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Thread: SARS-CoV-2 respiratory failure: risk SNPs, Bloodtype A is a risk, O is protective

  1. #101
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    I looked up the two main SNP in the UK Biobank data on COVID 19 deaths (364 COVID-19 deaths vs. 486,956 negative/unknown UKBB control).

    rs13078854 Beta 0.454 p-value 0.00192 odds ratio 1,575
    rs8176645 Beta 0.105 p-value 0.24990 odds ratio 1,101

    rs8176645 is the best proxy I found for chr9 rs9411378 ABO gene. Like the other proxies, it is not even nominally significantly associated with COVID 19 death vs. population.
    I'd say that the chromosome 3 hit on severity is reflected in the death analysis, but the OR of ~1,6 is comparable or even lower than the odds of being hospitalized with severe disease from the Ellinghaus or 23andme paper. Overall, it doesn't reach genome wide significance for death as an outcome, but probably would in a larger analysis.
    A number of other positions do, like the APOE locus rs429358, which codes for the APOE ∊3 and APOE ∊4 alleles with an OR of 1,45 and a p-value of 5x10^-7.

    data from here:
    https://grasp.nhlbi.nih.gov/Covid19GWASResults.aspx
    Last edited by Nive1526; 09-10-2020 at 01:33 PM.

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  3. #102
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    Quote Originally Posted by Nive1526 View Post
    I looked up the two main SNP in the UK Biobank data on COVID 19 deaths (364 COVID-19 deaths vs. 486,956 negative/unknown UKBB control).

    rs13078854 Beta 0.454 p-value 0.00192 odds ratio 1,575
    rs81766450 Beta 0.105 p-value 0.24990 odds ratio 1,101

    rs81766450 is the best proxy I found for chr9 rs9411378 ABO gene. Like the other proxies, it is not even nominally significantly associated with COVID 19 death vs. population.
    I'd say that the chromosome 3 hit on severity is reflected in the death analysis, but the OR of ~1,6 is comparable or even lower than the odds of being hospitalized with severe disease from the Ellinghaus or 23andme paper. Overall, it doesn't reach genome wide significance for death as an outcome, but probably would in a larger analysis.
    A number of other positions do, like the APOE locus rs429358, which codes for the APOE ∊3 and APOE ∊4 alleles with an OR of 1,45 and a p-value of 5x10^-7.

    data from here:
    https://grasp.nhlbi.nih.gov/Covid19GWASResults.aspx
    How did you select rs81766450 as a proxy for rs9411378?
    I just looked up rs81766450 in dbSNP, it wasn't there.
    https://www.ncbi.nlm.nih.gov/snp/?term=rs81766450
    The following term was not found in SNP: rs81766450.
    No items found.
    YFull: YF14620 (Dante Labs 2018)

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  5. #103
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    There is a zero too much, it's rs8176645. I'll edit it.

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  7. #104
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    Quote Originally Posted by pmokeefe View Post
    Trans-ethnic analysis reveals genetic and non-genetic associations with COVID-19 susceptibility and severity

    ABO: In our phenotype contrasting COVID-19 test positive individuals to test negative
    individuals, we identified an association at chr9q34.2, with index SNP rs9411378 (p-value =
    5.3e-20, C allele OR = 0.857; Figure 5).
    Another proxy for rs9411378 is rs635634. It is conservative, in the sense that it appears that people with rs635634-T are extremely likely to have rs9411378-A, which I believe is the risk variant - if I read the paper correctly.
    I checked population statistics here: https://ldlink.nci.nih.gov/?tab=ldhap.
    On the other hand, the risk variant is not covered by rs635634-T all the time - but it is for me. rs635634 was included in both my 23andMe and AncestryDNA test results.
    Generally speaking there appear to be quite a few adverse health consequences for rs635634-T https://www.ebi.ac.uk/gwas/variants/rs635634, independent of Covid19.

    Anyone else unlucky enough to have a copy of rs635634-T?
    YFull: YF14620 (Dante Labs 2018)

  8. #105
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    Quote Originally Posted by Nive1526 View Post
    There is a zero too much, it's rs8176645. I'll edit it.
    Thanks.
    BTW rs8176719, the most common variant for blood type O, is nearly identical to rs8176645 in non-Africans .
    They are not highly correlated for SSA however.
    https://ldlink.nci.nih.gov/?tab=ldhap
    YFull: YF14620 (Dante Labs 2018)

  9. #106
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    Covid-19 and Interferon

    Hidden immune weakness found in 14% of gravely ill COVID-19 patients
    By Meredith Wadman

    Inborn errors of type I IFN immunity in patients with life-threatening COVID-19
    Some of the variants mentioned are:
    TLR3 p.Pro554Ser rs121434431 is tested at 23andMe and AncestryDNA (sometimes) the risk variant T is quite rare.

