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Genet Epidemiol. 2019 Apr;43(3):318-329. doi: 10.1002/gepi.22192. Epub 2019 Feb 11.

Assessing pleiotropy and mediation in genetic loci associated with chronic obstructive pulmonary disease.

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Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Department of Biostatistics and Informatics, University of Colorado, Anschutz Medical Campus, Denver, Colorado.
Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Division of Pulmonary, Allergy, and Critical Care Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
Division of General Internal Medicine and Primary Care, Brigham and Women's Hospital, Boston, Massachusetts.
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
Department of Epidemiology, University of Colorado, Denver, Aurora, Colorado.


Genetic association studies have increasingly recognized variant effects on multiple phenotypes. Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease with environmental and genetic causes. Multiple genetic variants have been associated with COPD, many of which show significant associations to additional phenotypes. However, it is unknown if these associations represent biological pleiotropy or if they exist through correlation of related phenotypes ("mediated pleiotropy"). Using 6,670 subjects from the COPDGene study, we describe the association of known COPD susceptibility loci with other COPD-related phenotypes and distinguish if these act directly on the phenotypes (i.e., biological pleiotropy) or if the association is due to correlation (i.e., mediated pleiotropy). We identified additional associated phenotypes for 13 of 25 known COPD loci. Tests for pleiotropy between genotype and associated outcomes were significant for all loci. In cases of significant pleiotropy, we performed mediation analysis to test if SNPs had a direct association to phenotype. Most loci showed a mediated effect through the hypothesized causal pathway. However, many loci also had direct associations, suggesting causal explanations (i.e., emphysema leading to reduced lung function) are incomplete. Our results highlight the high degree of pleiotropy in complex disease-associated loci and provide novel insights into the mechanisms underlying COPD.


COPD; GWAS; causal inference; emphysema; mediation; pleiotropy

[Available on 2020-04-01]

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