SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Nuevos componentes de las rutas de señalización de ácido abscísico y giberelinas en semillas de Arabidopsis thaliana

La semilla es un órgano fundamental para la supervivencia y la dispersión de las plantas. La transición entre los estados de maduración, quiescencia o dormición y germinación están regulados por factores ambientales y genéticos donde, principalmente dos fitohormonas, el ácido abscísico (ABA) y las giberelinas (GAs), juegan un papel regulador antagónico

Investigating how perceived risk and availability of marijuana relate to marijuana use among adolescents in Argentina, Chile, and Uruguay over time

AimsAmid changing marijuana policies in the Southern Cone, we examined relationships between marijuana-related risk factors and marijuana use among adolescents in Argentina, Chile, and Uruguay from 2001 to 2016.MethodsUsing cross-sectional surveys from 8th, 10th, and 12th graders and weighted time-varying effect models, we estimated associations between perceived risk (no/low risk versus moderate/great risk) and perceived availability (easy/very easy versus difficult/very difficult/not able to obtain) of marijuana, and any past-month marijuana use.ResultsIn all countries, marijuana use increased over time and adolescents who perceived no/low risk and easy availability had higher odds of use. In Argentina, the bivariate risk/use association weakened from 2001 (OR = 15.24, 95%CI = 9.63, 24.12) to 2004 [OR = 3.86 (2.72, 5.48)] and strengthened until 2011 [OR = 8.22 (7.56, 10.30)]; the availability/use association strengthened from 2005 [OR = 5.32 (4.05, 6.98)] to 2009 [OR = 20.77 (15.57, 27.70)] and weakened until 2014 [OR = 11.00 (9.11, 13.27)]. In Chile, the risk/use association weakened from 2001 [OR = 7.22 (6.57, 7.95)] to 2015 [OR = 5.58 (4.82, 6.48)]; the availability/use association weakened from 2001 [OR = 5.92 (4.96, 7.06)] to 2015 [OR = 4.10 (3.15, 5.34)]. In Uruguay, the risk/use association weakened from 2003 [OR = 34.22 (22.76, 51.46)] to 2016 [OR = 6.23 (4.96, 7.83)]; the availability/use association weakened from 2005 [OR = 29.13 (13.39, 63.39) to 2007 [OR = 9.42 (3.85, 23.07)], and strengthened until 2016 [OR = 22.68 (12.03, 42.76)].ConclusionsOverall, the association between risk and use weakened in all countries, suggesting risk perceptions became a weaker determinant of marijuana use. Perceived availability remained strongly associated with use and may become an increasingly important driver of use (particularly in Uruguay and Argentina)

Cycles in spatial and temporal chromosomal organization driven by the circadian clock

Dynamic transitions in the epigenome have been associated with regulated patterns of nuclear organization. The accumulating evidence that chromatin remodeling is implicated in circadian function prompted us to explore whether the clock may control nuclear architecture. We applied the 3C-derived 4C technology (Chromosome Conformation Capture on Chip) in mouse embryonic fibroblasts (MEFs) to demonstrate the presence of circadian long-range interactions, using the clock-controlled Dbp gene as bait. The circadian genomic interactions with Dbp are highly specific and are absent in MEFs whose clock is disrupted by ablation of the Bmal1 gene. We establish that the Dbp circadian interactome contains a wide variety of genes and clock-related DNA elements. These findings reveal a previously unappreciated circadian and clock-dependent shaping of the nuclear landscape

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans

GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes.

Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans

COVID-19 Host Genetics Initiative. A first update on mapping the human genetic architecture of COVID-19

The COVID-19 pandemic continues to pose a major public health threat, especially in countries with low vaccination rates. To better understand the biological underpinnings of SARS-CoV-2 infection and COVID-19 severity, we formed the COVID-19 Host Genetics Initiative1. Here we present a genome-wide association study meta-analysis of up to 125,584 cases and over 2.5 million control individuals across 60 studies from 25 countries, adding 11 genome-wide significant loci compared with those previously identified2. Genes at new loci, including SFTPD, MUC5B and ACE2, reveal compelling insights regarding disease susceptibility and severity.</p