Organized neuronal firing is crucial for cortical processing and is disrupted in schizophrenia. Using rapid amplification of 5′ complementary DNA ends in human brain, we identified a primate-specific isoform (3.1) of the ether-a-go-go–related K+ channel KCNH2 that modulates neuronal firing. KCNH2-3.1 messenger RNA levels are comparable to full-length KCNH2 (1A) levels in brain but three orders of magnitude lower in heart. In hippocampus from individuals with schizophrenia, KCNH2-3.1 expression is 2.5-fold greater than KCNH2-1A expression. A meta-analysis of five clinical data sets (367 families, 1,158 unrelated cases and 1,704 controls) shows association of single nucleotide polymorphisms in KCNH2 with schizophrenia. Risk-associated alleles predict lower intelligence quotient scores and speed of cognitive processing, altered memory-linked functional magnetic resonance imaging signals and increased KCNH2-3.1 mRNA levels in postmortem hippocampus. KCNH2-3.1 lacks a domain that is crucial for slow channel deactivation. Overexpression of KCNH2-3.1 in primary cortical neurons induces a rapidly deactivating K+ current and a high-frequency, nonadapting firing pattern. These results identify a previously undescribed KCNH2 channel isoform involved in cortical physiology, cognition and psychosis, providing a potential new therapeutic drug target.
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Ioannidis, J.P., Ntzani, E.E., Trikalinos, T.A. & Contopoulos-Ioannidis, D.G. Replication validity of genetic association studies. Nat. Genet. 29, 306–309 (2001).
Trikalinos, T.A., Ntzani, E.E., Contopoulos-Ioannidis, D.G. & Ioannidis, J.P. Establishment of genetic associations for complex diseases is independent of early study findings. Eur. J. Hum. Genet. 12, 762–769 (2004).
Weiss, K.M. & Terwilliger, J.D. How many diseases does it take to map a gene with SNPs? Nat. Genet. 26, 151–157 (2000).
Frayling, T.M. et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007).
Grarup, N. et al. Studies of association of variants near the HHEX, CDKN2A/B, and IGF2BP2 genes with type 2 diabetes and impaired insulin release in 10,705 Danish subjects: validation and extension of genome-wide association studies. Diabetes 56, 3105–3111 (2007).
Callicott, J.H. et al. Abnormal fMRI response of the dorsolateral prefrontal cortex in cognitively intact siblings of patients with schizophrenia. Am. J. Psychiatry 160, 709–719 (2003).
Cannon, T.D. et al. The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia. Am. J. Hum. Genet. 67, 369–382 (2000).
Egan, M.F. et al. Relative risk of attention deficits in siblings of patients with schizophrenia. Am. J. Psychiatry 157, 1309–1316 (2000).
Egan, M.F. et al. Relative risk for cognitive impairments in siblings of patients with schizophrenia. Biol. Psychiatry 50, 98–107 (2001).
Honea, R.A. et al. Is gray matter volume an intermediate phenotype for schizophrenia? A voxel-based morphometry study of patients with schizophrenia and their healthy siblings. Biol. Psychiatry 63, 465–474 (2008).
Winterer, G. et al. Prefrontal broadband noise, working memory and genetic risk for schizophrenia. Am. J. Psychiatry 161, 490–500 (2004).
Winterer, G. & Weinberger, D.R. Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci. 27, 683–690 (2004).
Straub, R.E. & Weinberger, D.R. Schizophrenia genes—famine to feast. Biol. Psychiatry 60, 81–83 (2006).
Peirce, T.R. et al. Convergent evidence for 2′,3′-cyclic nucleotide 3′-phosphodiesterase as a possible susceptibility gene for schizophrenia. Arch. Gen. Psychiatry 63, 18–24 (2006).
Talkowski, M.E., Chowdari, K., Lewis, D.A. & Nimgaonkar, V.L. Can RGS4 polymorphisms be viewed as credible risk factors for schizophrenia? A critical review of the evidence. Schizophr. Bull. 32, 203–208 (2006).
