes: (1) direct collaboration and training from three mentors and four consultants who are leaders in core aspects of this application; (2) coursework in bioinformatics, statistical genetics, psychiatry, and evolutionary genetics; (3) attendance at workshops and conferences covering analysis of genomic data, psychiatric genetics, and evolutionary genetics; (4) teaching courses and mentoring graduate students; and (5) guidance in writing an R01 application. The Institute for Behavioral Genetics offers rich intellectual environments for achieving this training. The research project will use whole genome SNP data from several sources to examine how CNVs and EH are related to schizophrenia and major depression. Studying CNVs and EH allows assessment of common as well as rare genetic variants. This is important in its own right, but also can provide important clues to the evolutionary history of mental disorders and the genes affecting them. This research has the potential to further the evolutionary understanding of mental disorders, lead to concrete data on the molecular mechanisms that contribute to their risk, and suggest specific avenues of future research. PUBLIC HEALTH RELEVANCE: The proposed project should increase the molecular genetic and evolutionary understanding of schizophrenia and major depression, clarifying the degree to which rare versus common variants account for their risk, leading to follow-up (e.g., resequencing) investigations of important genomic regions, and potentially informing translational research aimed at developing diagnostic tests and treatments related to gene dosage.