期刊
PSYCHOLOGICAL MEDICINE
卷 50, 期 3, 页码 384-395出版社
CAMBRIDGE UNIV PRESS
DOI: 10.1017/S0033291719000072
关键词
Major depressive disorder; MRI; parallel ICA; whole exome sequencing
资金
- National Nature Science Foundation of China Key Project [91332205, 81130024, 81630030]
- National Key Technology R&D Program of the Ministry of Science and Technology of China [2016YFC0904300]
- National Natural Science Foundation of China/Research Grants Council of Hong Kong Joint Research Scheme [8141101084]
- Natural Science Foundation of China [8157051859]
- Sichuan Science & Technology Department [2015JY0173]
- 1.3.5 Project for disciplines of excellence, West China Hospital of Sichuan University [ZY2016103, ZY2016203]
Background Major depressive disorder (MDD) is a leading cause of disability worldwide and influenced by both environmental and genetic factors. Genetic studies of MDD have focused on common variants and have been constrained by the heterogeneity of clinical symptoms. Methods We sequenced the exome of 77 cases and 245 controls of Han Chinese ancestry and scanned their brain. Burden tests of rare variants were performed first to explore the association between genes/pathways and MDD. Secondly, parallel Independent Component Analysis was conducted to investigate genetic underpinnings of gray matter volume (GMV) changes of MDD. Results Two genes (CSMD1, p = 5.32x10(-6); CNTNAP5, p = 1.32x10(-6)) and one pathway (Neuroactive Ligand Receptor Interactive, p = 1.29x10(-5)) achieved significance in burden test. In addition, we identified one pair of imaging-genetic components of significant correlation (r = 0.38, p = 9.92x10(-6)). The imaging component reflected decreased GMV in cases and correlated with intelligence quotient (IQ). IQ mediated the effects of GMV on MDD. The genetic component enriched in two gene sets, namely Singling by G-protein coupled receptors [false discovery rate (FDR) q = 3.23x10(-4)) and Alzheimer Disease Up (FDR q = 6.12x10(-4)). Conclusions Both rare variants analysis and imaging-genetic analysis found evidence corresponding with the neuroinflammation and synaptic plasticity hypotheses of MDD. The mediation of IQ indicates that genetic component may act on MDD through GMV alteration and cognitive impairment.
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