心律失常与强迫症的遗传共病机制:基于多组学整合分析的心脑轴研究OA

Background Arrhythmia and obsessive-compulsive disorder(OCD)frequently co-occur in clinical and epidemiological settings,yet their shared genetic basis and potential heart-brain axis mechanisms remain unclear.Objective To systematically evaluate the genetic correlation between arrhythmia and OCD,and to elucidate their underlying molecular genetic mechanisms,so as to provide molecular evidence for the"heart-brain axis"to support risk assessment and integrated clinical strategies for these comorbidities.Methods The aggregated data from the genome-wide association study(GWAS)of arrhythmia in the UK Biobank(7 207 cases and 477 391 controls)and the GWAS data of OCD released by the Psychiatric Genomics Consortium(2 688 cases and 7 037 controls)were integrated,all of which were limited to individuals of European ancestry.The genome-wide genetic correlations were estimated using the linkage disequilibrium score regression(LDSC)and the high-definition likelihood(HDL).Local genetic correlation analysis was conducted using the local analysis of variance annotation(LAVA).Multi-trait analysis of GWAS(MTAG)was employed to identify pleiotropic loci.Shared risk genes were identified by combining summary-data based Mendelian randomization(SMR)and transcriptome-wide association study(TWAS).Functional enrichment analysis was performed based on the functional mapping and annotation(FUMA)platform.Results Both LDSC(rg=0.248,95%CI:0.159-0.336,P=4.82×10-3)and HDL(rg=0.294,95%CI:0.237-0.351,P=5.87×10-4)revealed significant positive genetic correlation between arrhythmia and OCD.LAVA identified 23 significantly local correlated regions in the genome(P<2.0×10-5).MTAG discovered 11 genome-wide significant pleiotropic SNPs,among which rs12754189(intron of KCNN3)had potential functional harmfulness(CADD>12.37).SMR and TWAS jointly identified 20 shared genes,enriched in neural-cardiovascular tissues such as the cerebral cortex,amygdala,and left ventricle,and involved in DNA damage response,RNA metabolism,transcriptional regulation,and FAS signaling pathway(FDR<0.05).Conclusion Arrhythmia and OCD share a common genetic basis.The co-morbidity mechanism may involve the common vulnerability of neurons and cardiac muscle cells in terms of gene expression regulation and stress response,supporting the role of the brain-heart axis in the pathophysiology of both conditions.