Prabakaran, S. et al. Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol. Psychiatry. 9, 684–697, 643 (2004).
Horvath, S., Xu, X. & Laird, N.M. The family based association test method: strategies for studying general genotype-phenotype associations. Eur. J. Hum. Genet. 9, 301–306 (2001).
The International HapMap Project. The International HapMap Project. Nature 426, 789–796 (2003).
Cloninger, C.R. et al. Genome-wide search for schizophrenia susceptibility loci: the NIMH Genetics Initiative and Millennium Consortium. Am. J. Med. Genet. 81, 275–281 (1998).
Nicodemus, K.K. Catmap: case-control and TDT meta-analysis package. BMC Bioinformatics 9, 130 (2008).
Chanock, S.J. et al. Replicating genotype-phenotype associations. Nature 447, 655–660 (2007).
Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).
Allen, N.C. et al. Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nat. Genet. 40, 827–834 (2008).
Ioannidis, J.P. et al. Assessment of cumulative evidence on genetic associations: interim guidelines. Int. J. Epidemiol. 37, 120–132 (2008).
Guasti, L. et al. Expression pattern of the ether-a-go-go-related (ERG) family proteins in the adult mouse central nervous system: evidence for coassembly of different subunits. J. Comp. Neurol. 491, 157–174 (2005).
Harrison, P.J. The neuropathology of schizophrenia. A critical review of the data and their interpretation. Brain 122, 593–624 (1999).
Weinberger, D.R. et al. Prefrontal neurons and the genetics of schizophrenia. Biol. Psychiatry 50, 825–844 (2001).
Genderson, M.R. et al. Factor analysis of neurocognitive tests in a large sample of schizophrenic probands, their siblings, and healthy controls. Schizophr. Res. 94, 231–239 (2007).
Hariri, A.R. & Weinberger, D.R. Imaging genomics. Br. Med. Bull. 65, 259–270 (2003).
Hariri, A.R. et al. Brain-derived neurotrophic factor val66met polymorphism affects human memory-related hippocampal activity and predicts memory performance. J. Neurosci. 23, 6690–6694 (2003).
Bookheimer, S.Y. et al. Patterns of brain activation in people at risk for Alzheimer's disease. N. Engl. J. Med. 343, 450–456 (2000).
Egan, G. et al. Neural correlates of the emergence of consciousness of thirst. Proc. Natl. Acad. Sci. USA 100, 15241–15246 (2003).
Davachi, L. & Goldman-Rakic, P.S. Primate rhinal cortex participates in both visual recognition and working memory tasks: functional mapping with 2-DG. J. Neurophysiol. 85, 2590–2601 (2001).
Royall, D.R. et al. Executive control function: a review of its promise and challenges for clinical research. A report from the Committee on Research of the American Neuropsychiatric Association. J. Neuropsychiatry Clin. Neurosci. 14, 377–405 (2002).
Gray, J.R., Chabris, C.F. & Braver, T.S. Neural mechanisms of general fluid intelligence. Nat. Neurosci. 6, 316–322 (2003).
Duncan, J. et al. A neural basis for general intelligence. Science 289, 457–460 (2000).
Callicott, J.H. et al. Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cereb. Cortex 10, 1078–1092 (2000).
Kongsamut, S., Kang, J., Chen, X.L., Roehr, J. & Rampe, D. A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs. Eur. J. Pharmacol. 450, 37–41 (2002).
Warmke, J.W. & Ganetzky, B. A family of potassium channel genes related to eag in Drosophila and mammals. Proc. Natl. Acad. Sci. USA 91, 3438–3442 (1994).
Wimmers, S., Bauer, C.K. & Schwarz, J.R. Biophysical properties of heteromultimeric erg K+ channels. Pflugers Arch. 445, 423–430 (2002).
Sanguinetti, M.C. & Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 440, 463–469 (2006).
Morais Cabral, J.H. et al. Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Cell 95, 649–655 (1998).
