Identified Pleiotropic Genetic Susceptible Loci Associated With Alcohol Dependence And Bipolar Disorder Based On Genome-wide Association Study Data

Objective: Bipolar disorder and alcohol dependence are common mental disorders,and there is a significant co-disease between them,but the basis of the two diseases is not clear.In this study,based on the whole gene association data of bipolar disorder and alcohol dependence,the multiple susceptibility sites associated with the two diseases were identified and the biological functions of the multiple susceptibility sites were preliminarily discussed,to provide scientific clues for the study of the genetic basis of co-diseases of the two diseases.Methods: The genome-wide association data in this study were all from an open database.The whole-genome association data for bipolar disorder were obtained from 20352 patients with bipolar disorder and31358 normal controls.The genome-wide association data for alcohol dependence were collected from 941280 subjects.First of all,in this study,we can determine the overlap of single nucleotide polymorphism sites between bipolar disorder and alcohol dependence by constructing conditional fractal map,and then evaluate the enrichment degree between bipolar disorder and alcohol dependence.Secondly,using the conditional false discovery rate and taking the association degree between the genetic variation locus and one of the diseases as the reference condition,the association degree between the genetic variation locus and the other disease was calculated,and then the susceptibility sites with significant association between the two diseases were found.Finally,based on the research results of the above conditional false discovery rate,the conjunctional conditional false discovery rate method is used to identify the multiple genetic loci significantly associated with the two diseases at the same time.In addition,gene annotation was performed for the loci found in this study,and pathway enrichment analysis was used to explore their biological functions.Results:(1)Conditional quantile map showed significant genetic pleiotropy enrichment in bipolar disorder and alcohol dependence.(2)Using conditional false discovery rate method,30 susceptible sites were identified and significantly associated with bipolar disorder(cond FDR <0.01),of which 21 were newly found.The results of gene annotation and pathway enrichment analysis showed that the susceptible loci were concentrated in somatic development(somatodendritic compartment,GO:0036477;P=1.60E-02;FDR=2.35E-03),neuronal cell body(neuronal cell body,GO:0043025;P=2.00E-02;FDR=2.38E-03),calmodulin binding(calmodulin binding,GO:0005516;p=2.31E-02;FDR=2.60E-02),organic acid metabolism process(organic acid metabolic process,GO:0006082;P=3.86E-02;FDR=5.76E-03),actin cytoskeleton organization(actin cytoskeleton organization,GO:0030036;P=3.90E-02;FDR=5.76E-03).(3)The study found 18 loci of variation associated with alcohol dependence,all at significant levels,including nine that were new to the study,which are enriched in carbohydrate metabolism process(carbohydrate metabolic process,GO:0005975;P=6.41E-03,FDR=0.18),monosaccharide metabolism process(monosaccharide metabolism process,GO:0005996;P=1.56E-02,FDR=0.18),generation of precursor metabolites and energy,(generation of precursor metabolites and energy,GO:0006091;P=3.96E-02,FDR=0.18),integral component of the membrane(integral component of membrane,GO:0016021;P=4.30E-02,FDR=0.18).(4)With Conj FDR <0.05 as the significance threshold,a total of 5 pleiotrogenic genetic loci associated with bipolar disorder and alcohol dependence were found,including 5 newly discovered in this study.These loci were concentrated in the following pathways,including intracellular protein transport(intracellular protein transport,GO:0006886;P=1.87E-02.FDR=0.08),RNA binding(RNA bending,GO:0003723;P=4.00E-02;FDR=0.04),cellular protein localization(cellular protein localization,GO:0034613;P=4.84E-02;FDR=0.08).Conclusion: This study found that genetic pleiotropy exists between bipolar disorder and alcohol dependence.30 susceptible sites of bipolar disorder and 18 susceptible sites of alcohol dependence were identified by conditional false discovery rate analysis.In addition,five pleiotropy susceptibility sites were identified to be significantly associated with the two.Pathway analysis showed that the pleiotropy susceptibility sites were enriched in the pathways related to protein and RNA expression,which suggested that there was a potential common genetic mechanism between the two.The results of this study provide important clues and scientific basis for the study of their common pathological mechanism.