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Cereb Cortex. 2017 Mar 1;27(3):2034-2040. doi: 10.1093/cercor/bhw056.

ALDH2 Glu504Lys Confers Susceptibility to Schizophrenia and Impacts Hippocampal-Prefrontal Functional Connectivity.

Zheng F1,2,3, Yan H2,3, Liu B1,4, Yue W2,3, Fan L1, Liao J2,3, Cui Y1,4, Lu T2,3, Jiang T1,4,5,6, Zhang D2,7,8,3.

Author information

1
Brainnetome Center.
2
Institute of Mental Health, The Sixth Hospital.
3
Key Laboratory of Mental Health, Ministry of Health & National Clinical Research Center for Mental Disorders (Peking University), Beijing, China.
4
National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing, China.
5
Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
6
Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu, China.
7
Peking-Tsinghua Center for Life Sciences.
8
PKU-IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.

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.

KEYWORDS:

Glu504Lys; PFC; functional connectivity; hippocampus; schizophrenia

PMID:
26941382
DOI:
10.1093/cercor/bhw056
[Indexed for MEDLINE]

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