Bracci, E., Vreugdenhil, M., Hack, S.P. & Jefferys, J.G. On the synchronizing mechanisms of tetanically induced hippocampal oscillations. J. Neurosci. 19, 8104–8113 (1999).
Bazhenov, M., Timofeev, I., Steriade, M. & Sejnowski, T.J. Potassium model for slow (2–3 Hz) in vivo neocortical paroxysmal oscillations. J. Neurophysiol. 92, 1116–1132 (2004).
Canolty, R.T. et al. High gamma power is phase-locked to theta oscillations in human neocortex. Science 313, 1626–1628 (2006).
Chiesa, N., Rosati, B., Arcangeli, A., Olivotto, M. & Wanke, E. A novel role for HERG K+ channels: spike-frequency adaptation. J. Physiol. (Lond.) 501, 313–318 (1997).
Sacco, T., Bruno, A., Wanke, E. & Tempia, F. Functional roles of an ERG current isolated in cerebellar Purkinje neurons. J. Neurophysiol. 90, 1817–1828 (2003).
Wang, Y. et al. Heterogeneity in the pyramidal network of the medial prefrontal cortex. Nat. Neurosci. 9, 534–542 (2006).
Spector, P.S., Curran, M.E., Keating, M.T. & Sanguinetti, M.C. Class III antiarrhythmic drugs block HERG, a human cardiac delayed rectifier K+ channel. Open-channel block by methanesulfonanilides. Circ. Res. 78, 499–503 (1996).
O'Donovan, M.C. et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat. Genet. 40, 1053–1055 (2008).
Sullivan, P.F. et al. Genomewide association for schizophrenia in the CATIE study: results of stage 1. Mol. Psychiatry 13, 570–584 (2008).
Witchel, H.J., Hancox, J.C., Nutt, D.J. & Wilson, S. Antipsychotics, HERG and sudden death. Br. J. Psychiatry 182, 171–172 (2003).
Livak, K.J. Allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Genet. Anal. 14, 143–149 (1999).
Lipska, B.K. et al. Expression of Drosoph. Inf. Serv.C1 binding partners is reduced in schizophrenia and associated with Drosoph. Inf. Serv.C1 SNPs. Hum. Mol. Genet. 15, 1245–1258 (2006).
Smyth, G.K. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat. Appl. Genet. Mol. Biol. 3, Article3 (2004).
Nagappan, G. et al. Control of extracellular cleavage of ProBDNF by high frequency neuronal activity. Proc. Natl. Acad. Sci. USA 106, 1267–1272 (2009).
Luna, A. & Nicodemus, K.K. snp.plotter: an R-based SNP/haplotype association and linkage disequilibrium plotting package. Bioinformatics 23, 774–776 (2007).
We thank J. Hardy, J. Duckworth and P. Momeni for technical assistance with high G-C content sequencing. We also thank J. Hardy, D. Goldman, A. Law and W. Chen for their very helpful review of the manuscript. We thank R. Straub and M. Mayhew for their input on statistical genetics analysis, M. Barenboim for help with bioinformatics and M. Herman and S. Mitkus for their help with postmortem tissue. We are extremely grateful for the assistance of G. Liu and S. Chen in the cloning and sequencing of KCNH2-3.1. We also would like to thank H.-J. Möller, P. Muglia and coworkers at the Department of Psychiatry, Ludwig Maximilians University for their help with subject recruitment and evaluation. S.J. Huffaker was partially supported by the US National Institutes of Health/Cambridge University Health Science Scholars and Medical Scientist Training Programs. Recruitment of the individuals with schizophrenia at Ludwig Maximilians University was supported by GlaxoSmithKline. Human fetal tissue was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland.
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Huffaker, S., Chen, J., Nicodemus, K. et al. A primate-specific, brain isoform of KCNH2 affects cortical physiology, cognition, neuronal repolarization and risk of schizophrenia. Nat Med 15, 509–518 (2009). https://doi.org/10.1038/nm.1962
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