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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Scientist Development Award - Research & Training (K01)
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Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Rosemond, Erica K
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University of Colorado at Boulder
Schools of Arts and Sciences
United States
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Verweij, Karin J H; Abdellaoui, Abdel; Veijola, Juha et al. (2014) The association of genotype-based inbreeding coefficient with a range of physical and psychological human traits. PLoS One 9:e103102
Power, Robert A; Keller, Matthew C; Ripke, Stephan et al. (2014) A recessive genetic model and runs of homozygosity in major depressive disorder. Am J Med Genet B Neuropsychiatr Genet 165B:157-66
Simonson, Matthew A; McQueen, Matthew B; Keller, Matthew C (2014) Whole-genome pathway analysis on 132,497 individuals identifies novel gene-sets associated with body mass index. PLoS One 9:e78546
Keller, Matthew C (2014) Gene × environment interaction studies have not properly controlled for potential confounders: the problem and the (simple) solution. Biol Psychiatry 75:18-24
Gratten, Jacob; Wray, Naomi R; Keller, Matthew C et al. (2014) Large-scale genomics unveils the genetic architecture of psychiatric disorders. Nat Neurosci 17:782-90
Lencz, T; Knowles, E; Davies, G et al. (2014) Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT). Mol Psychiatry 19:168-74
de Candia, Teresa R; Lee, S Hong; Yang, Jian et al. (2013) Additive genetic variation in schizophrenia risk is shared by populations of African and European descent. Am J Hum Genet 93:463-70
Keller, Matthew C; Garver-Apgar, Christine E; Wright, Margaret J et al. (2013) The genetic correlation between height and IQ: shared genes or assortative mating? PLoS Genet 9:e1003451
Keller, Matthew C; Simonson, Matthew A; Ripke, Stephan et al. (2012) Runs of homozygosity implicate autozygosity as a schizophrenia risk factor. PLoS Genet 8:e1002656
Lee, S Hong; DeCandia, Teresa R; Ripke, Stephan et al. (2012) Estimating the proportion of variation in susceptibility to schizophrenia captured by common SNPs. Nat Genet 44:247-50

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