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.
authors: 1] College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China [2] Department of Ophthalmology and Flaum Eye Institute, University of Rochester, Rochester, NY, USA.
authors: X-J
authors: XJ
authors: Luo
authors: Lieber Institute for Brain Development, Johns Hopkins Medical Campus, Baltimore, MD, USA.
authors: M
authors: M
authors: Li
authors: 1] Nanchang University, Nanchang, China [2] Gannan Medical University, Ganzhou, China [3] Jiangxi Provincial People's Hospital, Nanchang, China.
authors: L
authors: L
authors: Huang
authors: deCODE Genetics, Reykjavik, Iceland.
authors: S
authors: S
authors: Steinberg
authors: Department of Biomedicine, Aarhus University, Aarhus C, Denmark.
authors: M
authors: M
authors: Mattheisen
authors: College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China.
authors: G
authors: G
authors: Liang
authors: 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.
authors: G
authors: G
authors: Donohoe
authors: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
authors: Y
authors: Y
authors: Shi
authors: Department of Psychology and Social Behavior, University of California, Irvine, CA, USA.
authors: C
authors: C
authors: Chen
authors: 1] Institute of Mental Health, Peking University, Beijing, China [2] Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
authors: W
authors: W
authors: Yue
authors: Department of Psychiatry, Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: A
authors: A
authors: Alkelai
authors: Department of Psychiatry, Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: B
authors: B
authors: Lerer
authors: Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), Shanghai Jiao Tong University, Shanghai, China.
authors: Z
authors: Z
authors: Li
authors: Department of Psychiatry, the First Teaching Hospital of Xinjiang Medical University, Urumqi, China.
authors: Q
authors: Q
authors: Yi
authors: Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, University of Mannheim, Mannheim, Germany.
authors: M
authors: M
authors: Rietschel
authors: Department of Genomics, Life and Brain Center, and Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors: S
authors: S
authors: Cichon
authors: 1] Social, Genetic and Developmental Psychiatry Research Centre, Institute of Psychiatry, King's College, London, UK [2] Eli Lilly and Co. Ltd, Erl Wood Manor, Surrey, UK.
authors: D A
authors: DA
authors: Collier
authors: Section of Psychiatry, University of Verona, Verona, Italy.
authors: S
authors: S
authors: Tosato
authors: Mental Health and Substance Abuse Services, National Institute for Health and Welfare THL, Helsinki, Finland.
authors: J
authors: J
authors: Suvisaari
authors: 1] Division of Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig-Maximilians University, Munich, Germany [2] Department of Psychiatry, University of Halle-Wittenberg, Halle, Germany.
authors: Dan
authors: D
authors: Rujescu
authors: Mental Health Research Center, Russian Academy of Medical Sciences, Moscow, Russia.
authors: V
authors: V
authors: Golimbet
authors: Department of Psychiatry and Drug Addiction, Tbilisi State Medical University (TSMU), Tbilisi, Georgia.
authors: T
authors: T
authors: Silagadze
authors: Department of Child and Adolescent Psychiatry, University of Skopje, Skopje, Macedonia.
authors: N
authors: N
authors: Durmishi
authors: Medical Faculty, University of Belgrade, Belgrade, Serbia.
authors: M P
authors: MP
authors: Milovancevic
authors: deCODE Genetics, Reykjavik, Iceland.
authors: H
authors: H
authors: Stefansson
authors: Department of Psychiatry and Psychotherapy, University Medical Center Georg-August-Universität, Goettingen, Germany.
authors: T G
authors: TG
authors: Schulze
authors: Department of Genomics, Life and Brain Center, and Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors: M M
authors: MM
authors: Nöthen
authors: State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China.
authors: C
authors: C
authors: Chen
authors: 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.
authors: R
authors: R
authors: Lyne
authors: 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.
authors: D W
authors: DW
authors: Morris
authors: 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.
authors: M
authors: M
authors: Gill
authors: 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.
authors: A
authors: A
authors: Corvin
authors: 1] Institute of Mental Health, Peking University, Beijing, China [2] Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China.
authors: D
authors: D
authors: Zhang
authors: State Key Laboratory of Cognitive Neuroscience and Learning, Beijing Normal University, Beijing, China.
authors: Q
authors: Q
authors: Dong
authors: Department of Biological Chemistry, University of California, Irvine, CA, USA.
authors: R K
authors: RK
authors: Moyzis
authors: 1] deCODE Genetics, Reykjavik, Iceland [2] School of Medicine, University of Iceland, Reykjavik, Iceland.
authors: K
authors: K
authors: Stefansson
authors: 1] School of Medicine, University of Iceland, Reykjavik, Iceland [2] Department of Psychiatry, National University Hospital, Reykjavik, Iceland.
authors: E
authors: E
authors: Sigurdsson
authors: Affiliated Eye Hospital of Nanchang University, Nanchang, China.
authors: F
authors: F
authors: Hu
authors: State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China.
authors: B
authors: B
authors: Su
authors: 1] College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou, China [2] Department of Ophthalmology and Flaum Eye Institute, University of Rochester, Rochester, NY, USA.
authors: L
authors: L
authors: Gan
mesh_terms: D000483:Alleles; D044466:Asian People / Q000235:genetics; D001921:Brain / Q000378:metabolism; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D003071:Cognition; D030541:Databases, Genetic; D015536:Down-Regulation; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D010551:Personality / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D060066:Protein Interaction Maps / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*; D012565:Schizophrenic Psychology; D044465:White People / Q000235:genetics
chemical_list: C517698:CAMKK2 protein, human; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase
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