Original Article

The Gene Encoding Protocadherin 9 (PCDH9), a Novel Risk Factor for Major Depressive Disorder

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Abstract

Genomic analyses have identified only a handful of robust risk loci for major depressive disorder (MDD). In addition to the published genome-wide significant genes, it is believed that there are undiscovered ‘treasures’ underlying the current MDD genome-wide association studies (GWASs) and gene expression data sets, and digging into these data will allow better understanding of the illness and development of new therapeutic approaches. For this purpose, we performed a meta-analytic study combining three MDD GWAS data sets (23andMe, CONVERGE, and PGC), and then conducted independent replications of significant loci in two additional samples. The genome-wide significant variants then underwent explorative analyses on MDD-related phenotypes, cognitive function alterations, and gene expression in brains. In the discovery meta-analysis, a previously unidentified single-nucleotide polymorphism (SNP) rs9540720 in the PCDH9 gene was genome-wide significantly associated with MDD (p=1.69 × 10–8 in a total of 89 610 cases and 246 603 controls), and the association was further strengthened when additional replication samples were included (p=1.20 × 10–8 in a total of 136 115 cases and 355 275 controls). The risk SNP was also associated with multiple MDD-related phenotypes and cognitive function impairment in diverse samples. Intriguingly, the risk allele of rs9540720 predicted lower PCDH9 expression, consistent with the diagnostic analysis results that PCDH9 mRNA expression levels in the brain and peripheral blood tissues were reduced in MDD patients compared with healthy controls. These convergent lines of evidence suggest that PCDH9 is likely a novel risk gene for MDD. Our study highlights the necessity and importance of excavating the public data sets to explore risk genes for MDD, and this approach is also applicable to other complex diseases.

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Acknowledgements

This work was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No., XDB13000000), CAS Pioneer Hundred Talents Program (to ML), the National Natural Science Foundation of China (81601176 to FZ), the Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB02020003 to Y-GY), and the Bureau of Frontier Sciences and Education, Chinese Academy of Sciences (QYZDJ-SSW-SMC005 to Y-GY). The microarray data in MDD sample used for the expression analyses described in this manuscript were obtained from dbGaP accession number phs000979.v1.p1. This research was supported by the Intramural Research Program of the NIMH(NCT00001260, 900142).

Author information

Author notes

    • Xiao Xiao
    •  & Fanfan Zheng

    Co-first authors.

    • Xiong-Jian Luo
    •  & Ming Li

    Co-senior authors.

Affiliations

  1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China

    • Xiao Xiao
    • , Hong Chang
    • , Yong-Gang Yao
    • , Xiong-Jian Luo
    •  & Ming Li
  2. Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing, China

    • Fanfan Zheng
  3. State Key Laboratory of Cognitive Neuroscience and Learning, IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing, China

    • Yina Ma
  4. Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China

    • Yong-Gang Yao
    •  & Ming Li

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Corresponding author

Correspondence to Ming Li.

Supplementary information

Supplementary Information accompanies the paper on the Neuropsychopharmacology website (http://www.nature.com/npp)