| Objective: To identify the genetic loci and explore the common genetic basis between major depressive disorder and insomnia by using condFDR and conjFDR based on the genome-wide association study data related to major depressive disorder and insomnia.Methods: The genome-wide association study(GWAS)data sets were downloaded from the Psychiatric Genomics Consortium and Sleep Disorder Knowledge Portal.The major depressive disorder related GWAS data including 561190 controls and 246363 cases,and the insomnia related GWAS data involving 1331010 subjects.Firstly,we used the stratified conditional quantile-quantile plots to compare the degree of association between the overlapping SNPs and to assess the the pleiotropic enrichment between major depressive disorder and insomnia.Then,the condFDR and conjFDR was used to identify pleiotropic genetic loci significantly associated with major depressive disorder and insomnia.And all identified susceptibility loci were annotated in the corresponding chromosomal and genes.Finally,we used gene function annotation and path enrichment analysis to further determine the biological functions of the susceptibility sites.Results:1.The stratified conditional quantile-quantile plot and conditional enrichment graph showed that there was significant genetic pleiotropic enrichment between major depressive disorder and insomnia.2.A total of 21 susceptibility loci and major depressive disorder were identified in this study with a significance threshold of condFDR<0.01,including 17 new genetic variation loci.Pathway enrichment analysis showed that these susceptibility loci were enriched in synaptic transmission related pathways,including "intrinsic component of postsynaptic membrane"(GO:0098936;P=1.07E-04;FDR=2.35E-03),"integral component of synaptic membrane"(GO:0099699;P=2.17E-04;FDR=2.38E-03),"intrinsic component of postsynaptic density membrane"(GO:0099146;P=7.92E-04;FDR=5.76E-03),"integral component of postsynaptic specialization membrane"(GO:0099060;P=1.48E-03;FDR=5.76E-03)and "postsynaptic density membrane"(GO:0098839;P=1.52E-03;FDR=5.76E-03).At the same time,38 genetic variation loci were identified with significant associations with insomnia,including 28 newly discovered susceptibility loci.3.The conjFDR analysis identified 16 independent pleiotropic SNPs for both major depressive disorder and insomnia(conjFDR<0.05),15 of which were newly discovered.Pathway enrichment analysis showed that the enrichment of susceptibility loci associated with synaptic transmission path,including the "postsynaptic density"(GO:0014069;P=4.91E-04;FDR=4.84E-03),"asymmetric synapse"(GO:0032279;P=5.09E-04;FDR=4.84E-03),"regulation of postsynaptic membrane neurotransmitter receptor levels"(GO:0099072;P=5.11E-04;FDR=1.69E-02),"dendritic spine"(GO:0043197;P=3.14E-03;FDR=1.99E-02)and "protein C-terminus binding"(GO:0008022;P=4.05E-03;FDR=2.84E-02).Conclusion:Based on the method of condFDR and conjFDR,this study found that there was a significant pleiotropic enrichment between major depressive disorder and insomnia.Multiple new genetic pleiotropic loci were identified by conjFDR analysis,and the functions of the genes located at these loci were enriched in synaptic pathways,indicating some potential common genetic mechanisms between major depressive disorder and insomnia.The results provide important clues and scientific basis for studying the etiology and comorbidity of major depressive disorder and insomnia. |
