REVIEW ARTICLE TCF4 (e2-2; ITF2): A Schizophrenia-Associated Gene With Pleiotropic Effects on Human Disease Katherinne Navarrete, 1 Inti Pedroso, 1 Simone De Jong, 2 Hreinn Stefansson, 3 Stacy Steinberg, 3 Kari Stefansson, 3,4 Roel A. Ophoff, 2,5 Leonard C. Schalkwyk, 1 and David A. Collier 1,6 * 1 Social, Genetic and Developmental Psychiatry Centre, King’s College London, Institute of Psychiatry, London, UK 2 UCLA Center for Neurobehavioral Genetics, Gonda Center, Los Angeles, California 3 Decode Genetics, Reykjavik, Iceland 4 Faculty of Medicine, University of Iceland, Reykjavik, Iceland 5 Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands 6 Eli Lilly and Company Ltd, Discovery Neuroscience Research, Erl Wood Manor, Windlesham, UK Manuscript Received: 6 April 2012; Manuscript Accepted: 27 September 2012 Common SNPs in the transcription factor 4 (TCF4; ITF2, E2-2, SEF-2) gene, which encodes a basic Helix-Loop-Helix (bHLH) transcription factor, are associated with schizophrenia, confer- ring a small increase in risk. Other common SNPs in the gene are associated with the common eye disorder Fuch’s corneal dys- trophy, while rare, mostly de novo inactivating mutations cause Pitt-Hopkins syndrome. In this review, we present a systematic bioinformatics and literature review of the genomics, biological function and interactome of TCF4 in the context of schizophre- nia. The TCF4 gene is present in all vertebrates, and although protein length varies, there is high conservation of primary sequence, including the DNA binding domain. Humans have a unique leucine-rich nuclear export signal. There are two main isoforms (A and B), as well as complex splicing generating many possible N-terminal amino acid sequences. TCF4 is highly expressed in the brain, where plays a role in neurodevelopment, interacting with class II bHLH transcription factors Math1, HASH1, and neuroD2. The Ca 2þ sensor protein calmodulin interacts with the DNA binding domain of TCF4, inhibiting transcriptional activation. It is also the target of microRNAs, including mir137, which is implicated in schizophrenia. The schizophrenia-associated SNPs are in linkage disequilibrium with common variants within putative DNA regulatory ele- ments, suggesting that regulation of expression may underlie association with schizophrenia. Combined gene co-expression analyses and curated protein–protein interaction data provide a network involving TCF4 and other putative schizophrenia sus- ceptibility genes. These findings suggest new opportunities for understanding the molecular basis of schizophrenia and other mental disorders. Ó 2012 Wiley Periodicals, Inc. Key words: Pitt-Hopkins syndrome; Fuch’s corneal dystrophy; genome-wide association; protein–protein interaction; gene network INTRODUCTION The TCF4 gene on chromosome 18q21.2 (Entrez Gene ID 6925; ensemble ENSG00000196628) encodes a basic helix-turn-helix (bHLH) Ephrussi-box (‘‘E-box’’ or E-) protein transcription fac- tor. The gene spans 437 kb and has 41 exons. It has multiple aliases in addition to the official HUGO name TCF4 and is also known as E2-2, ITF2, PTHS, SEF2, SEF2-1, SEF2-1A, SEF2-1B, bHLHb19, MGC149723, and MGC149724. The pleiotropic disease associations of TCF4 include rare non-synonymous mutations and gene dele- tions in Pitt-Hopkins syndrome (PHS), and common risk variants for Fuch’s corneal dystrophy (FCD) and schizophrenia, which are genetically distinct from each other. It should not be confused with Additional supporting information may be found in the online version of this article. *Correspondence to: Prof. David A. Collier, Social, Genetic and Developmental Psychiatry Centre, King’s College London, Institute of Psychiatry, De Crespigny Park, Denmark Hill, London SE5 8AF, UK. E-mail: david.collier@kcl.ac.uk Article first published online in Wiley Online Library (wileyonlinelibrary.com): 00 Month 2012 DOI 10.1002/ajmg.b.32109 How to Cite this Article: Navarrete K, Pedroso I, De Jong S, Stefansson H, Steinberg S, Stefansson K, Ophoff RA, Schalkwyk LC, Collier DA. 2012. TCF4 (e2-2; ITF2): A schizophrenia-associated gene with pleiotropic effects on human disease. Am J Med Genet Part B 9999:1–16. Ó 2012 Wiley Periodicals, Inc. 1 Neuropsychiatric Genetics