Psychiatric diagnoses are complex and heterogeneous constructs. Rather than natural kinds, they describe clusters of frequently co-occurring symptoms, which often lack a distinct border between health and disease. This makes it difficult to establish if a dysregulation within a particular brain system contributes to the intial occurrence of an illness, or emerges as a result of pathophysiological processes following onset. Here we propose parsing the heterogeneity of anxiety and affective disorders through the identification of neural and genetic pathways associated with illness risk, onset, and maintenance. With a focus on amygdala-medial prefrontal cortex (mPFC) circuitry, this project will: (1) Establish relations between dimensional measures of affective and social functioning and amygdala-mPFC circuit integrity in psychiatrically healthy treatment naive young adults;(2) Identify associations between previously validated polygenic risk factors for affective illnesses, derived through large-scale case-control GWAS analyses, and amygdala-mPFC circuit integrity;and (3) Establish novel polygenic scores that co-vary with the anatomical and intrinsic integrity of amygdala-mPFC circuitry in healthy young adults, assessing the relations between these scores and the presence of psychiatric illness in an independent case-control dataset. The genetic and biological architecture of the major psychiatric disorders remains largely unknown. The proposed research may enable the identification of new genetic variants, anatomical features, or patterns of brain activity that are characteristic of certain disorders. The identification of novel biological pathways, even ones that contribute a small increment of risk, can suggest new etiological hypotheses and possible treatment targets. Dr. Avram Holmes'primary career goal is to study biological pathways contributing to individual differences in psychiatric illness risk. The proposed project will allow Dr. Holmes to receive training in genetics, advanced imaging methods, and systems neuroscience. In doing so he will develop a translational inter-disciplinary research program that combines molecular genetic and neuroimaging methods. The project will be conducted in the Department of Psychiatry at Massachusetts General Hospital. The specific research sites include the Athinoula A. Martinos Center for Biomedical Imaging and the Center for Human Genetic Research. The associated facilities, resources and environment provide the equipment, space and expertise required for the execution of this research. The proposed project, associated training, and mentorship will form the foundation of Dr. Holmes'independent research program, which will have anxiety and affective disorders as a core clinical focus.

Public Health Relevance

The genetic and biological architecture of the major psychiatric disorders remains largely unknown. The proposed project will combine neuroimaging and genetic methods to identify biological pathways in anxiety and affective disorders. The resulting data may enable the identification of novel genetic risks, anatomical features, or patterns of brain activity that are characteristic of certain disorders.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Scientist Development Award - Research & Training (K01)
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Adult Psychopathology and Disorders of Aging Study Section (APDA)
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Chavez, Mark
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Yale University
Schools of Arts and Sciences
New Haven
United States
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Sabuncu, Mert R; Ge, Tian; Holmes, Avram J et al. (2016) Morphometricity as a measure of the neuroanatomical signature of a trait. Proc Natl Acad Sci U S A 113:E5749-56
Lee, P H; Baker, J T; Holmes, A J et al. (2016) Partitioning heritability analysis reveals a shared genetic basis of brain anatomy and schizophrenia. Mol Psychiatry 21:1680-1689
Holmes, Avram J; Hollinshead, Marisa O; Roffman, Joshua L et al. (2016) Individual Differences in Cognitive Control Circuit Anatomy Link Sensation Seeking, Impulsivity, and Substance Use. J Neurosci 36:4038-49
Franke, Barbara; Stein, Jason L; Ripke, Stephan et al. (2016) Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept. Nat Neurosci 19:420-31
Treadway, Michael T; Waskom, Michael L; Dillon, Daniel G et al. (2015) Illness progression, recent stress, and morphometry of hippocampal subfields and medial prefrontal cortex in major depression. Biol Psychiatry 77:285-94
Admon, R; Nickerson, L D; Dillon, D G et al. (2015) Dissociable cortico-striatal connectivity abnormalities in major depression in response to monetary gains and penalties. Psychol Med 45:121-31
Holmes, Avram J; Hollinshead, Marisa O; O'Keefe, Timothy M et al. (2015) Brain Genomics Superstruct Project initial data release with structural, functional, and behavioral measures. Sci Data 2:150031
(2015) Common genetic variants influence human subcortical brain structures. Nature 520:224-9
Holmes, Avram J; Yeo, B T Thomas (2015) From phenotypic chaos to neurobiological order. Nat Neurosci 18:1532-4
Wang, Danhong; Buckner, Randy L; Fox, Michael D et al. (2015) Parcellating cortical functional networks in individuals. Nat Neurosci 18:1853-60

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