Genome-wide gene-by-smoking interaction study of Chronic Obstructive Pulmonary Disease

Risk for Chronic Obstructive Pulmonary Disease (COPD) is determined by both cigarette smoking and genetic susceptibility, but little is known about gene-by-smoking interactions. We performed a genome-wide association analysis of 179,689 controls and 21,077 COPD cases from UK Biobank subjects of European ancestry, considering genetic main effects and gene-by-smoking interaction effects simultaneously (2-degree-of-freedom (2df) test) as well as interaction effects alone (1-degree-of-freedom (1df) interaction test). We sought to replicate significant results in the COPDGene study and SpiroMeta Consortium. We considered two smoking variables: (1) ever/never and (2) current/non-current. In the 1df interaction test, we identified one genome-wide significant locus on 15q25.1 (CHRNB4) and identified PI*Z allele (rs28929474) SERPINA1 and 3q26.2 (MECOM) in an analysis of previously reported COPD loci. In the 2df test, most of the significant signals were also significant for genetic marginal effects, aside from 16q22.1 (SMPD3) and 19q13.2 (EGLN2). The significant effects at 15q25.1 and 19q13.2 loci, both previously described in prior genome-wide association studies of COPD or smoking, but not 16q22.1 or 3q26.2, were replicated in the COPDGene and SpiroMeta. In our study, we identified interaction effects at previously reported COPD loci, however, we failed to identify novel susceptibility loci

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease