Schizophrenia (SZ) is a severe psychiatric disorder with a strong genetic susceptibility. Heritability is estimated to be 70-90% for SZ. Intense efforts using both linkage and association studies to identify susceptibility loci thus far have met only limited success. Recently it has been appreciated that widespread copy number variation (CNV), in the form of duplications and deletions, frequently occurs in the human genome and is a largely unsurveyed source of individual genetic variation. CNV may be an unrecognized source of SZ genetic susceptibility and potentially a confounding influence on prior genetic studies. We propose here to survey the entire nonrepetitive human genome, using arrays with oligonucleotide markers at an average spacing of 1.5 kb, in 1,000 unrelated Ashkenazi Jewish SZ cases and controls as well as in parents of 300 of the SZ cases. Using this population isolate to limit genetic heterogeneity, we will identify large (>100 kb) and small (-15 - 100 kb) CNV, both frequent (>1%) and rare (<1%). We will confirm selected CNV from each of these four classes by quantitative TaqMan PCR. We will characterize breakpoints by long-range PCR followed by DNA sequencing or by FISH to metaphase chromosomes. Using prior high-density SNP genotyping in four genomic regions in these samples, we will investigate linkage disequilibrium patterns between individual CNVs and flanking SNPs. We will compare the CNV of the 300 trios to confirm genetic transmission and, along with the remaining 200 SZ cases and 500 controls, we will code CNV loci. CNVs with overlapping breakpoints will be initially coded as alleles of one locus but will also be evaluated as distinct loci as well. We expect to identify ~1,700 nonredundant CNVs in this study and we will publicly release this data within one month of its generation. These data will be evaluated by joint analysis of trios, cases, and controls for statistically significant evidence of association of one or more CNV loci with SZ. This study will result in a detailed examination of CNV in the Ashkenazim, providing one of the first large-scale evaluations of CNV in humans, and identify CNV loci that may influence SZ susceptibility. Schizophrenia (SZ) is a severe psychiatric disorder that is caused, at least in part, by variation in the DNA of patients'genomes. A new class of variation is the deletion or duplications of stretches of DNA. Using arrays that can scan the human genome for this """"""""copy number variation"""""""", we will examine 1,000 unrelated Ashkenazi Jewish cases and controls as well as in 600 SZ parents. Although SZ is not found at an elevated frequency in individuals of AJ decent, the relative isolation of this population will reduce genome complexity, easing analysis. This study will not only be one of the first large-scale examinations of this type of variation in humans but may also identify variants that may influence whether or not an individual will suffer from SZ.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Bender, Patrick
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Emory University
Schools of Medicine
United States
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Goes, Fernando S; McGrath, John; Avramopoulos, Dimitrios et al. (2015) Genome-wide association study of schizophrenia in Ashkenazi Jews. Am J Med Genet B Neuropsychiatr Genet 168:649-59
Alpatov, Roman; Lesch, Bluma J; Nakamoto-Kinoshita, Mika et al. (2014) A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response. Cell 157:869-81
Mulle, Jennifer Gladys; Pulver, Ann E; McGrath, John A et al. (2014) Reciprocal duplication of the Williams-Beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia. Biol Psychiatry 75:371-7
Satten, Glen A; Allen, Andrew S; Ikeda, Morna et al. (2014) Robust regression analysis of copy number variation data based on a univariate score. PLoS One 9:e86272
Kenny, Eimear E; Pe'er, Itsik; Karban, Amir et al. (2012) A genome-wide scan of Ashkenazi Jewish Crohn's disease suggests novel susceptibility loci. PLoS Genet 8:e1002559
Kaminsky, Erin B; Kaul, Vineith; Paschall, Justin et al. (2011) An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genet Med 13:777-84
Moreno-De-Luca, Daniel; SGENE Consortium; Mulle, Jennifer G et al. (2010) Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia. Am J Hum Genet 87:618-30
Bray, Steven M; Mulle, Jennifer G; Dodd, Anne F et al. (2010) Signatures of founder effects, admixture, and selection in the Ashkenazi Jewish population. Proc Natl Acad Sci U S A 107:16222-7
Bassell, Gary J; Warren, Stephen T (2008) Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 60:201-14