Genetic overlap of severe psychiatric disorders with lung function and asthma suggests shared biological mechanisms.

Background: Severe psychiatric disorders are frequently comorbid with lung function decline and asthma. Despite their considerable heritability, the genetic relationships between them are unclear.

Methods: We investigated the shared genetic architecture for three severe psychiatric disorders (schizophrenia, bipolar disorder, and anorexia nervosa) with lung function and asthma using results from genome-wide association studies. We performed MiXeR analyses to quantify their genetic overlap. A conditional/conjunctional false discovery rate (cond/conjFDR) approach was employed to detect shared genomic loci. Gene-based enrichment analyses were adopted to explore the shared biological mechanisms. Transcriptome analyses results were incorporated to prioritize biologically plausible shared genes in relevant tissues.

Results: MiXeR analyses demonstrated consistent moderate polygenic overlap (∼400 to 800 shared variants) across all pairs of psychiatric and respiratory phenotypes. The cond/conjFDR analyses found that lung function shared 227 loci with SCZ, 83 loci with BIP and 13 loci with AN, whereas asthma shared 132 loci with SCZ, 25 loci with BIP and 2 loci with AN, among which there were 268 novel loci for psychiatric disorders and 244 novel loci for the respiratory phenotypes. Gene-based enrichment analyses demonstrated that genes shared with psychiatric disorders for lung function were enriched for less specific non-immune GO terms (i.e. muscle organ development, mitochondrial matrix and cellular response to ion zinc), whereas genes shared with asthma were mostly enriched for GO term categories involving immune mechanisms (i.e. lymphocyte activation, immune response, metabolism, protein metabolism and regulation of JAK-STAT cascade), indicating divergent shared etiology. A total of 55 shared genes were prioritized as biologically plausible in tissues including brain, lung, whole blood and adrenal gland.

Conclusions: This study elucidates a complex shared genetic architecture for three severe psychiatric disorders with lung function and asthma and implicates overlapping immune and non-immune mechanisms. Our findings present novel evidence and putative mechanisms for a lung-brain axis underlying psychiatric disorders and lung diseases, which may inspire the development of novel treatments.