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Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene

Molecular Psychiatry volume 19, pages 774–783 (2014)Cite this article

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Abstract

Genes that are differentially expressed between schizophrenia patients and healthy controls may have key roles in the pathogenesis of schizophrenia. We analyzed two large-scale genome-wide expression studies, which examined changes in gene expression in schizophrenia patients and their matched controls. We found calcium/calmodulin (CAM)-dependent protein kinase kinase 2 (CAMKK2) is significantly downregulated in individuals with schizophrenia in both studies. To seek the potential genetic variants that may regulate the expression of CAMKK2, we investigated the association between single-nucleotide polymorphisms (SNPs) within CAMKK2 and the expression level of CAMKK2. We found one SNP, rs1063843, which is located in intron 17 of CAMKK2, is strongly associated with the expression level of CAMKK2 in human brains (P=1.1 × 10–6) and lymphoblastoid cell lines (the lowest P=8.4 × 10–6). We further investigated the association between rs1063843 and schizophrenia in multiple independent populations (a total of 130 623 subjects) and found rs1063843 is significantly associated with schizophrenia (P=5.17 × 10–5). Interestingly, we found the T allele of rs1063843, which is associated with lower expression level of CAMKK2, has a higher frequency in individuals with schizophrenia in all of the tested samples, suggesting rs1063843 may be a causal variant. We also found that rs1063843 is associated with cognitive function and personality in humans. In addition, protein–protein interaction (PPI) analysis revealed that CAMKK2 participates in a highly interconnected PPI network formed by top schizophrenia genes, which further supports the potential role of CAMKK2 in the pathogenesis of schizophrenia. Taken together, these converging lines of evidence strongly suggest that CAMKK2 may have pivotal roles in schizophrenia susceptibility.

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References

  1. Tandon R, Keshavan MS, Nasrallah HA . Schizophrenia, "just the facts" what we know in 2008. 2. Epidemiology and etiology. Schizophr Res 2008; 102: 1–18.

    Article  PubMed  Google Scholar 

  2. Ng MY, Levinson DF, Faraone SV, Suarez BK, DeLisi LE, Arinami T et al. Meta-analysis of 32 genome-wide linkage studies of schizophrenia. Mol Psychiatry 2009; 14: 774–785.

    Article  CAS  PubMed  Google Scholar 

  3. Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 2003; 73: 34–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hodgkinson CA, Goldman D, Jaeger J, Persaud S, Kane JM, Lipsky RH et al. Disrupted in schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet 2004; 75: 862–872.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Funke B, Finn CT, Plocik AM, Lake S, DeRosse P, Kane JM et al. Association of the DTNBP1 locus with schizophrenia in a US population. Am J Hum Genet 2004; 75: 891–898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ripke S, Sanders AR, Kendler KS, Levinson DF, Sklar P, Holmans PA et al. Genome-wide association study identifies five new schizophrenia loci. Nat Genet 2011; 43: 969–976.

    Article  CAS  Google Scholar 

  7. Rietschel M, Mattheisen M, Degenhardt F, Muhleisen TW, Kirsch P, Esslinger C et al. Association between genetic variation in a region on chromosome 11 and schizophrenia in large samples from Europe. Mol Psychiatry 2011; 17: 906–917.

    Article  PubMed  CAS  Google Scholar 

  8. Steinberg S, de Jong S, Andreassen OA, Werge T, Borglum AD, Mors O et al. Common variants at VRK2 and TCF4 conferring risk of schizophrenia. Hum Mol Genet 2011; 20: 4076–4081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hamshere ML, Walters JT, Smith R, Richards AL, Green E, Grozeva D et al. Genome-wide significant associations in schizophrenia to ITIH3/4, CACNA1C and SDCCAG8, and extensive replication of associations reported by the Schizophrenia PGC. Mol Psychiatry 2012; 18: 708–712.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Ikeda M, Aleksic B, Yamada K, Iwayama-Shigeno Y, Matsuo K, Numata S et al. Genetic evidence for association between NOTCH4 and schizophrenia supported by a GWAS follow-up study in a Japanese population. Mol Psychiatry 2012; 18: 636–638.

