Fredrik Nyberg, Per Lundmark, Anders Blomberg, Koen Dekkers, Arne Egesten, Jonas Eriksson Ström, Bruna Gigante, Anders Gummesson, Cecilia Gunnarsson, Christer Janson, Andrei Malinovschi, Anna-Carin Olin, Marju Orho-Melander, Hans Lennart Persson, Ida Pesonen, Magnus Sköld, Stefan Söderberg, Hanan Tanash, Lowie E G W Vanfleteren, Tove Fall
This study, based on the largest unselected population sample to date, provides novel insights into the genetic architecture of emphysema. However, no signals were detected in never-smokers despite the large sample-size, likely due to the low prevalence of emphysema in that group. The proposed genetic risk loci require external replication.
BACKGROUND: Despite the high prevalence and clinical significance of emphysema, few genetic risk loci have been consistently replicated. We conducted a genome-wide association study (GWAS) of CT-based emphysema, with a particular focus on non-smoking-related genetic determinants.
METHODS: We analyzed 25,639 individuals of European ancestry from the SCAPIS national cohort, aged 50-65 years, of which 51% were never-smokers. Emphysema was assessed through semi-quantitative visual scoring of CT scans. GWAS was performed in the whole sample and stratified on smoking status. We also examined the association of previously reported emphysema- and lung function-related variants with emphysema in our dataset.
RESULTS: Emphysema criteria were fulfilled for 1,479 participants (5.6%), with higher prevalence among current (N = 576, 18.2%) and former smokers (N = 612, 6.5%) compared to never-smokers (N = 263, 2.0%). We identified three independent genetic loci for emphysema in smokers and no signals in never-smokers. The strongest signal was observed in the well-established nicotinic acetylcholine receptor cluster (CHRNA5-A3-B4) locus on chromosome 15. Additionally, we discovered novel associations near the dysferlin (DYSF) gene on chromosome 2 and in an intergenic region on chromosome 3. By assessing previously lung phenotype-associated variants we also found evidence supporting association with emphysema in smokers for variants in the EFEMP1/MIR217HG/PNPT1 locus on chromosome 2, previously linked to reduced FEV1/FVC ratio.
CONCLUSION: This study, based on the largest unselected population sample to date, provides novel insights into the genetic architecture of emphysema. However, no signals were detected in never-smokers despite the large sample-size, likely due to the low prevalence of emphysema in that group. The proposed genetic risk loci require external replication.