Rare genetic variants explain missing heritability in smoking

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this ‘missing heritability’. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability (hSNP2) was estimated from 0.13 to 0.28 (s.e., 0.10–0.13) in European ancestries, with 35–74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5–4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability (hped2, 0.18–0.34). In the African ancestry samples, hSNP2 was estimated from 0.03 to 0.33 (s.e., 0.09–0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking

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 hospitalization2,3,4 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

Miocene foraminifera from the Finniss Clay and Cadell Marl, western Murray Basin: taxonomic and taphonomic contrasts and their environmental significance.

Sandwiched between Miocene limestones of the Mannum Formation and Morgan Limestone in the western Murray Basin, the Finniss Clay and Cadell Marl contain different foraminiferal faunas with varying taphonomic grades. At the Mannum Pumping Station section, the Finniss Clay fauna has a low diversity, frequent shallow-water forms, and a poor taphonomic grade. In what was the deeper part of the basin at Waikerie, a diverse fauna with well-preserved small species is recorded in sediments equivalent to the Finniss Clay. In contrast, the Cadell Marl from various localities comprises a well-preserved and diverse biofacies with both shallow and deeper water taxa. These contrasts suggest different depositional environments: shallower and warm during deposition of the Finniss Clay and nutrient-rich, dysaerobic and deeper water during deposition of the Cadell Marl. The shallowing event indicated by faunas from the Finniss Clay was due to falling sea level close to the early/middle Miocene boundary, whereas the Cadell fauna appears to reflect the global carbon buildup at the peak of the Monterey carbon excursion during the Miocene climatic optimum, about 16 million years ago. © 1999 Association of Australasian Palaeontologists.Li, Qianyu McGowran, Bria