    Article  PubMed  CAS  Google Scholar 

  11. Shi Y, Li Z, Xu Q, Wang T, Li T, Shen J et al. Common variants on 8p12 and 1q24.2 confer risk of schizophrenia. Nat Genet 2011; 43: 1224–1227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yue WH, Wang HF, Sun LD, Tang FL, Liu ZH, Zhang HX et al. Genome-wide association study identifies a susceptibility locus for schizophrenia in Han Chinese at 11p11.2. Nat Genet 2011; 43: 1228–1231.

    Article  CAS  PubMed  Google Scholar 

  13. Li J, Zhou G, Ji W, Feng G, Zhao Q, Liu J et al. Common variants in the BCL9 gene conferring risk of schizophrenia. Arch Gen Psychiatry 2011; 68: 232–240.

    Article  CAS  PubMed  Google Scholar 

  14. Purcell SM, Wray NR, Stone JL, Visscher PM, O'Donovan MC, Sullivan PF et al. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009; 460: 748–752.

    CAS  PubMed  Google Scholar 

  15. Stefansson H, Ophoff RA, Steinberg S, Andreassen OA, Cichon S, Rujescu D et al. Common variants conferring risk of schizophrenia. Nature 2009; 460: 744–747.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. O'Donovan MC, Craddock N, Norton N, Williams H, Peirce T, Moskvina V et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 2008; 40: 1053–1055.

    Article  CAS  PubMed  Google Scholar 

  17. Ayalew M, Le-Niculescu H, Levey DF, Jain N, Changala B, Patel SD et al. Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction. Mol Psychiatry 2012; 17: 887–905.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Devon RS, Anderson S, Teague PW, Burgess P, Kipari TM, Semple CA et al. Identification of polymorphisms within disrupted in schizophrenia 1 and disrupted in schizophrenia 2, and an investigation of their association with schizophrenia and bipolar affective disorder. Psychiatr Genet 2001; 11: 71–78.

    Article  CAS  PubMed  Google Scholar 

  19. Hennah W, Varilo T, Kestila M, Paunio T, Arajarvi R, Haukka J et al. Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Hum Mol Genet 2003; 12: 3151–3159.

    Article  CAS  PubMed  Google Scholar 

  20. Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M et al. Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short- and long-term memory. Arch Gen Psychiatry 2005; 62: 1205–1213.

    Article  CAS  PubMed  Google Scholar 

  21. Stefansson H, Sigurdsson E, Steinthorsdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S et al. Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 2002; 71: 877–892.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Williams NM, Preece A, Spurlock G, Norton N, Williams HJ, Zammit S et al. Support for genetic variation in neuregulin 1 and susceptibility to schizophrenia. Mol Psychiatry 2003; 8: 485–487.

    Article  CAS  PubMed  Google Scholar 

  23. Georgieva L, Dimitrova A, Ivanov D, Nikolov I, Williams NM, Grozeva D et al. Support for neuregulin 1 as a susceptibility gene for bipolar disorder and schizophrenia. Biol Psychiatry 2008; 64: 419–427.

    Article  CAS  PubMed  Google Scholar 

  24. Riley B, Thiselton D, Maher BS, Bigdeli T, Wormley B, McMichael GO et al. Replication of association between schizophrenia and ZNF804A in the Irish Case-Control Study of Schizophrenia sample. Mol Psychiatry 2010; 15: 29–37.

    Article  CAS  PubMed  Google Scholar 

  25. Li M, Luo XJ, Xiao X, Shi L, Liu XY, Yin LD et al. Allelic differences between Han Chinese and Europeans for functional variants in ZNF804A and their association with schizophrenia. Am J Psychiatry 2011; 168: 1318–1325.

    Article  PubMed  Google Scholar 

  26. Li T, Li Z, Chen P, Zhao Q, Wang T, Huang K et al. Common variants in major histocompatibility complex region and TCF4 gene are significantly associated with schizophrenia in Han Chinese. Biol Psychiatry 2010; 68: 671–673.

    Article  CAS  PubMed  Google Scholar 

  27. Maycox PR, Kelly F, Taylor A, Bates S, Reid J, Logendra R et al. Analysis of gene expression in two large schizophrenia cohorts identifies multiple changes associated with nerve terminal function. Mol Psychiatry 2009; 14: 1083–1094.

