The Depression GWAS Risk Allele Predicts Smaller Cerebellar Gray Matter Volume and Reduced SIRT1 mRNA Expression in Chinese Population

Major depressive disorder (MDD) is recognized as a primary cause of disability worldwide, and effective management of this illness has been a great challenge. While genetic component is supposed to play pivotal roles in MDD pathogenesis, its genetic and phenotypic heterogeneity has hampered successful discovery of its genetic determinants. In this study, we conducted replication analyses of genetic loci highlighted in a previous Chinese MDD genome-wide association studies (GWAS) in an independent Han Chinese sample (1,824 MDD cases and 3,031 controls), and have confirmed the significant association between MDD and a previous highlighted single nucleotide polymorphism (SNP) rs12415800 near SIRT1. Subsequently, using hypothesis-free whole-brain analysis in two independent Han Chinese imaging samples, we found that individuals carrying the MDD risk allele of rs12415800 exhibited aberrant gray matter volume in the left posterior cerebellar lobe compared with those carrying the non-risk allele. Further, in two independent Han Chinese postmortem brain samples, the MDD risk allele of rs12415800 predicted lower SIRT1 mRNA levels, which was consistent with the reduced expression of this gene in MDD patients compared with healthy subjects. These results provide further evidence for the involvement of SIRT1 in MDD, and suggest that this gene might participate in the illness via affecting the development of cerebellum, a brain region that is potentially underestimated in previous MDD studies. Funding Statement: This work was supported by grants from National Natural Science Foundation of China (81722019 to M.L., 31701133 to X.X., 81825009 to W.Y., 81571313 to W.Y.); Yunnan Applied Basic Research Projects (2018FB051 to X.X.); National Key RD the medical and health science and technology project in Zhejiang (2018KY721 to D.S.Z.); the Major Science and Technology Projects in Ningbo, Zhejiang Province, China (2017C510012); the Medical Science and Technology Project in Ningbo, Zhejiang Province, China (2017A10). Xiao Xiao was also supported by the Chinese Academy of Sciences Western Light Program, and Youth Innovation Promotion Association, CAS. Ming Li was also supported by CAS Pioneer Hundred Talents Program and the 1000 Young Talents Program. Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: All the protocols and methods were approved by the institutional review board of Kunming Institute of Zoology, Chinese Academy of Sciences, and the ethics committees of all participating hospitals and universities. Written informed consents from all participants were obtained prior to the study.