Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Data from: Combined genetic and telemetry data reveal high rates of gene flow, migration, and long-distance dispersal potential in Arctic ringed seals (Pusa hispida)

Ringed seals (Pusa hispida) are broadly distributed in seasonally ice covered seas, and their survival and reproductive success is intricately linked to sea ice and snow. Climatic warming is diminishing Arctic snow and sea ice and threatens to endanger ringed seals in the foreseeable future. We investigated the population structure and connectedness within and among three subspecies: Arctic (P. hispida hispida), Baltic (P. hispida botnica), and Lake Saimaa (P. hispida saimensis) ringed seals to assess their capacity to respond to rapid environmental changes. We consider (a) the geographical scale of migration, (b) use of sea ice, and (c) the amount of gene flow between subspecies. Seasonal movements and use of sea ice were determined for 27 seals tracked via satellite telemetry. Additionally, population genetic analyses were conducted using 354 seals representative of each subspecies and 11 breeding sites. Genetic analyses included sequences from two mitochondrial regions and genotypes of 9 microsatellite loci. We found that ringed seals disperse on a pan-Arctic scale and both males and females may migrate long distances during the summer months when sea ice extent is minimal. Gene flow among Arctic breeding sites and between the Arctic and the Baltic Sea subspecies was high; these two subspecies are interconnected as are breeding sites within the Arctic subspecies

Data from: Combined genetic and telemetry data reveal high rates of gene flow, migration, and long-distance dispersal potential in Arctic ringed seals (Pusa hispida)

Ringed seals (Pusa hispida) are broadly distributed in seasonally ice covered seas, and their survival and reproductive success is intricately linked to sea ice and snow. Climatic warming is diminishing Arctic snow and sea ice and threatens to endanger ringed seals in the foreseeable future. We investigated the population structure and connectedness within and among three subspecies: Arctic (P. hispida hispida), Baltic (P. hispida botnica), and Lake Saimaa (P. hispida saimensis) ringed seals to assess their capacity to respond to rapid environmental changes. We consider (a) the geographical scale of migration, (b) use of sea ice, and (c) the amount of gene flow between subspecies. Seasonal movements and use of sea ice were determined for 27 seals tracked via satellite telemetry. Additionally, population genetic analyses were conducted using 354 seals representative of each subspecies and 11 breeding sites. Genetic analyses included sequences from two mitochondrial regions and genotypes of 9 microsatellite loci. We found that ringed seals disperse on a pan-Arctic scale and both males and females may migrate long distances during the summer months when sea ice extent is minimal. Gene flow among Arctic breeding sites and between the Arctic and the Baltic Sea subspecies was high; these two subspecies are interconnected as are breeding sites within the Arctic subspecies

Pusa hispida Microsatellite Genotypes

Microsatellite genotypes in the data input format of the program GenAlEx. The data are codominant genotypic microsatellite data, with loci scored as fragment size. There are 9 microsatellite loci, and 354 individuals sampled from 11 breeding sites. For a map showing the geographic locations of the breeding sites (i.e., sample sites) see Figure 2A in our publication ``Combined Genetic and Telemetry Data Reveal High Rates of Gene Flow, Migration, and Long-Distance Dispersal Potential in Arctic Ringed Seals (Pusa hispida)''

Pusa hispida mtDNA Control Region (bps 90-565)

Sequences from the mtDNA control region (CR). 99 individuals were sequenced. The ReadMe file contains the breeding site (i.e., sample site) of each individual. Uncertainty in sequence accuracy occurred at the ends of each sequence; therefore, we used a 476 bp subset (bps 90–565) of CR. A map of the sample sites can be found in Figure 2A of our publication ``Combined Genetic and Telemetry Data Reveal High Rates of Gene Flow, Migration, and Long-Distance Dispersal Potential in Arctic Ringed Seals (Pusa hispida)''

Pusa hispida mtDNA COI (bps 92-450)

Sequences of the mtDNA Cytochrome oxidase I region (COI) from 113 individuals from 8 breeding sites. Uncertainty in sequence accuracy occurred at the ends of each sequence; thus, we used a 359 base pair (bp) subset (bps 92-450) of the COI region. The breeding site (i.e., sample site) associated with each sequence is in the ReadMe file. A map of the sample sites can be found in Figure 2A of our publication ``Combined Genetic and Telemetry Data Reveal High Rates of Gene Flow, Migration, and Long-Distance Dispersal Potential in Arctic Ringed Seals (Pusa hispida)''

Panmixia and genetic differentiation between subspecies and breeding populations of ringed seals.

<p>Breeding sites from left-to-right: Kotzebue, Peard Bay, Paktoa, Tuktoyaktuk, Ulukhaktok/Holman, Baltic Sea, and Lake Saimaa. Populations with the same color and connected by a line were deemed panmictic based on pairwise permutation tests using (A) mtDNA Cytochrome Oxidase I, (B) mtDNA control region, and (C) microsatellites. Non-panmictic sites are significantly differentiated from other sites (p-values <0.05). Breeding sites left-to-right in panel C: Kotzebue, Peard Bay, Barrow, Oliktok, Prudhoe, Kaktovik, Paktoa, Tuktoyaktuk, Ulukhaktok/Holman, Baltic Sea, and Lake Saimaa.</p

COI haplotype frequencies in 7 populations.

<p>The populations are arranged from left to right as follows: Kotzebue (n = 6), Peard Bay (n = 17), Paktoa (n = 14), Tuktoyaktuk (n = 27), Ulukhaktok/Holman (n = 15), Baltic Sea (n = 11), and Lake Saimaa (n = 22). Oliktok was excluded from this figure because we only had one sample from there. Each of the 31 haplotypes is represented by a different color. Lake Saimaa has low haplotype diversity with all but one individual sharing the same haplotype. The Baltic Sea, Ulukhaktok/Holman, Tuktoyaktuk, Paktoa, and Peard Bay all had two prevalent haplotypes (represented by the orange bar and golden bar). Whereas, the haplotypes found in Kotzebue were absent or at low frequency in the other Arctic sites, possibly as an artifact of the low sample size in Kotzebue.</p

Analysis of molecular variance (AMOVA) based on Cytochrome Oxidase I (COI), the Control Region (CR), and 9 microsatellite loci. AMOVA I contains Arctic, Baltic, and Lake Saimaa subspecies; AMOVA II excludes the Lake Saimaa subspecies.

a<p>p-value obtained from significance test (16000 permutation); P(random value>observed value of variation among sites).</p

Maximum likelihood parameter estimates of mutation-rate-scaled effective population sizes and migration rates.

<p>(A) Mutation-scaled effective population size (Θ) estimates based on mtDNA. Each circle represents a ringed seal subspecies and the relative size of the circle is indicative of the effective population size. Arrows are labeled with the estimated number of migrants per generation. (B) Estimates based on nuclear microsatellites.</p