While human behavioral phenotypes are invariably heterogeneous, an emerging literature supports the supposition that both genetic heritability and environmental influences contribute to behavioral conditions and disorders commonly diagnosed in children. Nevertheless, the pathways by which genetics, as well as maternal stress, depression and anxiety influence childhood behavior remain obscure. Utilizing a publically available, unbiased genome-wide association study (GWAS), we identified polymorphisms in genes associated with measures of childhood conduct problems, inattention, hyperactivity emotional symptoms, peer problems and prosocial behavior in children with ADHD. We hypothesize that maternal mental illness during pregnancy, or its pharmacological treatment, may alter the offspring's vulnerability to later psychopathology and that genetic variation will increase the offspring's risk developing childhood psychopathology. This hypothesis will be tested by examining associations of 1) polymorphisms in evidence-based candidate genes with phenotypes prospectively-evaluated, high-risk children born to women who were mentally ill during pregnancy 2) methylation patterns of those candidate genes in placental tissue with traits and behaviors measured in these children, and 3) the expression of mRNA encoded by those genes in placental tissue. This research proposal along with the didactic coursework and interaction with the multidisciplinary mentoring team provides a training platform designed to accomplish the following training goals: acquiring proficiency with 1) phenotypic characterization and the biological underpinnings of childhood psychopathology 2) the principles of bioinformatics and biostatistics as they apply to the design, conduct, and analysis of family-based association studies and 3) the technical and methodological issues related to methylation and gene expression analysis as they apply to psychiatric genetic research. Upon completion of the proposed project and the formal training described in the education plan, the candidate will have made significant progress towards initiating an independent academic career.

Public Health Relevance

The children of women with mood or anxiety disorders ate at increased risk for the development of psychopathology. The examination of environmental and genetic predictors in prospectively- evaluated children will provide insight into the development of mental illness and will help to identify those requiring intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01MH085806-01A1
Application #
7894270
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Sesma, Michael A
Project Start
2010-04-21
Project End
2014-02-28
Budget Start
2010-04-21
Budget End
2011-02-28
Support Year
1
Fiscal Year
2010
Total Cost
$128,119
Indirect Cost
Name
Emory University
Department
Psychiatry
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Smith, Alicia K; Jovanovic, Tanja; Kilaru, Varun et al. (2017) A Gene-Based Analysis of Acoustic Startle Latency. Front Psychiatry 8:117
Maddox, S A; Kilaru, V; Shin, J et al. (2017) Estrogen-dependent association of HDAC4 with fear in female mice and women with PTSD. Mol Psychiatry :
Johnson, Nicholas D; Wiener, Howard W; Smith, Alicia K et al. (2017) Non-linear patterns in age-related DNA methylation may reflect CD4+ T cell differentiation. Epigenetics 12:492-503
Smearman, Erica L; Almli, Lynn M; Conneely, Karen N et al. (2016) Oxytocin Receptor Genetic and Epigenetic Variations: Association With Child Abuse and Adult Psychiatric Symptoms. Child Dev 87:122-34
Parets, Sasha E; Conneely, Karen N; Kilaru, Varun et al. (2015) DNA methylation provides insight into intergenerational risk for preterm birth in African Americans. Epigenetics 10:784-92
Kaminsky, Z; Wilcox, H C; Eaton, W W et al. (2015) Epigenetic and genetic variation at SKA2 predict suicidal behavior and post-traumatic stress disorder. Transl Psychiatry 5:e627
Logue, Mark W; Amstadter, Ananda B; Baker, Dewleen G et al. (2015) The Psychiatric Genomics Consortium Posttraumatic Stress Disorder Workgroup: Posttraumatic Stress Disorder Enters the Age of Large-Scale Genomic Collaboration. Neuropsychopharmacology 40:2287-97
Smith, Alicia K; Kilaru, Varun; Klengel, Torsten et al. (2015) DNA extracted from saliva for methylation studies of psychiatric traits: evidence tissue specificity and relatedness to brain. Am J Med Genet B Neuropsychiatr Genet 168B:36-44
Almli, Lynn M; Fani, Negar; Smith, Alicia K et al. (2014) Genetic approaches to understanding post-traumatic stress disorder. Int J Neuropsychopharmacol 17:355-70
Smith, Alicia K; Kilaru, Varun; Kocak, Mehmet et al. (2014) Methylation quantitative trait loci (meQTLs) are consistently detected across ancestry, developmental stage, and tissue type. BMC Genomics 15:145

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