    Article  CAS  PubMed  Google Scholar 

  28. Roussos P, Katsel P, Davis KL, Siever LJ, Haroutunian V . A system-level transcriptomic analysis of schizophrenia using postmortem brain tissue samples. Arch Gen Psychiatry 2012; 69: 1–11.

    Google Scholar 

  29. Fillman SG, Cloonan N, Catts VS, Miller LC, Wong J, McCrossin T et al. Increased inflammatory markers identified in the dorsolateral prefrontal cortex of individuals with schizophrenia. Mol Psychiatry 2012; 18: 2017.

    Google Scholar 

  30. Mistry M, Gillis J, Pavlidis P . Genome-wide expression profiling of schizophrenia using a large combined cohort. Mol Psychiatry 2013; 18: 215–225.

    Article  CAS  PubMed  Google Scholar 

  31. Anderson KA, Means RL, Huang QH, Kemp BE, Goldstein EG, Selbert MA et al. Components of a calmodulin-dependent protein kinase cascade. Molecular cloning, functional characterization and cellular localization of Ca2+/calmodulin-dependent protein kinase kinase beta. J Biol Chem 1998; 273: 31880–31889.

    Article  CAS  PubMed  Google Scholar 

  32. Peters M, Mizuno K, Ris L, Angelo M, Godaux E, Giese KP . Loss of Ca2+/calmodulin kinase kinase beta affects the formation of some, but not all, types of hippocampus-dependent long-term memory. J Neurosci 2003; 23: 9752–9760.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lewis DA, Levitt P . Schizophrenia as a disorder of neurodevelopment. Annu Rev Neurosci 2002; 25: 409–432.

    Article  CAS  PubMed  Google Scholar 

  34. Wayman GA, Kaech S, Grant WF, Davare M, Impey S, Tokumitsu H et al. Regulation of axonal extension and growth cone motility by calmodulin-dependent protein kinase I. J Neurosci 2004; 24: 3786–3794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wayman GA, Impey S, Marks D, Saneyoshi T, Grant WF, Derkach V et al. Activity-dependent dendritic arborization mediated by CaM-kinase I activation and enhanced CREB-dependent transcription of Wnt-2. Neuron 2006; 50: 897–909.

    Article  CAS  PubMed  Google Scholar 

  36. Peters J, Van Kammen DP, Gelernter J, Yao J, Shaw D . Neuropeptide Y-like immunoreactivity in schizophrenia. Relationships with clinical measures. Schizophr Res 1990; 3: 287–294.

    Article  CAS  PubMed  Google Scholar 

  37. Itokawa M, Arai M, Kato S, Ogata Y, Furukawa A, Haga S et al. Association between a novel polymorphism in the promoter region of the neuropeptide Y gene and schizophrenia in humans. Neurosci Lett 2003; 347: 202–204.

    Article  CAS  PubMed  Google Scholar 

  38. Perlstein WM, Carter CS, Noll DC, Cohen JD . Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia. Am J Psychiatry 2001; 158: 1105–1113.

    Article  CAS  PubMed  Google Scholar 

  39. Knable MB, Weinberger DR . Dopamine, the prefrontal cortex and schizophrenia. J Psychopharmacol 1997; 11: 123–131.

    CAS  PubMed  Google Scholar 

  40. Colantuoni C, Lipska BK, Ye T, Hyde TM, Tao R, Leek JT et al. Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature 2011; 478: 519–523.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Stranger BE, Montgomery SB, Dimas AS, Parts L, Stegle O, Ingle CE et al. Patterns of cis regulatory variation in diverse human populations. PLoS Genet 2012; 8: e1002639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Alkelai A, Lupoli S, Greenbaum L, Giegling I, Kohn Y, Sarner-Kanyas K et al. Identification of new schizophrenia susceptibility loci in an ethnically homogeneous, family-based, Arab-Israeli sample. FASEB J 2011; 25: 4011–4023.

    Article  CAS  PubMed  Google Scholar 

  43. Alkelai A, Lupoli S, Greenbaum L, Kohn Y, Kanyas-Sarner K, Ben-Asher E et al. DOCK4 and CEACAM21 as novel schizophrenia candidate genes in the Jewish population. Int J Neuropsychopharmacol 2011; 15: 459–469.

