The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to ...SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3,4,5,6,7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.
Abstract
Background
Identifying genetic factors that provide resilience against the clinical consequences of Alzheimer’s disease (AD) pathology is likely to accelerate the development of novel ...therapeutics. Sex differences in AD prevalence, neuropathological presentation, and clinical progression suggest that exploring the sex‐specific genetic architecture of resilience to AD may be a critical first step towards the characterization and development of precision interventions.
Method
We completed sex‐stratified and sex‐interaction genome‐wide association studies (GWAS) of resilience across 5,109 non‐Hispanic white individuals from two autopsy cohorts (ACT and ROS/MAP) and two positron emission tomography (PET) cohorts (ADNI and A4). A continuous measure of resilience was quantified using latent variable modeling and represented better‐than‐expected cognition for the given level of amyloid in the brain. The final dataset included 2,130 males (77 ± 9 years) and 2,979 females (77 ± 10 years), the majority of whom were cognitively normal (73% of males; 76% of females). GWAS of resilience were performed in the combined autopsy dataset and combined PET dataset individually and then meta‐analyzed. Covariates included age and three principal components. Analyses were run in all individuals as well as in the subset of cognitively normal individuals.
Result
An intergenic variant on chromosome 10 (rs827389, MAF = 0.46) showed a female‐specific genome‐wide significant association with resilience in cognitively normal females (β = 0.08, p = 7.6 × 10
−9
) but not in males (β = ‐5.3 × 10
‐3
, p = 0.77; sex interaction p = 1.4 × 10
−4
). This variant is a modest brain eQTL for the
KIN
gene that is implicated in DNA repair. We also observed a strong sex‐interaction effect among all individuals on chromosome 3 (rs113968105, MAF = 0.10, p = 7.5 × 10
−8
), in which the minor allele was associated with higher resilience in males (β = 0.10, p = 4.2 × 10
−7
) but lower resilience in females (β = ‐0.04, p = 0.03). This variant is an eQTL for three genes, including the acetylcholinesterase binding gene
COLQ
.
Conclusion
We identified two putative sex‐specific loci that provide protection against the downstream consequences of amyloid pathology. The associations implicate DNA damage repair genes among females, and acetylcholinesterase genes in males, suggesting the pathways providing neuroprotection may differ by sex.
Background
Identifying genetic factors that provide resilience against the clinical consequences of Alzheimer’s disease (AD) pathology is likely to accelerate the development of novel therapeutics. ...Sex differences in AD prevalence, neuropathological presentation, and clinical progression suggest that exploring the sex‐specific genetic architecture of resilience to AD may be a critical first step towards the characterization and development of precision interventions.
Method
We completed sex‐stratified and sex‐interaction genome‐wide association studies (GWAS) of resilience across 5,109 non‐Hispanic white individuals from two autopsy cohorts (ACT and ROS/MAP) and two positron emission tomography (PET) cohorts (ADNI and A4). A continuous measure of resilience was quantified using latent variable modeling and represented better‐than‐expected cognition for the given level of amyloid in the brain. The final dataset included 2,130 males (77 ± 9 years) and 2,979 females (77 ± 10 years), the majority of whom were cognitively normal (73% of males; 76% of females). GWAS of resilience were performed in the combined autopsy dataset and combined PET dataset individually and then meta‐analyzed. Covariates included age and three principal components. Analyses were run in all individuals as well as in the subset of cognitively normal individuals.
Result
An intergenic variant on chromosome 10 (rs827389, MAF = 0.46) showed a female‐specific genome‐wide significant association with resilience in cognitively normal females (β = 0.08, p = 7.6 × 10−9) but not in males (β = ‐5.3 × 10‐3, p = 0.77; sex interaction p = 1.4 × 10−4). This variant is a modest brain eQTL for the KIN gene that is implicated in DNA repair. We also observed a strong sex‐interaction effect among all individuals on chromosome 3 (rs113968105, MAF = 0.10, p = 7.5 × 10−8), in which the minor allele was associated with higher resilience in males (β = 0.10, p = 4.2 × 10−7) but lower resilience in females (β = ‐0.04, p = 0.03). This variant is an eQTL for three genes, including the acetylcholinesterase binding gene COLQ.
Conclusion
We identified two putative sex‐specific loci that provide protection against the downstream consequences of amyloid pathology. The associations implicate DNA damage repair genes among females, and acetylcholinesterase genes in males, suggesting the pathways providing neuroprotection may differ by sex.
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