The goal of this project is to identify quantitative trait loci associated with variation in brain structure and function. The ultimate promise of this research is the discovery of genes that predispose to brain disorders and mental illnesses. We believe that the analysis of genetic influences on brain structure and function in randomly sampled extended pedigrees will provide significant clues regarding the genes that are involved in both normal and pathological brain function. The focus of the project is on the genetic dissection of quantitative endophenotypes that more directly index the underlying biological basis of brain function than do discrete disease states themselves. To this end, we will perform neuroimaging and conduct neuropsychological examinations on Mexican American individuals who have been part of our ongoing genetic research studies for the past 15 years. All participants were previously genotyped and our plan is to utilize existing genome scan and genome-wide quantitative transcriptomic data for correlation with neuroanatomic and neurocognitive variables.
Our specific aims are to: 1) perform high quality brain magnetic resonance imaging and neuropsychological examinations on 1,000 Mexican Americans who are members of approximately 30 large extended families, 2) assess the quantitative genetic architecture of brain-related phenotypes by estimating their heritabilities and their genetic correlations, 3) classify specific brain morphological variables and quantitative leukocyte-derived gene expression measures as endophenotypes related to brain function, 4) localize QTLs influencing variation in the quantitative brain-related phenotypes by performing linkage-based genome scanning using the variance component method, 5) refine the position of localized QTLs and identify positional candidate loci using an objective prioritization strategy that jointly utilizes in silico bioinformatics, genetic, and transcriptional data, and 6) identify the most likely functional variations within the two best positional candidate genes. This project involves coordinated R01 applications from Dr. John Blangero, Southwest Foundation for Biomedical Research, and Drs. David Glahn and Peter Fox, University of Texas Health Science Center at San Antonio. If funded, our data and biomaterials will be incorporated into the NIMH Human Genetics Initiative making them available to qualified researchers in the wider scientific community. Relevance to agency mission: Brain-related mental diseases are a major public health burden whose biology is still largely unknown. By identifying genes involved in brain function and structure, we will provide novel biological candidates for the determinants of such diseases and thus improve potential for intervention. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
7R01MH078143-04
Application #
7786738
Study Section
Behavioral Genetics and Epidemiology Study Section (BGES)
Program Officer
Lehner, Thomas
Project Start
2006-08-01
Project End
2011-07-31
Budget Start
2009-03-05
Budget End
2009-07-31
Support Year
4
Fiscal Year
2008
Total Cost
$399,735
Indirect Cost
Name
Yale University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Knowles, Emma E M; Mathias, Samuel R; Mollon, Josephine et al. (2018) A QTL on chromosome 3q23 influences processing speed in humans. Genes Brain Behav :e12530
Knowles, Emma E M; Curran, Joanne E; Meikle, Peter J et al. (2018) Disentangling the genetic overlap between cholesterol and suicide risk. Neuropsychopharmacology 43:2556-2563
Hodgson, Karen; Almasy, Laura; Knowles, Emma E M et al. (2017) The genetic basis of the comorbidity between cannabis use and major depression. Addiction 112:113-123
Knowles, E E M; Huynh, K; Meikle, P J et al. (2017) The lipidome in major depressive disorder: Shared genetic influence for ether-phosphatidylcholines, a plasma-based phenotype related to inflammation, and disease risk. Eur Psychiatry 43:44-50
Hodgson, Karen; Carless, Melanie A; Kulkarni, Hemant et al. (2017) Epigenetic Age Acceleration Assessed with Human White-Matter Images. J Neurosci 37:4735-4743
Kulkarni, Hemant; Mamtani, Manju; Wong, Gerard et al. (2017) Genetic correlation of the plasma lipidome with type 2 diabetes, prediabetes and insulin resistance in Mexican American families. BMC Genet 18:48
Knowles, Emma E M; Kent Jr, Jack W; McKay, D Reese et al. (2016) Genome-wide linkage on chromosome 10q26 for a dimensional scale of major depression. J Affect Disord 191:123-31
Mamtani, Manju; Kulkarni, Hemant; Wong, Gerard et al. (2016) Lipidomic risk score independently and cost-effectively predicts risk of future type 2 diabetes: results from diverse cohorts. Lipids Health Dis 15:67
Kulkarni, Hemant; Mamtani, Manju; Peralta, Juan Manuel et al. (2016) Lack of Association between SLC30A8 Variants and Type 2 Diabetes in Mexican American Families. J Diabetes Res 2016:6463214
Kulkarni, Hemant; Mamtani, Manju; Peralta, Juan et al. (2016) Soluble Forms of Intercellular and Vascular Cell Adhesion Molecules Independently Predict Progression to Type 2 Diabetes in Mexican American Families. PLoS One 11:e0151177

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