Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene

• Published in: Molecular psychiatry Vol. 19; no. 7; pp. 774 - 783
• Main Authors: Luo, X-j, Li, M, Huang, L, Steinberg, S, Mattheisen, M, Liang, G, Donohoe, G, Shi, Y, Chen, C, Yue, W, Alkelai, A, Lerer, B, Li, Z, Yi, Q, Rietschel, M, Cichon, S, Collier, D A, Tosato, S, Suvisaari, J, Rujescu, Dan, Golimbet, V, Silagadze, T, Durmishi, N, Milovancevic, M P, Stefansson, H, Schulze, T G, Nöthen, M M, Lyne, R, Morris, D W, Gill, M, Corvin, A, Zhang, D, Dong, Q, Moyzis, R K, Stefansson, K, Sigurdsson, E, Hu, F, Su, B, Gan, L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2014; Nature Publishing Group
• Subjects: 631/208/205; 692/699/476/1799; Alleles; Asian Continental Ancestry Group - genetics; Behavioral Sciences; Biological Psychology; Brain - metabolism; Brain research; Calcium-binding protein; Calcium-Calmodulin-Dependent Protein Kinase Kinase - genetics; Calcium-Calmodulin-Dependent Protein Kinase Kinase - metabolism; Calmodulin; Case-Control Studies; Child & adolescent psychiatry; Cognition; Cognitive ability; Databases, Genetic; Disease susceptibility; Down-Regulation; European Continental Ancestry Group - genetics; Gene expression; Genetic aspects; Genetic diversity; Genetic Predisposition to Disease - genetics; Genetic research; Genetics; Genome-Wide Association Study; Genomes; Genomics; Genotype; Hospitals; Humans; Kinases; Laboratories; Lymphoblastoid cell lines; Medicine; Medicine & Public Health; Mental disorders; Mental health; Neurosciences; Ophthalmology; original-article; Pathogenesis; Personality - genetics; Pharmacotherapy; Polymorphism, Single Nucleotide - genetics; Protein Interaction Maps - genetics; Protein kinase; Proteins; Psychiatry; Risk factors; Schizophrenia; Schizophrenia - genetics; Schizophrenic Psychology; Single-nucleotide polymorphism; Beijing China; United Kingdom > UK; Tbilisi Georgia (country); United States > US; Georgia (country); China; Denmark; California; Iceland; Aarhus Denmark; Germany; protein–protein interaction; association; expression; eQTL; schizophrenia; CAMKK2
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2013.103

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 ( CAMKK 2) is significantly downregulated in individuals with schizophrenia in both studies. To seek the potential genetic variants that may regulate the expression of CAMKK 2, we investigated the association between single-nucleotide polymorphisms (SNPs) within CAMKK 2 and the expression level of CAMKK 2. We found one SNP, rs1063843, which is located in intron 17 of CAMKK 2, is strongly associated with the expression level of CAMKK 2 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 CAMKK 2, 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 CAMKK 2 participates in a highly interconnected PPI network formed by top schizophrenia genes, which further supports the potential role of CAMKK 2 in the pathogenesis of schizophrenia. Taken together, these converging lines of evidence strongly suggest that CAMKK 2 may have pivotal roles in schizophrenia susceptibility.