    Article  PubMed  CAS  Google Scholar 

  44. Steinberg S, de Jong S, Mattheisen M, Costas J, Demontis D, Jamain S et al. Common variant at 16p11.2 conferring risk of psychosis. Mol Psychiatry, advance online publication, 20 November 2012; doi:2010.1038/mp.2012.157.

    Article  PubMed  CAS  Google Scholar 

  45. Walters JT, Corvin A, Owen MJ, Williams H, Dragovic M, Quinn EM et al. Psychosis susceptibility gene ZNF804A and cognitive performance in schizophrenia. Arch Gen Psychiatry 2010; 67: 692–700.

    Article  CAS  PubMed  Google Scholar 

  46. Donohoe G, Walters J, Morris DW, Quinn EM, Judge R, Norton N et al. Influence of NOS1 on verbal intelligence and working memory in both patients with schizophrenia and healthy control subjects. Arch Gen Psychiatry 2009; 66: 1045–1054.

    Article  CAS  PubMed  Google Scholar 

  47. Li J, Chen C, Lei X, Wang Y, He Q, Moyzis RK et al. The NTSR1 gene modulates the association between hippocampal structure and working memory performance. Neuroimage 2012; 75: 79–86.

    Article  CAS  PubMed  Google Scholar 

  48. Chen CS, Chen CH, Robert KM, He QH, Lei XM, Li J et al. Genotypes over-represented among college students are linked to better cognitive abilities and socioemotional adjustment. Culture Brain 2013; 1: 47–63.

    Article  Google Scholar 

  49. Barrett JC, Fry B, Maller J, Daly MJ . Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 2005; 21: 263–265.

    Article  CAS  PubMed  Google Scholar 

  50. Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B et al. The structure of haplotype blocks in the human genome. Science 2002; 296: 2225–2229.

    Article  CAS  PubMed  Google Scholar 

  51. Lage K, Karlberg EO, Storling ZM, Olason PI, Pedersen AG, Rigina O et al. A human phenome-interactome network of protein complexes implicated in genetic disorders. Nat Biotechnol 2007; 25: 309–316.

    Article  CAS  PubMed  Google Scholar 

  52. Niculescu AB 3rd, Segal DS, Kuczenski R, Barrett T, Hauger RL, Kelsoe JR . Identifying a series of candidate genes for mania and psychosis: a convergent functional genomics approach. Physiol Genomics 2000; 4: 83–91.

    Article  CAS  PubMed  Google Scholar 

  53. Ogden CA, Rich ME, Schork NJ, Paulus MP, Geyer MA, Lohr JB et al. Candidate genes, pathways and mechanisms for bipolar (manic-depressive) and related disorders: an expanded convergent functional genomics approach. Mol Psychiatry 2004; 9: 1007–1029.

    Article  CAS  PubMed  Google Scholar 

  54. Bertsch B, Ogden CA, Sidhu K, Le-Niculescu H, Kuczenski R, Niculescu AB . Convergent functional genomics: a Bayesian candidate gene identification approach for complex disorders. Methods 2005; 37: 274–279.

    Article  CAS  PubMed  Google Scholar 

  55. Le-Niculescu H, Kurian SM, Yehyawi N, Dike C, Patel SD, Edenberg HJ et al. Identifying blood biomarkers for mood disorders using convergent functional genomics. Mol Psychiatry 2009; 14: 156–174.

    Article  CAS  PubMed  Google Scholar 

  56. Le-Niculescu H, Patel SD, Bhat M, Kuczenski R, Faraone SV, Tsuang MT et al. Convergent functional genomics of genome-wide association data for bipolar disorder: comprehensive identification of candidate genes, pathways and mechanisms. Am J Med Genet B Neuropsychiatr Genet 2009; 150B: 155–181.

    Article  CAS  PubMed  Google Scholar 

  57. Kurian SM, Le-Niculescu H, Patel SD, Bertram D, Davis J, Dike C et al. Identification of blood biomarkers for psychosis using convergent functional genomics. Mol Psychiatry 2011; 16: 37–58.

