Contributions of MTHFR Genotype to Frontal Lobe Dysfunction in Schizophrenia


Principal Investigator: JOSHUA LAWRENCE ROFFMAN
Abstract: This is an application for an NIMH Patient Oriented Research Career Development Award (K23) entitled "Contributions of MTHFR Genotype to Frontal Lobe Dysfunction in Schizophrenia." Although schizophrenia (Sz) is a strongly heritable disorder, the search for risk-conferring genes has been hindered by their relatively small individual contributions to clinical phenotypes. In recent years, Sz neuroimagers have attempted to amplify the signal of risk alleles by measuring their effects on the level of brain physiology, rather than behavior. This approach has yielded results that are robust and internally consistent, but largely disconnected from cellular and molecular pathophysiology, and more importantly, to drug discovery. The candidate's interest is in the full translational potential of imaging-genetics, as a way station connecting basic mechanisms and novel treatments for cognitive impairment in Sz. Toward this end, the candidate's previous and proposed work concerns how functional genetic variants at the intersection of two biochemical pathways implicated in Sz - folate and dopamine metabolism - contribute to prefrontal and working memory function. In retrospective studies, the candidate has associated the MTHFR C677T polymorphism with working memory and prefrontal dysfunction in Sz patients. These effects were further magnified through a diagnostically specific interaction with COMT Val158Met genotype, suggesting that the MTHFR T allele may exacerbate prefrontal dopamine deficiencies in Sz. The planned study, a prospective functional magnetic resonance imaging (fMRI) investigation of genetically matched Sz patients and healthy controls, will attempt to validate and fine-tune the proposed mechanism of deleterious MTHFR effects on working memory in Sz. MTHFR and COMT genotype will be mapped to prefrontal function during maintenance and temporal updating components of working memory, using tasks that have been tied to prefrontal dopamine signaling. The proposed research plan, didactic courses, and individual instruction from mentors, advisors, and other consultants will foster the candidate's development into an independent clinical investigator in the functional neuroimaging of gene effects in Sz. RELEVANCE (See instructions): There remain few effective treatments for cognitive impairment in schizophrenia. It is hoped that these Studies will lay a foundation for the development of new and more efficient cognitive enhancement strategies, based on individual genetic variation and its downstream effects on brain function. The genes of interest, MTHFR and COMT, contribute to two related biochemical pathways that have been implicated in schizophrenia, and are that amenable to targeted interventions with drugs currently in development.
Funding Period: 2009-07-01 - 2014-08-31
more information: NIH RePORT

Top Publications

  1. pmc Vitamin supplementation in the treatment of schizophrenia
    Hannah E Brown
    Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA
    CNS Drugs 28:611-22. 2014

Detail Information


  1. pmc Vitamin supplementation in the treatment of schizophrenia
    Hannah E Brown
    Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, MA, 02114, USA
    CNS Drugs 28:611-22. 2014

Research Grants30

    Fulton T Crews; Fiscal Year: 2013
    ..The ARC will conduct, promote, support, and mentor research on alcoholic pathology and educate broad groups of health professionals and youth in North Carolina. ..
  2. Defining and Treating Written Language Disabilities
    VIRGINIA WISE BERNINGER; Fiscal Year: 2013
    ..The proposed multidisciplinary research has practical significance for improving diagnosis and providing more effective services which may lower such risks. ..
  3. Schizophrenia Pharmacogenetics: cognition and symptom response to antipsychotics
    Jeffrey R Bishop; Fiscal Year: 2013
    ..Through the investigation of relationships between sensitive measures of brain function with common variations in genes related to drug treatments and disease we will advance our ability to predict response in individual patients. ..
  4. Antipsychotic Treatment Effects on Attention &Working Memory in Schizophrenia
    James L Reilly; Fiscal Year: 2013
    ..abstract_text> ..
    John Morris; Fiscal Year: 2013
    ..Together, these projects and their supporting cores will focus on preclinical DAT in comparison with healthy brain aging and address the issue of detecting preclinical disease. ..