Integrative genomics reveal genetic links of chronic cough with risk factors and brain regional volumes

Objectives Chronic cough is a common condition affecting particularly women in their sixties presenting with a high disease burden with quality-of-life impairment. Limited understanding of the risk factors and genetic associations represents a barrier towards effective management. Methods We used GWAS datasets for respiratory system and other diseases, and behavioral phenotypes from UK Biobank, FinnGen, Global Biobank Meta-analysis Initiative and Psychiatric Genomics Consortium. We identified pleiotropic genetic associations with chronic cough using linkage disequilibrium score regression, pleiotropy analysis, and Bayesian co-localization analysis. We conducted Mendelian Randomization analysis to determine the association of brain regional volumes with chronic cough risk. Results We found 19 significant genetic correlations between chronic cough and various risk factors and associations. Among 74 pleiotropic genomic loci identified, the 4p14 locus had the strongest effect on cough-associated asthma, with RFC1 linked to the Cerebellar Ataxia, Neuropathy and Vestibular Areflexia Syndrome. Gene enrichment analyses highlighted central nervous system and ion channel activity in the pathogenesis of cough. A reduction in the volume of isthmus cingulate, thalamus proper and pallidum was associated with an increased risk of chronic cough. In aging-associated cough, the direct effect of aging on chronic cough was an increase odds-ratio of 1.044, with an impact of a reduction in left pallidum volume of OR of 0.902. Conclusions This genetic basis of the chronic cough risk and associations highlights both the structural and functional genetic overlap of chronic cough, confirming the impact of reduction in brain regional volumes on chronic cough as a result of aging.