    Article  CAS  PubMed  Google Scholar 

  58. Rossin EJ, Lage K, Raychaudhuri S, Xavier RJ, Tatar D, Benita Y et al. Proteins encoded in genomic regions associated with immune-mediated disease physically interact and suggest underlying biology. PLoS Genet 2011; 7: e1001273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Luo XJ, Huang L, Li M, Gan L . Protein-protein interaction analysis reveals common molecular processes/pathways that contribute to risk of schizophrenia. Schizophr Res 2013; 143: 390–392.

    Article  PubMed  Google Scholar 

  60. Benita Y, Cao Z, Giallourakis C, Li C, Gardet A, Xavier RJ . Gene enrichment profiles reveal T-cell development, differentiation, and lineage-specific transcription factors including ZBTB25 as a novel NF-AT repressor. Blood 2010; 115: 5376–5384.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kang HJ, Kawasawa YI, Cheng F, Zhu Y, Xu X, Li M et al. Spatio-temporal transcriptome of the human brain. Nature 2011; 478: 483–489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Glatt SJ, Everall IP, Kremen WS, Corbeil J, Sasik R, Khanlou N et al. Comparative gene expression analysis of blood and brain provides concurrent validation of SELENBP1 up-regulation in schizophrenia. Proc Natl Acad Sci USA 2005; 102: 15533–15538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Collin T, Lory P, Taviaux S, Courtieu C, Guilbault P, Berta P et al. Cloning, chromosomal location and functional expression of the human voltage-dependent calcium-channel beta 3 subunit. Eur J Biochem 1994; 220: 257–262.

    Article  CAS  PubMed  Google Scholar 

  64. Buck-Koehntop BA, Mascioni A, Buffy JJ, Veglia G . Structure, dynamics, and membrane topology of stannin: a mediator of neuronal cell apoptosis induced by trimethyltin chloride. J Mol Biol 2005; 354: 652–665.

    Article  CAS  PubMed  Google Scholar 

  65. Hart GW, Haltiwanger RS, Holt GD, Kelly WG . Nucleoplasmic and cytoplasmic glycoproteins. Ciba Found Symp 1989; 145: 102–112, discussion 112-108.

    CAS  PubMed  Google Scholar 

  66. Luciani MF, Denizot F, Savary S, Mattei MG, Chimini G . Cloning of two novel ABC transporters mapping on human chromosome 9. Genomics 1994; 21: 150–159.

    Article  CAS  PubMed  Google Scholar 

  67. Hsu LS, Tsou AP, Chi CW, Lee CH, Chen JY . Cloning, expression and chromosomal localization of human Ca2+/calmodulin-dependent protein kinase kinase. J Biomed Sci 1998; 5: 141–149.

    CAS  PubMed  Google Scholar 

  68. Raney MA, Turcotte LP . Evidence for the involvement of CaMKII and AMPK in Ca2+-dependent signaling pathways regulating FA uptake and oxidation in contracting rodent muscle. J Appl Physiol 2008; 104: 1366–1373.

    Article  CAS  PubMed  Google Scholar 

  69. Sun CY, Qi SS, Lou XF, Sun SH, Wang X, Dai KY et al. Changes of learning, memory and levels of CaMKII, CaM mRNA, CREB mRNA in the hippocampus of chronic multiple-stressed rats. Chin Med J 2006; 119: 140–147.

    Article  CAS  PubMed  Google Scholar 

  70. Cao W, Sohail M, Liu G, Koumbadinga GA, Lobo VG, Xie J . Differential effects of PKA-controlled CaMKK2 variants on neuronal differentiation. RNA Biol 2011; 8: 1061–1072.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Erk S, Meyer-Lindenberg A, Schnell K, Opitz von Boberfeld C, Esslinger C, Kirsch P et al. Brain function in carriers of a genome-wide supported bipolar disorder variant. Arch Gen Psychiatry 2010; 67: 803–811.

    Article  PubMed  Google Scholar 

  72. Ho BC, Milev P, O'Leary DS, Librant A, Andreasen NC, Wassink TH . Cognitive and magnetic resonance imaging brain morphometric correlates of brain-derived neurotrophic factor Val66Met gene polymorphism in patients with schizophrenia and healthy volunteers. Arch Gen Psychiatry 2006; 63: 731–740.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Barnett JH, Heron J, Ring SM, Golding J, Goldman D, Xu K et al. Gender-specific effects of the catechol-O-methyltransferase Val108/158Met polymorphism on cognitive function in children. Am J Psychiatry 2007; 164: 142–149.

