Abstract
Accumulating evidence suggests that genetic factors have a role in major depressive disorder (MDD). However, only limited MDD risk loci have been identified so far. Here we perform a meta-analysis (a total of 90,150 MDD cases and 246,603 controls) through combing three genome-wide association studies of MDD, including 23andMe (cases were self-reported with a clinical diagnosis or treatment of depression), CONVERGE (cases were diagnosed using the Composite International Diagnostic Interview) and PGC (cases were diagnosed using direct structured diagnostic interview (by trained interviewers) or clinician-administered DSM-IV checklists). Genetic variants from two previously unreported loci (rs10457592 on 6q16.2 and rs2004910 on 12q24.31) showed significant associations with MDD (P < 5 × 10−8) in a total of 336,753 subjects. SNPs (a total of 171) with a P < 1 × 10−7 in the meta-analysis were further replicated in an independent sample (GS:SFHS, 2,659 MDD cases (diagnosed with DSM-IV) and 17,237 controls) and one additional risk locus (rs3785234 on 16p13.3, P = 1.57 × 10−8) was identified in the combined samples (a total of 92,809 cases and 263,840 controls). Risk variants on the identified risk loci were associated with gene expression in human brain tissues and mRNA expression analysis showed that FBXL4 and RSRC1 were significantly upregulated in brains of MDD cases compared with controls, suggesting that genetic variants may confer risk of MDD through regulating the expression of these two genes. Our study identified three novel risk loci (6q16.2, 12q24.31, and 16p13.3) for MDD and suggested that FBXL4 and RSRC1 may play a role in MDD. Further functional characterization of the identified risk genes may provide new insights for MDD pathogenesis.
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Acknowledgements
This study was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB13000000 to X.-J.L), the National Key Research and Development Program of China (Stem Cell and Translational Research) (2016YFA0100900 to X.-J.L), the National Natural Science Foundation of China (31722029 to X.-J.L, 81471358 and 81671326 to C.Z.), and the Key Research Project of Yunnan Province (2017FA008 to X.-J.L). X.-J.L was also supported by the 1000 Young Talents Program. Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award “STratifying Resilience and Depression Longitudinally” (STRADL) Reference 104036/Z/14/Z). We would like to thank the research participants and employees of 23andMe for making this work possible. We thank the following members of the 23andMe Research Team: Michelle Agee, Babak Alipanahi, Adam Auton, Robert K. Bell, Katarzyna Bryc, Sarah L. Elson, Pierre Fontanillas, Nicholas A. Furlotte, David A. Hinds, Karen E. Huber, Aaron Kleinman, Nadia K. Litterman, Jennifer C. McCreight, Matthew H. McIntyre, Joanna L. Mountain, Elizabeth S. Noblin, Carrie A.M. Northover, Steven J. Pitts, J. Fah Sathirapongsasuti, Olga V. Sazonova, Janie F. Shelton, Suyash Shringarpure, Chao Tian, Joyce Y. Tung, Vladimir Vacic, and Catherine H. Wilson, who generated and made the summary statistics available for us, which made this work possible.
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Li, X., Luo, Z., Gu, C. et al. Common variants on 6q16.2, 12q24.31 and 16p13.3 are associated with major depressive disorder. Neuropsychopharmacol 43, 2146–2153 (2018). https://doi.org/10.1038/s41386-018-0078-9
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DOI: https://doi.org/10.1038/s41386-018-0078-9
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