Major depressive disorder (MDD) is common, with first onset.often in adolescence, recurrent into adulthood, a leading cause of disability woridwide, with a heritability pf 31-50%. It is widely accepted that MDD may involve a vulnerability to natural or experimental alterations in serotonin in certain individuals. Our overall contribution will be to understand how variation in genes and neurocircuitry related to serotonergic tone can modify the risk for MDD by taking advantage of a unique cohort of 3 generations of families at high/low risk for MDD. The cohort has been followed prospectively up to five times over 25 years. All assessments have been conducted blind to previous clinical history, diagnoses of other family members, and include extensive clinical data and biological markers. The design has allowed us to study high-risk populations prior to onset of illness, and thereby disentangle causal effects from compensatory mechanisms. We have clinical data on over 900 subjects, DNA on 307 subjects, structural/functional images on 216 subjects, and EEG on 234 subjects, resulting in the largest available sample of families with MDD who have biological markers. We have strong published clinical and MRI findings. We propose to further study this cohort. We will collect DNA on 150 additional subjects, first targeting subjects who already have MRI and/or EEG data, but not DNA, so that we can more comprehensively address how iserotonin-related genetic variation may lead to changes in brain morphology or function, and whether these changes might mediate the relationship between serotonin genes and MDD. We will expand the number of polymorphisms to test new candidates, and will test for gene by gene (epistatic) and gene by environment interactions. We will conduct focused gene-based genotyping in order to facilitate family-based tests of genetic association to the diagnostic, EEG, and MRI phenotypes collected in this sample. Additionally, we have over 3000 samples of subjects with MDD and about 3000 controls who have been genotyped and characterized whom we will use to follow up genetic findings. There are 4 aims: (1) To collect 150 new 3-generation samples and isolate genomic DNA, (2) to genotype 69 DNA variants in the 3-generation samples, (3) to examine the DNA variants with MDD and other related clinical phenotypes, with MRI, and with EEG phenotypes, and (4) to replicate the top 10% findings in available large genetic samples of MDD and controls. Our findings will be used to guide and generate hypotheses from the other Projects and will also test findings from the other Projects. We will contribute to the translational linking of population, clinical, and basic science and training of investigators in these links.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
5P50MH090966-03
Application #
8378317
Study Section
Special Emphasis Panel (ZMH1-ERB-M)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$103,093
Indirect Cost
$16,219
Name
New York State Psychiatric Institute
Department
Type
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Talati, Ardesheer; Odgerel, Zagaa; Wickramaratne, Priya J et al. (2017) Associations between serotonin transporter and behavioral traits and diagnoses related to anxiety. Psychiatry Res 253:211-219
Hao, Xuejun; Talati, Ardesheer; Shankman, Stewart A et al. (2017) Stability of Cortical Thinning in Persons at Increased Familial Risk for Major Depressive Disorder Across 8 Years. Biol Psychiatry Cogn Neurosci Neuroimaging 2:619-625
Anderson, Micheline R; Miller, Lisa; Wickramaratne, Priya et al. (2017) Genetic Correlates of Spirituality/Religion and Depression: A Study in Offspring and Grandchildren at High and Low Familial Risk for Depression. Spiritual Clin Pract (Wash D C ) 4:43-63
Desai, Jay; Huo, Yuankai; Wang, Zhishun et al. (2017) Reduced perfusion in Broca's area in developmental stuttering. Hum Brain Mapp 38:1865-1874
Svob, Connie; Liu, Jie; Wickramaratne, Priya et al. (2017) Neuroanatomical correlates of familial risk-for-depression and religiosity/spirituality. Spiritual Clin Pract (Wash D C ) 4:32-42
Talati, Ardesheer; Wickramaratne, Priya J; Wesselhoeft, Rikke et al. (2017) Prenatal tobacco exposure, birthweight, and offspring psychopathology. Psychiatry Res 252:346-352
Weissman, Myrna M; Berry, Obianuju O; Warner, Virginia et al. (2016) A 30-Year Study of 3 Generations at High Risk and Low Risk for Depression. JAMA Psychiatry 73:970-7
Talati, Ardesheer; Odgerel, Zagaa; Wickramaratne, Priya J et al. (2016) Brain derived neurotrophic factor moderates associations between maternal smoking during pregnancy and offspring behavioral disorders. Psychiatry Res 245:387-391
Subaran, Ryan L; Odgerel, Zagaa; Swaminathan, Rajeswari et al. (2016) Novel variants in ZNF34 and other brain-expressed transcription factors are shared among early-onset MDD relatives. Am J Med Genet B Neuropsychiatr Genet 171B:333-41
Bansal, Ravi; Peterson, Bradley S; Gingrich, Jay et al. (2016) Serotonin signaling modulates the effects of familial risk for depression on cortical thickness. Psychiatry Res 248:83-93

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