    Article  PubMed  Google Scholar 

  74. Kokubo M, Nishio M, Ribar TJ, Anderson KA, West AE, Means AR . BDNF-mediated cerebellar granule cell development is impaired in mice null for CaMKK2 or CaMKIV. J Neurosci 2009; 29: 8901–8913.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Alberini CM, Ghirardi M, Metz R, Kandel ER . C/EBP is an immediate-early gene required for the consolidation of long-term facilitation in aplysia. Cell 1994; 76: 1099–1114.

    Article  CAS  PubMed  Google Scholar 

  76. Bartsch D, Ghirardi M, Skehel PA, Karl KA, Herder SP, Chen M et al. Aplysia CREB2 represses long-term facilitation: relief of repression converts transient facilitation into long-term functional and structural change. Cell 1995; 83: 979–992.

    Article  CAS  PubMed  Google Scholar 

  77. Yin JC, Wallach JS, Del Vecchio M, Wilder EL, Zhou H, Quinn WG et al. Induction of a dominant negative CREB transgene specifically blocks long-term memory in Drosophila. Cell 1994; 79: 49–58.

    Article  CAS  PubMed  Google Scholar 

  78. Yin JC, Del Vecchio M, Zhou H, Tully T . CREB as a memory modulator: induced expression of a dCREB2 activator isoform enhances long-term memory in Drosophila. Cell 1995; 81: 107–115.

    Article  CAS  PubMed  Google Scholar 

  79. Yin JC, Tully T . CREB and the formation of long-term memory. Curr Opin Neurobiol 1996; 6: 264–268.

    Article  CAS  PubMed  Google Scholar 

  80. Bourtchuladze R, Frenguelli B, Blendy J, Cioffi D, Schutz G, Silva AJ . Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein. Cell 1994; 79: 59–68.

    Article  CAS  PubMed  Google Scholar 

  81. Takemoto-Kimura S, Terai H, Takamoto M, Ohmae S, Kikumura S, Segi E et al. Molecular cloning and characterization of CLICK-III/CaMKIgamma, a novel membrane-anchored neuronal Ca2+/calmodulin-dependent protein kinase (CaMK). J Biol Chem 2003; 278: 18597–18605.

    Article  CAS  PubMed  Google Scholar 

  82. Chow FA, Anderson KA, Noeldner PK, Means AR . The autonomous activity of calcium/calmodulin-dependent protein kinase IV is required for its role in transcription. J Biol Chem 2005; 280: 20530–20538.

    Article  CAS  PubMed  Google Scholar 

  83. Lu Y, Christian K, Lu B . BDNF: a key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol Learn Mem 2008; 89: 312–323.

    Article  CAS  PubMed  Google Scholar 

  84. Gilman SR, Chang J, Xu B, Bawa TS, Gogos JA, Karayiorgou M et al. Diverse types of genetic variation converge on functional gene networks involved in schizophrenia. Nat Neurosci 2012; 15: 1723–1728.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Papaleo F, Yang F, Garcia S, Chen J, Lu B, Crawley JN et al. Dysbindin-1 modulates prefrontal cortical activity and schizophrenia-like behaviors via dopamine/D2 pathways. Mol Psychiatry 2010; 17: 85–98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Le-Niculescu H, Balaraman Y, Patel S, Tan J, Sidhu K, Jerome RE et al. Towards understanding the schizophrenia code: an expanded convergent functional genomics approach. Am J Med Genet B Neuropsychiatr Genet 2007; 144B: 129–158.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant no. 81271006 to LG), Hangzhou City Health Science Foundation (Grant no. 20120633B01to LG), the National Natural Science Foundation of China (81060081 to LH), the Jiangxi Provincial Natural Science Foundation (2010GZY0089 to LH, 20114BAB215006 to FH), the Natural Science Foundation of China (U1202225 to BS, 81130022, 81272302, 31000553), the 863 Program (2012AA02A515). EU-Grant HEALTH-2011-286213 (Project PsychDPC). The 111 Project of the Ministry of Education of China (B07008). EU-Grant HEALTH-F2-2009-223423 (Project PsychCNVs), Grants from the Israel Science Foundation (to BL). Schizophrenia PGC data were obtained from Ricopili (http://www.broadinstitute.org/mpg/ricopili/). We thank members of schizophrenia PGC and Stephan Ripke, who developed the Ricopili.

