Article open access publication

Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene

Molecular Psychiatry, Springer Nature, ISSN 1359-4184

Volume 19, 7, 2014

DOI:10.1038/mp.2013.103, Dimensions: pub.1027347506, PMID: 23958956,


Luo, X-j * (1) (2)
Li, M (3)
Huang, L (4) (5) (6)
Liang, G (2)
Shi, Y (10)
Chen, C (11)
Yue, W (12) (13)
Alkelai, A (14)
Lerer, B (14)
Li, Z (10)
Yi, Q (15)
Cichon, S (17)
Collier, D A (18) (19)
Tosato, S (20)
Rujescu, Dan (22) (23)
Chen, C (29)
Lyne, R (9)
Gill, M (9)
Corvin, A (9)
Zhang, D (12) (13)
Dong, Q (29)
Stefansson, K (7) (30)
Sigurdsson, E (30) (31)
Hu, F (6)
Su, B (32)
Gan, L * (1) (2)

* Corresponding author



  1. (1) University of Rochester, grid.16416.34
  2. (2) Hangzhou Normal University, grid.410595.c
  3. (3) Lieber Institute for Brain Development, grid.429552.d
  4. (4) Gannan Medical University, grid.440714.2
  5. (5) Jiangxi Provincial People's Hospital, grid.415002.2
  6. (6) Nanchang University, grid.260463.5
  7. (7) deCODE Genetics (Iceland), grid.421812.c
  8. (8) Aarhus University, grid.7048.b, AU
  9. (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
  10. (10) Shanghai Jiao Tong University, grid.16821.3c
  11. (11) University of California, Irvine, grid.266093.8
  12. (12) National Health and Family Planning Commission, grid.453135.5
  13. (13) Peking University Sixth Hospital, grid.459847.3
  14. (14) Hadassah Medical Center, grid.17788.31
  15. (15) First Affiliated Hospital of Xinjiang Medical University, grid.412631.3
  16. (16) Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Mannheim, Mannheim, Germany
  17. (17) University of Bonn, grid.10388.32
  18. (18) Eli Lilly (United Kingdom), grid.418786.4
  19. (19) King's College London, grid.13097.3c
  20. (20) University of Verona, grid.5611.3
  21. (21) National Institute for Health and Welfare, grid.14758.3f
  22. (22) Ludwig Maximilian University of Munich, grid.5252.0
  23. (23) Martin Luther University Halle-Wittenberg, grid.9018.0
  24. (24) Department of Medical Sciences, grid.466123.4
  25. (25) Tbilisi State Medical University, grid.412274.6
  26. (26) Saints Cyril and Methodius University of Skopje, grid.7858.2
  27. (27) University of Belgrade, grid.7149.b
  28. (28) University of Göttingen, grid.7450.6
  29. (29) Beijing Normal University, grid.20513.35
  30. (30) University of Iceland, grid.14013.37
  31. (31) National University Hospital of Iceland, grid.410540.4
  32. (32) Kunming Institute of Zoology, grid.419010.d


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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