title: ALDH2 Glu504Lys Confers Susceptibility to Schizophrenia and Impacts Hippocampal-Prefrontal Functional Connectivity.
abstract: Although previous evidence suggested that ALDH2 is a candidate gene for schizophrenia, the association and underlying mechanisms have never been investigated. Therefore, we investigated ALDH2 as a susceptibility gene for schizophrenia and explored the effect of its polymorphisms on brain functions. In the discovery stage, we detected a positive association between a dominant-negative mutant, Glu504Lys, and schizophrenia (P= 8.01E-5, OR = 1.34, 95% CI = 1.16-1.55). This association was confirmed in the validation stage (P= 3.48E-6, OR = 1.28, 95% CI = 1.15-1.42). The combined P reached a genome-wide significance (Pcombined= 1.32E-9, OR = 1.30, 95% CI = 1.20-1.42). To investigate the neural mechanism linking Glu504Lys to schizophrenia, we calculated the functional connectivity (FC) and applied an imaging genetics strategy using resting-state fMRI data. The imaging analysis revealed a significant interaction of diagnostic group by genotype for FC between the left hippocampus and the prefrontal cortex. In the Glu homozygotes, hippocampal-prefrontal FC correlated inversely with memory performance in the healthy controls and with the PANSS negative score in the schizophrenia patients. Our results supported a role for ALDH2 in the pathophysiology of schizophrenia. Moreover, variation at Glu504Lys disrupts hippocampal-prefrontal FC, which might be the neural mechanism linking it to the disease.
authors.affiliation: Brainnetome Center.|Institute of Mental Health, The Sixth Hospital.|Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, China.
authors.forename: Fanfan
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Institute of Mental Health, The Sixth Hospital.|Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Yan
authors.affiliation: Brainnetome Center.|National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.affiliation: Institute of Mental Health, The Sixth Hospital.|Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Yue
authors.affiliation: Brainnetome Center.
authors.forename: Lingzhong
authors.initials: L
authors.lastname: Fan
authors.affiliation: Institute of Mental Health, The Sixth Hospital.|Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, China.
authors.forename: Jinmin
authors.initials: J
authors.lastname: Liao
authors.affiliation: Brainnetome Center.|National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Institute of Mental Health, The Sixth Hospital.|Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, China.
authors.forename: Tianlan
authors.initials: T
authors.lastname: Lu
authors.affiliation: Brainnetome Center.|National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.|Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.|Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China.
authors.forename: Tianzi
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Institute of Mental Health, The Sixth Hospital.|Peking-Tsinghua Center for Life Sciences.|PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.|Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, China.
authors.forename: Dai
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000071396:Aldehyde Dehydrogenase, Mitochondrial / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D001931:Brain Mapping; D002681:China; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000503:physiopathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D009434:Neural Pathways / Q000000981:diagnostic imaging / Q000503:physiopathology; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000503:physiopathology*; D011569:Psychiatric Status Rating Scales; D012146:Rest; D012559:Schizophrenia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology*
chemical_list: C096127:ALDH2 protein, human; D000071396:Aldehyde Dehydrogenase, Mitochondrial
keywords: Glu504Lys; PFC; functional connectivity; hippocampus; schizophrenia