Abstract

This project aims to investigate genomic underpinnings for NMDAR hypofunction in schizophrenia and its possible association with the behavioral phenotypes of asociality during development. NMDARs exist as a macromolecular complex, in which members of various pathways can interact and influence NMDAR funcfion. Thus, the NMDAR pathway could be a molecular substrate for convergent interacfions of genefic variants that can lead to behavioral phenotypes of schizophrenia. We hypothesize that the NMDAR pathway as a whole may contain common and rare genetic variants that are enriched in schizophrenia. Some of these variants may impact the function of basolateral amygdala (BLA) via modulation of gene transcripts. As such, they may play a critical role for the expression of behavioral traits of asociality during development. The NMDAR pathway is highly represented in the BLA transcriptome and our recent GWAS study has shown that common variants of the NMDAR pathways as a whole were associated with schizophrenia. To assess the genomic impact of NMDAR pathway on negative symptoms, we will conduct deep sequencing for NMDAR pathway genes in DNAs from 100 patients with schizophrenia. To assess their roles in BLA function, we will analyze the transcriptome of postmortem BLAs of 50 schizophrenia patients and their matched controls using RNA-Seq, which will then be tested for their association with DNA variants. Genetic variants linked to transcript alterations in the BLA with may play a role in the expression of schizophrenia phenotypes during development. We will assess the association between NMDAR pathway genetic variants that can modulate BLA transcripts with asociality behavioral phenotypes of 1000 adolescents who have been examined by GWAS and behavioral phenotypes.

Public Health Relevance

This project aims to investigate genomic underpinnings for NMDAR hypofunction in schizophrenia and its possible association with the behavioral phenotypes of asociality during development. NMDARs exist as a macromolecular complex, in which members of various pathways can interact and influence NMDAR function. Thus, the NMDAR pathway could be a molecular substrate for convergent interactions of genetic variants that can lead to behavioral phenotypes of schizophrenia.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
4P50MH096891-05
Application #
9118374
Study Section
Special Emphasis Panel (ZMH1)
Project Start
Project End
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
5
Fiscal Year
2016
Total Cost
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Baum, Graham L; Roalf, David R; Cook, Philip A et al. (2018) The impact of in-scanner head motion on structural connectivity derived from diffusion MRI. Neuroimage 173:275-286
Xia, Cedric Huchuan; Ma, Zongming; Ciric, Rastko et al. (2018) Linked dimensions of psychopathology and connectivity in functional brain networks. Nat Commun 9:3003
Gandal, Michael J; Haney, Jillian R; Parikshak, Neelroop N et al. (2018) Shared molecular neuropathology across major psychiatric disorders parallels polygenic overlap. Science 359:693-697
Liu, Yichuan; Chang, Xiao; Hahn, Chang-Gyu et al. (2018) Non-coding RNA dysregulation in the amygdala region of schizophrenia patients contributes to the pathogenesis of the disease. Transl Psychiatry 8:44
Curtis, David (2018) Polygenic risk score for schizophrenia is more strongly associated with ancestry than with schizophrenia. Psychiatr Genet 28:85-89
Chang, Xiao; Lima, Leandro de Araujo; Liu, Yichuan et al. (2018) Common and Rare Genetic Risk Factors Converge in Protein Interaction Networks Underlying Schizophrenia. Front Genet 9:434
Moore, Tyler M; Calkins, Monica E; Reise, Steven P et al. (2018) Development and public release of a computerized adaptive (CAT) version of the Schizotypal Personality Questionnaire. Psychiatry Res 263:250-256
Khan, Atlas; Liu, Qian; Wang, Kai (2018) iMEGES: integrated mental-disorder GEnome score by deep neural network for prioritizing the susceptibility genes for mental disorders in personal genomes. BMC Bioinformatics 19:501
Amiri, Anahita; Coppola, Gianfilippo; Scuderi, Soraya et al. (2018) Transcriptome and epigenome landscape of human cortical development modeled in organoids. Science 362:
Barzilay, Ran; White, Lauren K; Calkins, Monica E et al. (2018) Sex-Specific Association Between High Traumatic Stress Exposure and Social Cognitive Functioning in Youths. Biol Psychiatry Cogn Neurosci Neuroimaging 3:860-867

Showing the most recent 10 out of 87 publications