Our goal is to identify genes that are enriched for rare or de novo genomic deletions or duplications in persons with schizophrenia and to determine the functional consequences of these mutations. Structural genomic variants are important causes of human genetic variation and are increasingly implicated in human disease. We have shown that rare deletions and duplications that impact genes are significantly more frequent among individuals with schizophrenia than among controls. These mutations disproportionately affect genes involved with neural development. Other investigators have shown that de novo structural mutations are 8-fold more frequent among individuals with sporadic schizophrenia compared to controls. Using a gene-based design, we propose to identify genes that are disproportionately altered by structural mutations in persons with schizophrenia. We anticipate that a gene important to schizophrenia will harbor different disease-causing mutations in different affected individuals (Aim 1). We also will identify genes with de novo structural mutations in patients with sporadic schizophrenia (Aim 2). The consequences of structural mutations in the most significant candidate genes will be characterized experimentally to determine the impacts of mutations on gene function (Aim 3). Cases have been assessed and sampled by four NIMH projects. These projects together have enrolled 1155 probands, 259 affected relatives, and 2965 unaffected relatives, including 431 proband-parent trios. Controls will be drawn from >3000 unrelated unaffected persons age >30 years from NIMH distribution 5. All cases and controls will be screened identically genome-wide with NimbleGen 2.1-million feature HD2 arrays, which can detect deletions and duplications as small as 3kb. Screening of the NIMH controls is supported by independent funds. If successful, our approach will identify multiple genes important for schizophrenia. Each of these genes should stimulate future efforts to develop more effective treatment and prevention strategies.
Structural mutations are increasingly recognized to play an important role in human disease. Our goal is to use state-of-the-art genomic tools to detect these mutations anywhere in the genome, and to identify genes that are more often impacted by structural mutations in persons with schizophrenia compared to healthy controls.
|Gulsuner, Suleyman; McClellan, Jon M (2015) Copy number variation in schizophrenia. Neuropsychopharmacology 40:252-4|
|Gulsuner, Suleyman; McClellan, Jon M (2014) De novo mutations in schizophrenia disrupt genes co-expressed in fetal prefrontal cortex. Neuropsychopharmacology 39:238-9|
|Rippey, Caitlin; Walsh, Tom; Gulsuner, Suleyman et al. (2013) Formation of chimeric genes by copy-number variation as a mutational mechanism in schizophrenia. Am J Hum Genet 93:697-710|
|Gulsuner, Suleyman; Walsh, Tom; Watts, Amanda C et al. (2013) Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network. Cell 154:518-29|
|Frazier, Jean A; Giuliano, Anthony J; Johnson, Jacqueline L et al. (2012) Neurocognitive outcomes in the Treatment of Early-Onset Schizophrenia Spectrum Disorders study. J Am Acad Child Adolesc Psychiatry 51:496-505|
|Nord, Alex S; Roeb, Wendy; Dickel, Diane E et al. (2011) Reduced transcript expression of genes affected by inherited and de novo CNVs in autism. Eur J Hum Genet 19:727-31|
|Vacic, Vladimir; McCarthy, Shane; Malhotra, Dheeraj et al. (2011) Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature 471:499-503|
|McCarthy, Shane E; Makarov, Vladimir; Kirov, George et al. (2009) Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 41:1223-7|