A population-based study led by investigators from Brigham and Women’s Hospital expands the number of genetic variants associated with the risk of developing COPD, providing new insights into the disease.

The research, published in Nature Genetics, identified 82 loci — genetic locations — significantly associated with risk of COPD. Previous reports of 22 loci explained about 12% of the genetic risk of COPD. The 82 loci now explain about 17.5%.

“We have substantially expanded what’s known about the genetics of COPD,” said corresponding author Michael Cho, MD, MPH, physician-scientist in the Channing Division of Network Medicine and the Division of Pulmonary and Critical Care Medicine at the Brigham. “What we’re presenting here isn’t merely a list of genes. We’ve uncovered pathways and groups of variants that may affect different aspects of disease presentation and progression and find overlap with asthma and pulmonary fibrosis. These insights have implications for future investigations and drug development.”

Cigarette smoking is the leading risk factor for COPD but smoking does not fully account for why people develop COPD. Up to 20% of people with the disease have never smoked. The authors note that smoking remains a critical risk factor and that most people with COPD have smoked or currently smoke cigarettes.

“We see these genetic factors as additive or interactive with environmental risk factors,” said co-author Edwin Silverman, MD, PhD, chief of the Channing Division of Network Medicine. “Complete avoidance of smoking is the most important step that people can take to reduce their risk of COPD, but we know that there is this additional layer of susceptibility. Understanding variable susceptibility could help us diagnose patients more accurately, provide more accurate prognosis and come up with better treatments.”

In addition to the GWAS, the team also sought to determine which tissues and cell types were enriched for genetic variants of COPD. Not surprisingly, they saw the most significant enrichment in lung tissue, including endothelial cells and alveolar cells, but also found enrichment in smooth muscle from the gastrointestinal tract — likely because similar data from smooth muscle in lung is not available.

The team performed further analysis to identify candidate target genes, genetic pathways and potential drug targets. In addition, the investigators found overlapping loci for asthma and pulmonary fibrosis, two other lung diseases, increasing the number of overlaps for fibrosis and finding the first genome-wide evidence for specific regions shared with asthma.

Their findings also support a role for early life events in the risk of COPD.

“Questions about the role of early life events that may influence initial lung function and patterns of growth have been on the minds of COPD researchers for years,” said co-author Brian Hobbs, MD, MMSc, a physician-scientist in the Channing Division of Network Medicine and the Division of Pulmonary and Critical Care Medicine at the Brigham. “Our work opens the door to addressing some of those questions on the population level.”