Schizophrenia (SCZ) is a common, lifelong, disabling disorder with unsatisfactory treatment, motivating research into its causation and pathogenesis. The heritability of SCZ is estimated at over 70%, yet recent GWAS mega analyses have explained a relatively small fraction of the heritability. Another portion of the heritability is lkely due to rare loci. Although by definition the rare loci may affect risk in only a small number of individuals, investigations of diseases such as familial hypercholesterolemia show that the rare loci can potentially teach us much about the etiology of disease and even indicate new avenues of treatment. Recent publications support this contention. We propose to identify rare SCZ loci with large effects through highly selected extended pedigrees. We will leverage resources from an ongoing NIH funded Multiplex- Multigenerational Genetic Investigation (MGI). Over the past ten years, through a three- site collaboration, we have identified, intensively characterized and investigated over 43 multiplex, multigenerational SCZ pedigrees and community controls. MGI has a wealth of phenotypic data, including gene expression, structural and functional brain imaging, and neurocognitive performance measures, as well as standard clinical symptom, diagnostic and functional information on participants. From this sample, we have identified four extended families, each with three or more individuals with SCZ and an unusually high number of additional family members with non-SCZ Axis I diagnoses.
We aim to identify rare SCZ risk variants in these families using an efficient and cost effective strategy that combines novel founder-specific linkage analyses, whole genome sequencing of selected individuals and panels of selected SNPs. Using the available extensive quantitative data, we will investigate the expression of the risk loci beyond affection status and take a dimensional approach to vulnerability and severity. We will also investigate the expression of the rare variants in neurons differentiated from induced pluripotent stem cells. By investigating a range of highly relevant phenotypes, our proposal aims to go beyond disease gene mapping to initiate an understanding of SCZ pathogenesis. Our consortium brings expertise in SCZ, neurobiology, neurocognition, neuroimaging, and genetics to this effort. We have made all existing tissue samples and data available to the scientific community and will continue to do so.

Public Health Relevance

Schizophrenia is a highly heritable, complex brain disorder that has devastating effects on the individual and family. Understanding the genetic basis of the deficits in brain function is an important key to early detection and to advance treatments. Our goal is to identify rare genetic variations that contribute to the brain deficits and the risk for schizophrenia, using extensive family based resources that we have already accumulated. We will also exploit the latest genetic technologies to achieve our goals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH063480-14
Application #
9417083
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Koester, Susan E
Project Start
2001-07-24
Project End
2018-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
14
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Psychiatry
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Nimgaonkar, V L; Prasad, K M; Chowdari, K V et al. (2017) The complement system: a gateway to gene-environment interactions in schizophrenia pathogenesis. Mol Psychiatry 22:1554-1561
John, Jibin; Kukshal, Prachi; Bhatia, Triptish et al. (2017) Possible role of rare variants in Trace amine associated receptor 1 in schizophrenia. Schizophr Res 189:190-195
Kos, Mark Z; Carless, Melanie A; Peralta, Juan et al. (2017) Exome sequences of multiplex, multigenerational families reveal schizophrenia risk loci with potential implications for neurocognitive performance. Am J Med Genet B Neuropsychiatr Genet 174:817-827
Bhatia, Triptish; Mazumdar, Sati; Wood, Joel et al. (2017) A randomised controlled trial of adjunctive yoga and adjunctive physical exercise training for cognitive dysfunction in schizophrenia. Acta Neuropsychiatr 29:102-114
D'Aiuto, Leonardo; Williamson, Kelly; Dimitrion, Peter et al. (2017) Comparison of three cell-based drug screening platforms for HSV-1 infection. Antiviral Res 142:136-140
Mansour, Hader A; Wood, Joel; Chowdari, Kodavali V et al. (2017) Associations between period 3 gene polymorphisms and sleep- /chronotype-related variables in patients with late-life insomnia. Chronobiol Int 34:624-631
Bhatia, Triptish; Wood, Joel; Iyengar, Satish et al. (2017) Emotion discrimination in humans: Its association with HSV-1 infection and its improvement with antiviral treatment. Schizophr Res :
Prasad, Suman; Bhatia, Triptish; Kukshal, Prachi et al. (2017) Attempts to replicate genetic associations with schizophrenia in a cohort from north India. NPJ Schizophr 3:28
Singh, Sadhana; Singh, Kavita; Trivedi, Richa et al. (2016) Microstructural abnormalities of uncinate fasciculus as a function of impaired cognition in schizophrenia: A DTI study. J Biosci 41:419-26
Watson, Annie; Pribadi, Mochtar; Chowdari, Kodavali et al. (2016) C9orf72 repeat expansions that cause frontotemporal dementia are detectable among patients with psychosis. Psychiatry Res 235:200-2

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