Unveiling the hidden genetic conundrum linking pulmonary diseases and neuropsychiatric disorders: Novel insights from advanced omics-based analyses of the lung-brain axis

This study seeks to elucidate the shared genetic underpinnings between these pulmonary diseases and neuropsychiatric disorders, focusing on common genomic loci, implicated genes, and biochemical pathways. This study is a genome-wide pleiotropic association study that utilized genome-wide association summary statistics from publicly available data sources. Diverse bioinformatics and statistical genetics strategies were applied to sequentially investigate the pleiotropic associations from single-nucleotide variant (SNV), gene-level data, and biological pathways, with the aim to better understand the shared genetic etiology between 3 pulmonary diseases and 7 neuropsychiatric disorders. Significant genetic correlations and overlaps were observed among 20 of the 21 trait pairs. Pleiotropic analysis, using a composite null hypothesis, identified 3962 potentially pleiotropic SNVs across 20 trait pairs, along with 31 pleiotropic loci and 3 colocalized loci. Gene-based analysis revealed 103 unique candidate pleiotropic genes, which were notably enriched in phenotypes and tissues associated with the lung–brain axis (LBA). Pathway enrichment analysis highlighted key biological processes related to cell adhesion, synaptic structure and function, and immune cell differentiation. Several pleiotropic loci were also found to share causal variants with lung-related phenotypes. Mendelian randomization analysis suggested vertical pleiotropy across 8 trait pairs. These findings indicate that pleiotropic genetic factors connecting pulmonary and neuropsychiatric diseases are widely distributed throughout the genome. This provides robust evidence for a shared genetic basis underlying the lung-brain axis and has important implications for the potential for developing targeted intervention and treatment that simultaneously address both diseases types. • The study identifies significant genetic correlations among 20 of the 21 trait pairs, highlighting pleiotropic genetic factors that link pulmonary diseases and neuropsychiatric disorders. • A total of 3962 pleiotropic SNVs, 31 pleiotropic loci, and 3 colocalized loci were identified, along with 103 candidate pleiotropic genes enriched in lung-brain axis (LBA) related phenotypes and tissues. • Pathway enrichment analysis reveals that shared genetic factors influence critical biological processes such as cell adhesion, synaptic function, and immune cell differentiation, suggesting mechanistic links between pulmonary and neuropsychiatric conditions. • The MR analysis confirms vertical pleiotropy across 8 trait pairs, providing evidence for potential causal relationships between pulmonary diseases and neuropsychiatric disorders.