Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function

Tianzhong Yang, Victoria E. Jackson, Albert V. Smith, Han Chen, Traci M. Bartz, Colleen M. Sitlani, Bruce M. Psaty, Sina A. Gharib, George T. O’Connor, Josée Dupuis, Jiayi Xu, Kurt Lohman, Yongmei Liu, Stephen B. Kritchevsky, Patricia A. Cassano, Claudia Flexeder, Christian Gieger, Stefan Karrasch, Annette Peters, Holger SchulzSarah E. Harris, John M. Starr, Ian J. Deary, Ani Manichaikul, Elizabeth C. Oelsner, R. G. Barr, Kent D. Taylor, Stephen S. Rich, Tobias N. Bonten, Dennis O. Mook-Kanamori, Raymond Noordam, Ruifang Li-Gao, Marjo Riitta Jarvelin, Matthias Wielscher, Natalie Terzikhan, Lies Lahousse, Guy Brusselle, Stefan Weiss, Ralf Ewert, Sven Gläser, Georg Homuth, Nick Shrine, Ian P. Hall, Martin Tobin, Stephanie J. London, Peng Wei, Alanna C. Morrison

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4 Scopus citations


Genome-wide association studies have identified numerous common genetic variants associated with spirometric measures of pulmonary function, including forced expiratory volume in one second (FEV1), forced vital capacity, and their ratio. However, variants with lower minor allele frequencies are less explored. We conducted a large-scale gene-smoking interaction meta-analysis on exonic rare and low-frequency variants involving 44,429 individuals of European ancestry in the discovery stage and sought replication in the UK BiLEVE study with 45,133 European ancestry samples and UK Biobank study with 59,478 samples. We leveraged data on cigarette smoking, the major environmental risk factor for reduced lung function, by testing gene-by-smoking interaction effects only and simultaneously testing the genetic main effects and interaction effects. The most statistically significant signal that replicated was a previously reported low-frequency signal in GPR126, distinct from common variant associations in this gene. Although only nominal replication was obtained for a top rare variant signal rs142935352 in one of the two studies, interaction and joint tests for current smoking and PDE3B were significantly associated with FEV1. This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function.

Original languageEnglish (US)
Article number19365
JournalScientific reports
Issue number1
StatePublished - Dec 2021

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