| Objective: The pathogenesis of alcohol dependence and major depressive disorder is complex,and the comorbidity rate is high,causing a heavy social burden,however,the pathological mechanism of the comorbidity is still unclear.Genetics is an important factor in causing alcohol dependence and major depressive disorder.In this study,we aimed to explore the common genetic characteristics of the two diseases based on genome-wide screening of common susceptibility loci and genes between alcohol dependence and major depressive disorder.Methods: The conditional/conjunctional false discovery rate（cond FDR/conj FDR）approach,a statistical framework for analysis of Genome-wide association study（GWAS）summary data,which has improved yield of existing GWAS and enhanced the ability of findings of genetic overlap between a wide range of complex phenotypes.In this study,we analyzed independent GWAS summary statistics for alcohol dependence（14,904 cases and 37,944 controls）and major depressive disorder（346,363 cases and 561,190 controls）using a cond FDR/conj FDR to detect the genetic correlation between the two disorders and to screen the variation loci and genes of the two diseases.Results:1.In this study,we observed cross-trait polygenic enrichment in alcohol dependence conditional on associations with major depressive disorder,and vice versa,indicating polygenic overlap in the two disorders.2.Based on this enrichment,we identified 5 variation loci associated with alcohol dependence syndrome,including RBMS3 rs7644567,ADH1 B rs1229984,ADH1 C rs2453980,ADH1 C rs6827898,and OR9Q1rs78945376 in which OR9Q1 rs78945376 is a novel loci.Moreover,we found 8 variation loci associated with major depressive disorder,including LRRIQ3 rs12129573,RAB9BP1 rs12658032,PTPRD rs7869639,MIR3924 rs10825942,CNNM2 rs11191479,LRFN5 rs1950829,KC6rs72903982 and TCF4 rs2060886,in which PTPRD rs7869639,MIR3924 rs10825942,CNNM2 rs11191479,KC6 rs72903982 and TCF4rs2060886 were new variation loci at cond FDR < 0.01.3.We further identified 1 loci jointly（KCNG2 rs7236339）associated with alcohol dependence syndrome and major depressive disorder（conj FDR < 0.05）.Interestingly,this loci show concordant directions of effect for alcohol dependence syndrome and major depressive disorder.Conclusion: In this study,we identified 1 alcohol dependence new variation loci,5 major depressive disorder new variation loci and 1 loci jointly associated with alcohol dependence and major depressive disorder.These results highlight a shared underlying molecular genetic mechanism for alcohol dependence and major depressive disorder,which may help to explain the high comorbidity rates,overlapping pathophysiological and clinical symptoms between alcohol dependence and major depressive disorder.This study provide new ideas for elucidating the potential genetic mechanism of alcohol dependence and major depressive disorder comorbidity,and the development of pharmacological and other novel interventions based on the new loci identified may provide new strategies for the clinical treatment of this comorbidity. |
