Screening and validation of potential target genes for cardiomyopathy based on Mendelian randomization and Bayesian colocalization analysis

Bai Yu; Liu Jieyun

doi:10.3969/j.issn.1674-4055.2025.09.06

Abstract：Objective To screen and identify the potential targets related to cardiomyopathy treatment at gene level,and provide a preliminary theoretical basis for preventing and controlling this type of disease.Methods Firstly,a summary-data-based Mendelian randomization(SMR)was used to screen potential target genes from eQTLGen database(the source of genetic tissue was whole blood)that might significantly affect the risk of cardiomyopathy.Second,the same target genes were extracted from GTEx database(gene tissue source was myocardial tissue)and evaluated for their genetic impact on cardiomyopathy risk.Again,the genetic correlation between these target genes and cardiomyopathy was verified by Bayesian co-localization analysis,i.e.,whether they shared causal variant loci.Finally,SMR was utilized to assess the effects of these target genes on the risk of 3 specific types of cardiomyopathies,which included disease-associated cardiomyopathies(e.g,diabetic cardiomyopathy and other cardiomyopathies with a clear causative agent),pharmacologic cardiomyopathy,and alcoholic cardiomyopathy.Results There were 10 potential target genes screened among 15 639 alternative genes in eQTLGen database whose expressions in whole blood were significantly correlated to cardiomyopathy risk.Among these genes,7 genes,NARFL,HAGHL,FAM173A,CCDC136,IGHMBP2,CCDC116,and RNASEH2C,were significantly increased cardiomyopathy risk by elevated expression levels in whole blood(P=2.67×10-4,2.08×10-5,2.14×10-5,2.06×10-5,5.27×10-5,7.12×10-4 and 1.21×10-5,respectively).Whereas elevated expression levels of 3 genes,SPATA24,SNX32,and MRPL21,in whole blood significantly reduced cardiomyopathy risk(P=1.46×10-4,5.56×10-4 and 5.58×10-5,respectively).The above 10 genes were also screened in the myocardial tissue database of GTEx,and the effects of expressions of these genes in myocardial tissue on cardiomyopathy risk were consistent with their effects when expressed in whole blood(P＜0.05).The results of Bayesian co-localization analysis further supported the conclusions of SMR analysis described above,with the posterior probability of shared causal variants being greater than 50%for all target genes.However,the effects of these 10 target genes on risk of disease-related cardiomyopathy,pharmacologic cardiomyopathy,and alcoholic cardiomyopathy did not reach significance(P＞0.05).Conclusion NARFL,HAGHL,FAM173A,CCDC136,IGHMBP2,CCDC116,RNASEH2C,SPATA24,SNX32,and MRPL21,10 genes expressed in whole blood and myocardial tissues,may be important therapeutic targets for cardiomyopathy.