RAPID PUBLICATION Deletion Q1 at the SLC1A1 Glutamate Transporter Gene Co-Segregates With Schizophrenia and Bipolar Schizoaffective Disorder in a 5-Generation Family Marina Myles-Worsley, 1 * Josepha Tiobech, 2 Sharon R. Browning, 3 Jeremy Korn, 4 Sarah Goodman, 4 Karen Gentile, 4 Nadine Melhem, 5 William Byerley, 6 Stephen V. Faraone, 1,4 and Frank A. Middleton 1,4 1 Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, Syracuse, New York 2 Palau Q2 Ministry of Health, Palau, Republic of Palau 3 Department of Medical Genetics, University of Washington, Seattle, Washington 4 Department of Neuroscience & Physiology, SUNY Upstate Medical University, Syracuse, New York 5 Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 6 Department of Psychiatry, University of California San Francisco, San Francisco, California Manuscript Received: 21 May 2012; Manuscript Accepted: 27 November 2012 Growing evidence for genetic overlap between schizophrenia (SCZ) and bipolar disorder (BPD) suggests that causal variants of large effect on disease risk may cross-traditional diagnostic boundaries. Extended multigenerational families with both SCZ and BPD cases can be a valuable resource for discovery of shared biological pathways because they can reveal the natural evolution of the underlying genetic disruptions and their phe- notypic expression. We investigated a deletion at the SLC1A1 glutamate transporter gene originally identified as a copy num- ber variant exclusively carried by members of a 5-generation Palauan family. Using an expanded sample of 21 family mem- bers, quantitative PCR confirmed the deletion in all seven individuals with psychosis, three ‘‘obligate-carrier’’ parents and one unaffected sibling, while four marry-in parents were non-carriers. Linkage analysis under an autosomal dominant model generated a LOD-score of 3.64, confirming co-segregation of the deletion with psychosis. For more precise localization, we determined the approximate deletion end points using alignment of next-generation sequencing data for one affected deletion-carrier and then designed PCR amplicons to span the entire deletion locus. These probes established that the deletion spans 84,298 bp, thus eliminating the entire promoter, the tran- scription start site, and the first 59 amino acids of the protein, including the first transmembrane Na 2þ /dicarboxylate sym- porter domain, one of the domains that perform the glutamate transport action. Discovery of this functionally relevant SLC1A1 mutation and its co-segregation with psychosis in an extended multigenerational pedigree provides further support for the important role played by glutamatergic transmission in the pathophysiology of psychotic disorders. Ó 2012 Wiley Periodicals, Inc. Key words: schizophrenia; bipolar schizoaffective disorder; psychotic disorders; copy number variant; glutamate; extended multiplex pedigree; population isolate INTRODUCTION Schizophrenia (SCZ) and bipolar disorder (BPD) are highly her- itable, but only a small proportion of their genetic variation has been explained thus far. A productive research direction recently taken by the International Research Consortium [Purcell et al., 2009] and other European investigators [e.g., Moskvina et al., 2009; Frank et al., 2011] is the pursuit of genetic risk variants that cross- traditional diagnostic boundaries between SCZ and BPD. This line of research has revealed growing evidence for genetic overlap between the two disorders [Craddock et al., 2009]. Studies revealing that SCZ susceptibility genes such as Disrupted-in-Schizophrenia-1 The authors declare no conflict of interest. Grant sponsor: NIH; Grant numbers: MH 080373, MH 096257. *Correspondence to: Marina Myles-Worsley, Ph.D., Department of Psychiatry and Behavioral Sciences, SUNY Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210. E-mail: worsleym@upstate.edu Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2012 DOI 10.1002/ajmg.b.32125 How to Cite this Article: Myles-Worsley M, Tiobech J, Browning SR, Korn J, Goodman S, Gentile K, Melhem N, Byerley W, Faraone SV, Middleton FA. 2012. Deletion at the SLC1A1 Glutamate Transporter Gene Co-Segregates With Schizophrenia and Bipolar Schizoaffective Disorder in a Five-Generation Family. Am J Med Genet Part B 9999:1–9. Ó 2012 Wiley Periodicals, Inc. 1 AJMB-12-0089:R2ð32125Þ Neuropsychiatric Genetics