Hierarchical association of COPD to principal genetic components of biological systems

Daniel E. Carlin, Simon J. Larsen, Vikram Sirupurapu, Michael H. Cho, Edwin K. Silverman, Jan Baumbach, Trey Ideker

Research output: Contribution to journalArticlepeer-review


Many disease-causing genetic variants converge on common biological functions and pathways. Precisely how to incorporate pathway knowledge in genetic association studies is not yet clear, however. Previous approaches employ a two-step approach, in which a regular association test is first performed to identify variants associated with the disease phenotype, followed by a test for functional enrichment within the genes implicated by those variants. Here we introduce a concise one-step approach, Hierarchical Genetic Analysis (Higana), which directly computes phenotype associations against each function in the large hierarchy of biological functions documented by the Gene Ontology. Using this approach, we identify risk genes and functions for Chronic Obstructive Pulmonary Disease (COPD), highlighting microtubule transport, muscle adaptation, and nicotine receptor signaling pathways. Microtubule transport has not been previously linked to COPD, as it integrates genetic variants spread over numerous genes. All associations validate strongly in a second COPD cohort.

Original languageEnglish
Article numbere0286064
JournalPLoS ONE
Issue number5 May
StatePublished - May 2023
Externally publishedYes


Dive into the research topics of 'Hierarchical association of COPD to principal genetic components of biological systems'. Together they form a unique fingerprint.

Cite this