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Genetic Variation at the 22Q11 PRODH2 DGCR6 Locus Presents an Unusual Pattern and Increases Susceptibility to Schizophrenia

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Genetic Variation at the 22Q11 PRODH2 DGCR6 Locus Presents an Unusual Pattern and Increases Susceptibility to Schizophrenia Genetic variation at the 22q11 PRODH2͞DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia Hui Liu†, Simon C. Heath‡, Christina Sobin†, J. Louw Roos§, Brandi L. Galke†, Maude L. Blundell†, Marge Lenane¶, Brian Robertsonʈ, Ellen M. Wijsman**, Judith L. Rapoport¶, Joseph A. Gogos††, and Maria Karayiorgou†‡‡ †Human Neurogenetics Laboratory, The Rockefeller University, New York, NY 10021; ‡Memorial Sloan Kettering Cancer Center, New York, NY 10021; §Department of Psychiatry and Weskoppies Hospital, University of Pretoria, Pretoria 0083, Republic of South Africa; ¶Child Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892; ʈDepartment of Psychiatry and Valkenberg Hospital, University of Capetown, Capetown 7925, Republic of South Africa; **Division of Medical Genetics and Department of Biostatistics, University of Washington, Seattle, WA 98195; and ††College of Physicians and Surgeons, Department of Physiology and Cellular Biophysics, Center for Neurobiology and Behavior, Columbia University, New York, NY 10032 Communicated by David E. Housman, Massachusetts Institute of Technology, Cambridge, MA, December 26, 2001 (received for review September 25, 2001) The location of a schizophrenia susceptibility locus at chromosome region harbors genes that alone, or in combination, are causally 22q11 has been suggested by genome-wide linkage studies. Addi- implicated in schizophrenia in a certain proportion of patients. The tional support was provided by the observation of a higher-than- overwhelming majority of the 22q11 deletions are 3 Mb in size, expected frequency of 22q11 microdeletions in patients with schizo- whereas a smaller percentage (Ϸ8%) involve the same proximal Ϸ phrenia and the demonstration that 20–30% of individuals with breakpoint but a different distal breakpoint resulting in a smaller 22q11 microdeletions develop schizophrenia or schizoaffective dis- 1.5-Mb deletion (9, 10). At least one schizophrenic patient has been order in adolescence and adulthood. Analysis of the extent of these described as carrying the smaller 22q11 microdeletion, and there- microdeletions by using polymorphic markers afforded further re- fore the ‘‘schizophrenia critical region’’ has been defined to 1.5 Mb finement of this locus to a region of Ϸ1.5 Mb. Recently, a high rate of (ref. 6). The majority of the genes in the region are known (11). To GENETICS 22q11 microdeletions was also reported for a cohort of 47 patients with Childhood Onset Schizophrenia, a rare and severe form of address the role of individual genes from this chromosomal region, schizophrenia with onset by age 13. It is therefore likely that this we are undertaking systematic mutational screening of these genes 1.5-Mb region contains one or more genes that predispose to schizo- in combination with linkage disequilibrium (LD) studies in family phrenia. In three independent samples, we provide evidence for a samples (triads) that test for preferential transmission of single- contribution of the PRODH2͞DGCR6 locus in 22q11-associated schizo- nucleotide polymorphisms (SNPs) and multi-SNP haplotypes from phrenia. We also uncover an unusual pattern of PRODH2 gene parents to affected individuals. variation that mimics the sequence of a linked pseudogene. Several Materials and Methods of the pseudogene-like variants we identified result in missense changes at conserved residues and may prevent synthesis of a fully Patient Samples. Detailed information about the adult schizo- functional enzyme. Our results have implications for understanding phrenic (AS) sample is provided in ref. 12. The South African the genetic basis of the 22q11-associated psychiatric phenotypes and sample is part of our ongoing collection of schizophrenia patients provide further insights into the genomic instability of this region. of Afrikaner origin and will be described in detail elsewhere (M.K., M. Torrington, C.S., B.R., S.C.H., M.L.B., H. Pretorius, S. Lay, chizophrenia is a common severe mental illness that affects 1% J.A.G., and J.L.R., unpublished work). Probands in both samples Sof the population and is characterized by disordered thinking as met lifetime criteria for Diagnostic and Statistical Manual of well as deficits in emotional and social behavior. Microdeletions of Mental Disorders, 4th Ed. (DSM-IV) (13) schizophrenia or schizo- chromosome 22q11 are associated with variable phenotypic expres- affective disorder. Participants were interviewed by specially sion that often includes learning disabilities, palatal abnormalities, trained clinicians by using the Diagnostic Interview for Genetic