Schizophrenia (SZ) is a debilitating neuropsychiatric disease with a prevalence of ~1% across diverse cultures and geographic areas. The clinical syndrome likely represents a heterogeneous group of diseases and etiologic paths. Despite evidence of a substantial genetic component, findings from traditional genetic studies have been inconsistent and difficult to replicate [1;2;3;4] seriously hindering progress in the field. An alternative approach is to simplify the problem by using quantifiable neurobiological traits that are reproducible and have increased genetic component. Such traits may mark specific aspects of disease risk that delineate more specific molecular pathways linking susceptibility genes (of small effect) to translated protein or function compared to analysis of behavioral symptoms only [5]. One highly reproducible SZ biomarker (i.e., endophenotype) is the smooth pursuit eye movement abnormality (SPEM, also called eyetracking). The demonstration of SPEM abnormality in SZ has been replicated in over 50 studies with few negative reports [6]. We have shown that the predictive pursuit eyetracking subcomponent of SPEM has a higher heritability (i.e., genetic contribution) than traditional SPEM measures [7;8;9;10]. Notably, we have used predictive pursuit to parse differences in small gene effects between SZ and healthy controls that would otherwise have gone unnoticed using the traditional SPEM measure or clinical diagnosis [11;12]. Studies suggest that predictive pursuit is conceptually similar to working memory (WM) [13;14;15]. WM impairments have emerged as critical predictors of the poor functional outcome and disability observed in SZ [16;17;18]. Thus, identifying the molecular mechanisms underlying predictive pursuit impairment could facilitate the discovery of novel targets for the development of rational pharmacology for cognition enhancement in SZ. Our preliminary results suggest a significant effect of neurexin 3 gene (NRXN3;encodes a family of neuronal proteins essential for synaptic function) [19] variants on predictive pursuit and WM impairments in African-American (AA), but not European-American (EA) SZ individuals, and point to loci-of-interest for more extensive molecular characterization and gene mapping. We have begun fine mapping efforts, but there is an admixture problem. This prompted the need for a homogenous sub-Saharan African sample of Ibos in Nigeria. The African sample will also be useful for other endophenotype-based gene mapping efforts, beyond NRXN3. The goal of the proposed R21 is to build research capacity at the Neuropsychiatric Hospital Rumuigbo, Port Harcourt to generate pilot data in Ibos for a subsequent R01 in a deeply phenotyped sample. The advantages of the Nigerian site include, small linkage disequilibrium (LD) blocks ideal for gene mapping in an old population (similar to the Yoruba in the International HapMap Genome Project), with no admixture problems, and responding to the NIH Fogarty International Center's mission to "to support capacity-building, research infrastructure development, and research mentoring in order to develop a multidisciplinary mental health research workforce in low- and middle-income countries".

Public Health Relevance

This collaborative project between U.S and Nigerian investigators will build capacity for biomedical research at the Nigerian site. It will characterize schizophrenia endophenotypes (or liability markers) in an endogenous sub-Saharan African cohort of Igbo and test the feasibility of performing endophenotype-based genetic studies in this homogenous old population. Findings would provide important insights for future genetic studies, including gene mapping in a population with smaller LD blocks and different genetic architecture.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1-ICP2-B (51))
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Senthil, Geetha
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University of Maryland Baltimore
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United States
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