Schizophrenia (SCZ), bipolar disorder (BPD), and major depression (MDD) are responsible for an enormous burden of disability, personal suffering, and economic cost. Despite progress in the diagnosis and treatment of these disorders, crucial questions about their definition and etiology remain. The best-established risk factor for these disorders is genetic vulnerability, and the identification of susceptibility genes offers tremendous hope for the development of more effective treatment and prevention strategies. However, progress in this area has been limited by fundamental uncertainties in how psychiatric phenotypes are best defined. Genes appear to influence component phenotypes that cross DSM-IV diagnostic boundaries and that may have substantial impact on illness morbidity and even mortality (e.g., suicidality). This proposal is a response to RFA-MH-07-010 """"""""Treatment Response: Linking Genes with Behavioral Phenotypes of Relevance to Patients, Families and Policymakers"""""""". It represents the first, adequately powered study to dissect genetic influences on SCZ;BPD, and MDD as well as disabling symptoms and functional impairment that may be independent of diagnostic categories. This will be accomplished by combining phenotypic and genetic data from three large multicenter NIMH-funded treatment studies-the CATIE study of SCZ (N = 770), the STEP-BD study of BPD (N = 2090), and the STAR*D study of MOD (N = 1953)-as well as a large sample of screened controls (N = 2000).
The aims of the study are to 1) create a composite phenotypic database from these cohorts and derive key phenotypic variables for genetic analyses;2) genotype 768 SNPs in 15 genes selected for having the strongest prior probability of involvement in the mood- and psychosis-related phenotypes;3) perform analyses to determine whether phenotypic effects of these genes (a) support nosologic distinctions among psychotic and mood disorders and (b) influence clinical features (psychosis, suicidality) and functional outcomes independent of diagnosis. The proposed research will address fundamental questions about the nosology and genetic etiology of major mental illness and its functional consequences. As such, it will have implications for informing both the biological and clinical understanding of mood and psychotic disorders. Finally, the phenotypic and genetic database derived from these analyses will provide a valuable resource for future genetic studies by the scientific community.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1-ERB-A (04))
Program Officer
Muehrer, Peter R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
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
Ressler, Kerry J; Smoller, Jordan W (2016) Impact of Stress on the Brain: Pathology, Treatment and Prevention. Neuropsychopharmacology 41:1-2
Adams, Hieab H H (see original citation for additional authors) (2016) Novel genetic loci underlying human intracranial volume identified through genome-wide association. Nat Neurosci 19:1569-1582
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
Bergen, Sarah E; O'Dushlaine, Colm T; Lee, Phil H et al. (2014) Genetic modifiers and subtypes in schizophrenia: investigations of age at onset, severity, sex and family history. Schizophr Res 154:48-53
Solovieff, Nadia; Cotsapas, Chris; Lee, Phil H et al. (2013) Pleiotropy in complex traits: challenges and strategies. Nat Rev Genet 14:483-95
Roffman, Joshua L; Brohawn, David G; Nitenson, Adam Z et al. (2013) Genetic variation throughout the folate metabolic pathway influences negative symptom severity in schizophrenia. Schizophr Bull 39:330-8
Judy, Jennifer Toolan; Seifuddin, Fayaz; Pirooznia, Mehdi et al. (2013) Converging Evidence for Epistasis between ANK3 and Potassium Channel Gene KCNQ2 in Bipolar Disorder. Front Genet 4:87
McGrath, Lauren M; Cornelis, Marilyn C; Lee, Phil H et al. (2013) Genetic predictors of risk and resilience in psychiatric disorders: a cross-disorder genome-wide association study of functional impairment in major depressive disorder, bipolar disorder, and schizophrenia. Am J Med Genet B Neuropsychiatr Genet 162B:779-88
Stein, Jason L; Medland, Sarah E; Vasquez, Alejandro Arias et al. (2012) Identification of common variants associated with human hippocampal and intracranial volumes. Nat Genet 44:552-61

Showing the most recent 10 out of 24 publications