    IFNAR1 p.Pro335del rs72552343 not tested at 23andMe or AncestryDNA, risk variant is rare

    In the supplement to the paper there are two tables of variants. There are over one hundred, I have not gone through them to see if any are tested at 23andMe or AncestryDNA.
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  11. #107
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    The major genetic risk factor for severe COVID-19 is inherited from Neanderthals

    The major genetic risk factor for severe COVID-19 is inherited from Neanderthals

    by Hugo Zeberg & Svante Pääbo

    this paper was already available in preprint form a while ago, this version is in advance of publication in Nature.

    Note that rs35044562, the lead SNP in this study , is different from rs11385942 the SNP mentioned in other studies of the same region of chromosome 3.
    The ABO blood group locus and a chromosome 3 gene cluster associate with SARS-CoV-2 respiratory failure in an Italian-Spanish genome-wide association analysis

    Looking at COVID19-hg GWAS meta-analyses round 3

    rs35044562 does have a slightly higher p-value than rs11385942 for hospitalized covid vs. population ANA_B2_V2.

    Here's a rather skeptical remark on the prepring: Neanderthals and Covid-19, beyond the hype

    Another preprint with results on the Chromosome 3 variants.
    Using symptom-based case predictions to identify host genetic factors that contribute to
    COVID-19 susceptibility
    Last edited by pmokeefe; 09-30-2020 at 08:44 PM.
    YFull: YF14620 (Dante Labs 2018)

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  13. #108
    Such an interesting thread.

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  15. #109
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    Genetic mechanisms of critical illness in Covid-19

    Genetic mechanisms of critical illness in Covid-19
    by Pairo-Castineira etal
    Abstract
    The subset of patients who develop critical illness in Covid-19 have extensive inflammation affecting the lungs[PMID: 32526193] and are strikingly different from other patients: immunosuppressive therapy benefits critically-ill patients, but may harm some non-critical cases.[PMID: 32678530] Since susceptibility to life-threatening infections and immune-mediated diseases are both strongly heritable traits, we reasoned that host genetic variation may identify mechanistic targets for therapeutic development in Covid-19.[PMID: 24855243] GenOMICC (Genetics Of Mortality In Critical Care, <a href="https://genomicc.org">genomicc.org</a>) is a global collaborative study to understand the genetic basis of critical illness. Here we report the results of a genome-wide association study (GWAS) in 2244 critically-ill Covid-19 patients from 208 UK intensive care units (ICUs), representing >95% of all ICU beds. Ancestry-matched controls were drawn from the UK Biobank population study and results were confirmed in GWAS comparisons with two other population control groups: the 100,000 genomes project and Generation Scotland. We identify and replicate three novel genome-wide significant associations, at chr19p13.3 (rs2109069, p = 3.98 x 10-12), within the gene encoding dipeptidyl peptidase 9 (DPP9), at chr12q24.13 (rs10735079, p = 1.65 x 10-8) in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3), and at chr21q22.1 (rs2236757, p = 4.99 x 10-8) in the interferon receptor gene IFNAR2. Consistent with our focus on extreme disease in younger patients with less comorbidity, we detect a stronger signal at the known 3p21.31 locus than previous studies (rs73064425, p = 4.77 x 10-30).

    I am heterozygous for rs10735079 and rs2236757 which is common, ~40% for each. Both of those are from WGS tests, they did not appear on any commercial array tests I have access to. But there may be proxies, I haven't checked yet.

    rs2109069 does appear on some AncestryDNA and 23andMe tests. I am negative for that.

    How about you?
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  17. #110
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    A genetic variant protective for COVID-19 is inherited from Neandertals
    Hugo Zeberg, Svante Paabo
    Abstract
    It was recently shown that the major genetic risk factor associated with becoming severely ill with COVID-19 when infected by SARS-CoV-2 is inherited from Neandertals. Thanks to new genetic association studies additional risk factors are now being discovered. Using data from a recent genome-wide associations from the Genetics of Mortality in Critical Care (GenOMICC) consortium, we show that a haplotype at a region associated with requiring intensive care is inherited from Neandertals. It encodes proteins that activate enzymes that are important during infections with RNA viruses. As compared to the previously described Neandertal risk haplotype, this Neandertal haplotype is protective against severe COVID-19, is of more moderate effect, and is found at substantial frequencies in all regions of the world outside Africa.
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