Identification of genetic loci that overlap between major depressive disorder and insomnia using the conditional false discovery rate analysis / 四川精神卫生

ABSTRACT

BackgroundMajor depressive disorder and insomnia often coexist， and the two may share a mechanism of pathogenesis and be affected by common underlying genes with strong pleiotropic effects. Previous genome-wide association studies （GWAS） mainly focused on single-gene morphological characters analysis， which impose limitations on showing possible pleiotropic effects. ObjectiveTo identify genetic loci related to insomnia and major depressive disorder， and to examine whether there are common genetic factors underlying both insomnia and depression. MethodsThe GWAS data for major depressive disorder originates from the Psychiatric Genomics Consortium （PGC）， which comprises a total of 246 363 depressive cases and 561 190 controls. The insomnia GWAS data was downloaded from Sleep Disorder Knowledge Portal， involving 1 331 010 participants. Then the conditional false discovery rate （cFDR） and conjunction cFDR （ccFDR） were utilized to identify the genetic loci associated with major depressive disorder and insomnia， and pathway enrichment analysis was performed to examine the biological functions of these loci. ResultsA significant pleiotropic effect was detected between major depressive disorder and insomnia. By leveraging pleiotropic enrichment， 21 susceptibility loci （17 novel loci） for major depressive disorder and 38 susceptibility loci （28 novel loci） for insomnia were identified with the threshold of cFDR<0.01. A total of 16 pleiotropic loci （15 novel loci） related to both major depressive disorder and insomnia were identified with the threshold of ccFDR<0.05. pathway enrichment analysis indicated that the susceptibility loci were mainly enriched in synaptic transmission pathway， such as postsynaptic density （GO：0014069， P=4.91E-04， FDR=4.84E-03）， asymmetric synapse （GO：0032279， P=5.09E-04， FDR=4.84E-03）， and regulation of postsynaptic membrane neurotransmitter receptor levels （GO：0099072， P=5.11E-04， FDR=1.69E-02）. ConclusionA significant pleiotropic enrichment is found between major depressive disorder and insomnia， and the comorbidity mechanism is related to synaptic transmission. ［Funded by Tianjin Health Science and Technology Project （number， TJWJ2021QN065）； Tianjin Key Medical Discipline （Specialty） Construction Project （number， TJYXZDXK-033A）］