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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Koester, Susan E
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Children's Hospital of Philadelphia
United States
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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
Kos, Mark Z; Carless, Melanie A; Peralta, Juan et al. (2016) Exome Sequence Data From Multigenerational Families Implicate AMPA Receptor Trafficking in Neurocognitive Impairment and Schizophrenia Risk. Schizophr Bull 42:288-300
Roalf, David R; Vandekar, Simon N; Almasy, Laura et al. (2015) Heritability of subcortical and limbic brain volume and shape in multiplex-multigenerational families with schizophrenia. Biol Psychiatry 77:137-46
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Roalf, David R; Gur, Ruben C; Almasy, Laura et al. (2013) Neurocognitive performance stability in a multiplex multigenerational study of schizophrenia. Schizophr Bull 39:1008-17
Da Silva, Felipe N; Irani, Farzin; Richard, Jan et al. (2012) More than just tapping: index finger-tapping measures procedural learning in schizophrenia. Schizophr Res 137:234-40
Yokley, Jessica L; Prasad, Konasale M; Chowdari, Kodavali V et al. (2012) Genetic associations between neuregulin-1 SNPs and neurocognitive function in multigenerational, multiplex schizophrenia families. Psychiatr Genet 22:70-81
Tarbox, Sarah I; Almasy, Laura; Gur, Raquel E et al. (2012) The nature of schizotypy among multigenerational multiplex schizophrenia families. J Abnorm Psychol 121:396-406
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