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; Consortium36 SCZ Consortium36; B. Su; L. Gan

doi:10.1038/mp.2013.103

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 RujescuV. 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, Consortium36 SCZ Consortium36, B. Su, L. Gan

Research output: Contribution to journal › Article › peer-review

42 Scopus citations

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.

Original language	English (US)
Pages (from-to)	774-783
Number of pages	10
Journal	Molecular Psychiatry
Volume	19
Issue number	7
DOIs	https://doi.org/10.1038/mp.2013.103
State	Published - Jul 2014
Externally published	Yes

Keywords

CAMKK2
association
eQTL
expression
protein-protein interaction
schizophrenia

ASJC Scopus subject areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/mp.2013.103

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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., ... Gan, L. (2014). Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene. Molecular Psychiatry, 19(7), 774-783. https://doi.org/10.1038/mp.2013.103

Luo, XJ, 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, DA, Tosato, S, Suvisaari, J, Rujescu, D, Golimbet, V, Silagadze, T, Durmishi, N, Milovancevic, MP, Stefansson, H, Schulze, TG, Nöthen, MM, Chen, C, Lyne, R, Morris, DW, Gill, M, Corvin, A, Zhang, D, Dong, Q, Moyzis, RK, Stefansson, K, Sigurdsson, E, Hu, F, SCZ Consortium36, C, Su, B & Gan, L 2014, 'Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene', Molecular Psychiatry, vol. 19, no. 7, pp. 774-783. https://doi.org/10.1038/mp.2013.103

@article{2b1c92d6189346238dc2c13fda9ee732,

title = "Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene",

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.",

keywords = "CAMKK2, association, eQTL, expression, protein-protein interaction, schizophrenia",

author = "Luo, {X. J.} and M. Li and L. Huang and S. Steinberg and M. Mattheisen and G. Liang and G. Donohoe and Y. Shi and C. Chen and W. Yue and A. Alkelai and B. Lerer and Z. Li and Q. Yi and M. Rietschel and S. Cichon and Collier, {D. A.} and S. Tosato and J. Suvisaari and Dan Rujescu and V. Golimbet and T. Silagadze and N. Durmishi and Milovancevic, {M. P.} and H. Stefansson and Schulze, {T. G.} and N{\"o}then, {M. M.} and C. Chen and R. Lyne and Morris, {D. W.} and M. Gill and A. Corvin and D. Zhang and Q. Dong and Moyzis, {R. K.} and K. Stefansson and E. Sigurdsson and F. Hu and {SCZ Consortium36}, Consortium36 and B. Su and L. Gan",

note = "Funding Information: 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.",

year = "2014",

month = jul,

doi = "10.1038/mp.2013.103",

language = "English (US)",

volume = "19",

pages = "774--783",

journal = "Molecular Psychiatry",

issn = "1359-4184",

publisher = "Nature Publishing Group",

number = "7",

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TY - JOUR

T1 - Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene

AU - Luo, X. J.

AU - Li, M.

AU - Huang, L.

AU - Steinberg, S.

AU - Mattheisen, M.

AU - Liang, G.

AU - Donohoe, G.

AU - Shi, Y.

AU - Chen, C.

AU - Yue, W.

AU - Alkelai, A.

AU - Lerer, B.

AU - Li, Z.

AU - Yi, Q.

AU - Rietschel, M.

AU - Cichon, S.

AU - Collier, D. A.

AU - Tosato, S.

AU - Suvisaari, J.

AU - Rujescu, Dan

AU - Golimbet, V.

AU - Silagadze, T.

AU - Durmishi, N.

AU - Milovancevic, M. P.

AU - Stefansson, H.

AU - Schulze, T. G.

AU - Nöthen, M. M.

AU - Chen, C.

AU - Lyne, R.

AU - Morris, D. W.

AU - Gill, M.

AU - Corvin, A.

AU - Zhang, D.

AU - Dong, Q.

AU - Moyzis, R. K.

AU - Stefansson, K.

AU - Sigurdsson, E.

AU - Hu, F.

AU - SCZ Consortium36, Consortium36

AU - Su, B.

AU - Gan, L.

N1 - Funding Information: 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.

PY - 2014/7

Y1 - 2014/7

N2 - 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.

AB - 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.

KW - CAMKK2

KW - association

KW - eQTL

KW - expression

KW - protein-protein interaction

KW - schizophrenia

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Convergent lines of evidence support CAMKK2 as a schizophrenia susceptibility gene

Abstract

Keywords

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