Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene

X-j Luo, M Li, L Huang, S Steinberg, M Mattheisen, G Liang, G Donohoe, Y Shi, C Chen, W Yue, A Alkelai, B Lerer, Z Li, Q Yi, M Rietschel, S Cichon, D A Collier, S Tosato, J Suvisaari, Dan Rujescu, V Golimbet, T Silagadze, N Durmishi, M P Milovancevic, H Stefansson, T G Schulze, M M Nöthen, C Chen, R Lyne, D W Morris, M Gill, A Corvin, D Zhang, Q Dong, R K Moyzis, K Stefansson, E Sigurdsson, F Hu, B Su, L Gan

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.Molecular Psychiatry advance online publication, 20 August 2013; doi:10.1038/mp.2013.103.