Department of Method Development and analytics, Norwegian Institute of Public Health, Oslo, Norway.
Center for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway.
PLoS One. 2022 Jun 9;17(6):e0269105. doi: 10.1371/journal.pone.0269105. eCollection 2022.
Male sex and advanced age are associated with severe symptoms of COVID-19. Sex and age also exhibit substantial associations with genome-wide DNA methylation (DNAm) differences in humans. Using a random sample of Illumina EPIC-based genome-wide methylomes from peripheral whole blood of 1,976 parents, participating in The Norwegian Mother, Father and Child Cohort Study (MoBa), we explored whether DNAm in genes linked to SARS-CoV-2 host cell entry and to severe COVID-19 were associated with sex and age. This was carried out by testing 1,572 DNAm sites (CpGs) located near 45 genes for associations with age and sex. We found that DNAm in 281 and 231 of 1,572 CpGs were associated (pFDR<0.01) with sex and aging, respectively. CpGs linked to SARS-CoV-2 host cell entry genes were all associated with age and sex, except for the ACE2 receptor gene (located on the X-chromosome), which was only associated with sex (pFDR<0.01). Furthermore, we examined whether 1,487 autosomal CpGs associated with host-cell entry and severe COVID-19 were more or less associated with sex and age than what would be expected from the same number of randomly sampled genome-wide CpGs. We found that the CpGs associated with host-cell entry and severe COVID-19 were not more or less associated with sex (R2 = 0.77, p = 0.09) than the CpGs sampled from random genomic regions; age was actually found to be significantly less so (R2 = 0.36, p = 0.04). Hence, while we found wide-spread associations between sex and age at CpGs linked to genes implicated with SARS-CoV-2 host cell entry and severe COVID-19, the effect from the sum of these CpGs was not stronger than that from randomly sampled CpGs; for age it was significantly less so. These findings could suggest that advanced age and male sex may not be unsurmountable barriers for the SARS-CoV-2 virus to evolve increased infectiousness.
男性和高龄与 COVID-19 的严重症状相关。性和年龄也与人类全基因组 DNA 甲基化（DNAm）差异有很大关联。我们利用来自挪威母亲、父亲和儿童队列研究（MoBa）中 1976 对父母外周全血的 Illumina EPIC 全基因组甲基化组的随机样本，探索了与 SARS-CoV-2 宿主细胞进入和严重 COVID-19 相关的基因中的 DNAm 是否与性别和年龄相关。我们通过测试位于 45 个基因附近的 1572 个 DNAm 位点（CpG）与年龄和性别进行关联分析。我们发现，在 1572 个 CpG 中，有 281 个和 231 个与性别和衰老相关（pFDR<0.01）。与 SARS-CoV-2 宿主细胞进入基因相关的 CpG 除 ACE2 受体基因（位于 X 染色体上）外，均与年龄和性别相关（pFDR<0.01）。此外，我们还检查了与宿主细胞进入和严重 COVID-19 相关的 1487 个常染色体 CpG 是否比随机采样的全基因组 CpG 更或更少地与性别和年龄相关。我们发现，与宿主细胞进入和严重 COVID-19 相关的 CpG 与性别（R2=0.77，p=0.09）的关联程度并不比从随机基因组区域采样的 CpG 更多或更少；实际上，年龄的关联程度明显较小（R2=0.36，p=0.04）。因此，尽管我们发现与 SARS-CoV-2 宿主细胞进入和严重 COVID-19 相关的基因相关的 CpG 存在广泛的性别和年龄关联，但这些 CpG 的总和效应并不强于随机采样的 CpG；年龄的关联程度明显较小。这些发现表明，高龄和男性可能不是 SARS-CoV-2 病毒进化为更具传染性的不可逾越的障碍。
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