congenital heart defects, and mildly dysmorphic facial features (1). Studies (DIGS) (14). Detailed information about the COS sample One of the first clues that psychiatric symptomatology may also be is provided in refs. 7 and 15. All COS probands met unmodified associated with this microdeletion was a report of expressionless criteria for schizophrenia with onset of psychotic symptoms before face, monotonous speech, and flattened affect among children with their 13th birthday and mean age of onset of psychosis at 10.1 (Ϯ1.8 the microdeletion (2). In light of the evidence for suggestive linkage yr). The protocol and the consent forms were approved by the for schizophrenia on chromosome 22 (reviewed in ref. 3), patients Institutional Review Boards (IRBs) at all participating sites. The with the 22q11 microdeletion were evaluated for psychiatric symp- National Institute of Mental Health (NIMH) samples have been toms or disorders, and a relatively high frequency of severe mental obtained from the NIMH Human Genetics Inititative dataset illness has since been reported. Specifically, two independent (http:͞͞ zork.wustl.edu͞nimh). [Acknowledgment for this sample studies have reported that 25–31% of patients with the 22q11 can be found in the Appendix, which is published as supporting microdeletion met diagnostic criteria for schizophrenia or schizo- information on the PNAS web site (www.pnas.org)]. affective disorder (4, 5). Although the microdeletion occurs in the population at a rate of 0.025%, it has been found in 2% of adult schizophrenic patients (6) and in 6% of cases with childhood onset Abbreviations: LD, linkage disequilibrium; COS, childhood onset schizophrenia; SNP, single- schizophrenia (COS) (7). In addition, several studies have described nucleotide polymorphism; AS, adult schizophrenic; DSM-IV, Diagnostic and Statistical 22q11 microdeletions among schizophrenic patients of various Manual of Mental Disorders, fourth edition; NIMH, National Institute of Mental Health; LCR, low copy repeat sequence; RFLP, restriction fragment length polymorphism; HHRR, ethnic origins (8). These studies collectively suggest that the morbid haplotype-based haplotype relative risk; TDT, Transmission Disequilibrium Test; T͞nT, risk of schizophrenia for a patient with a 22q11 microdeletion may Transmitted͞non-Transmitted; CI, confidence interval. be approximately 20–30 times the general population risk of 1%, ‡‡To whom reprint requests should be addressed. E-mail: [email protected]. and that the rate of 22q11 microdeletions in schizophrenia, al- The publication costs of this article were defrayed in part by page charge payment. This though relatively low, may be approximately 80 times the estimated article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. general population rate. It therefore seems likely that the 22q11 §1734 solely to indicate this fact. www.pnas.org͞cgi͞doi͞10.1073͞pnas.042700699 PNAS ͉ March 19, 2002 ͉ vol. 99 ͉ no. 6 ͉ 3717–3722 Downloaded by guest on September 23, 2021 SNP Identification and Genotyping. Methods (16, 17), primers, and PCR conditions can be found in the Appendix, which is published as supporting information on the PNAS web site, www.pnas.org. Somatic Cell Hybrids. Somatic cell hybrid methods are as described in ref. 6. Statistical Analysis. Haplotype probabilities for each individual were calculated assuming no recombination between SNPs, summing over ambiguous haplotypes caused by missing phase information or genotype data. Haplotype frequences were estimated by using the Expectation Maximization algorithm (18) simultaneously with the calculation of haplotype probabilities. For the analyses on multilo- cus SNP haplotypes, trios with ambiguous haplotype reconstruc- tions were used only if there was one reconstruction with a probability of Ͼ0.95. Transmissions of single SNPs were analyzed by using both the haplotype-based Haplotype Relative Risk (HHRR) statistic (19) and the Transmission Disequilibrium Test (TDT) (20) (where the TDT considered only transmissions from heterozygous parents). The significance of the TDT analyses was assessed by using a standard 1 degree of freedom ␹2 test, and the significance of the HHRR tests was assessed by using Fisher’s exact test. Multilocus SNP haplotype transmissions were analyzed by using the HHRR, with the significance being estimated by using Fisher’s exact test. Because of the relatively small size of the COS sample and the stratified adult samples, exact P values are given only for P Ͼ 0.001. Results Association Between PRODH2͞HsPOX2 Locus Variation and Schizophre- nia. A first-stage scan of the 22q11 region involved a set of 18 SNPs from nine gene loci distributed across the entire 1.5 Mb (Fig. 1b, green shading). The inheritance of these variants by probands affected with schizophrenia from parents was examined in 107 independent triads from the U.S. (AS
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