Author information

Author notes

  1. X-j Luo and M Li: These authors contributed equally to this work.

  2. A full list of the members is provided in the Supplementary Data.

Authors and Affiliations

  1. College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China

    X-j Luo, G Liang & L Gan

  2. Department of Ophthalmology and Flaum Eye Institute, University of Rochester, Rochester, NY, USA

    X-j Luo & L Gan

  3. Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA

    M Li

  4. Nanchang University, Nanchang, China

    L Huang

  5. Gannan Medical University, Ganzhou, China

    L Huang

  6. Jiangxi Provincial People’s Hospital, Nanchang, China

    L Huang

  7. deCODE Genetics, Reykjavik, Iceland

    S Steinberg, H Stefansson & K Stefansson

  8. Department of Biomedicine, Aarhus University, Aarhus C, Denmark

    M Mattheisen

  9. Neuropsychiatric Genetics Group and Department of Psychiatry, Institute of Molecular Medicine and Trinity College Institute of Neuroscience, Trinity College Dublin, St James Hospital, Dublin, Ireland

    G Donohoe, R Lyne, D W Morris, M Gill & A Corvin

  10. Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China

    Y Shi & Z Li

  11. Department of Psychology and Social Behavior, University of California, Irvine, CA, USA

    C Chen

  12. Institute of Mental Health, Peking University, Beijing, China

    W Yue & D Zhang

  13. Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China

    W Yue & D Zhang

  14. Department of Psychiatry, Biological Psychiatry Laboratory, Hadassah–Hebrew University Medical Center, Jerusalem, Israel

    A Alkelai & B Lerer

  15. Department of Psychiatry, the First Teaching Hospital of Xinjiang Medical University, Urumqi, China

    Q Yi

  16. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Mannheim, Mannheim, Germany

    M Rietschel

  17. Department of Genomics, Life and Brain Center, and Institute of Human Genetics, University of Bonn, Bonn, Germany

    S Cichon & M M Nöthen

  18. Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King’s College, London, UK

    D A Collier

  19. Eli Lilly and Co. Ltd, Erl Wood Manor, Surrey, UK

    D A Collier

  20. Section of Psychiatry, University of Verona, Verona, Italy

    S Tosato

  21. Mental Health and Substance Abuse Services, National Institute for Health and Welfare THL, Helsinki, Finland

    J Suvisaari

  22. Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians University, Munich, Germany

    Dan Rujescu

  23. Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany

    Dan Rujescu

  24. Mental Health Research Center, Russian Academy of Medical Sciences, Moscow, Russia

    V Golimbet

  25. Department of Psychiatry and Drug Addiction, Tbilisi State Medical University (TSMU), Tbilisi, Georgia

    T Silagadze

  26. Department of Child and Adolescent Psychiatry, University of Skopje, Skopje, Macedonia

    N Durmishi

  27. Medical Faculty, University of Belgrade, Belgrade, Serbia

    M P Milovancevic

  28. Department of Psychiatry and Psychotherapy, University Medical Center Georg-August-Universität, Goettingen, Germany

    T G Schulze

  29. State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China

    C Chen & Q Dong

  30. Department of Biological Chemistry, University of California, Irvine, CA, USA

    R K Moyzis

  31. School of Medicine, University of Iceland, Reykjavik, Iceland

    K Stefansson & E Sigurdsson

  32. Department of Psychiatry, National University Hospital, Reykjavik, Iceland

    E Sigurdsson

  33. Affiliated Eye Hospital of Nanchang University, Nanchang, China

    F Hu

  34. State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China

    B Su

Authors
  1. X-j Luo
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  2. M Li
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  3. L Huang
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  39. B Su
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  40. L Gan
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MooDS SCZ Consortium

Corresponding authors

Correspondence to X-j Luo or L Gan.

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The authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website

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Luo, Xj., Li, M., Huang, L. et al. Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene. Mol Psychiatry 19, 774–783 (2014). https://doi.org/10.1038/mp.2013.103

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  • DOI: https://doi.org/10.1038/mp.2013.103

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