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Genomic and Ancestral Variation Underlies the Severity of COVID-19 Clinical Manifestation in Individuals of European Descent.

ABSTRACT: The coronavirus disease (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is characterized by a wide spectrum of clinical phenotypes ranging from asymptomatic to symptomatic with mild or moderate presentation and severe disease. COVID-19 susceptibility, severity and recovery have demonstrated high variability worldwide. Variances in the host genetic architecture may underlie the inter-individual and population-scale differences in COVID-19 presentation. We performed a genome-wide association analysis employing the genotyping data from AncestryDNA for COVID-19 patients of European descent and used asymptomatic subjects as the control group. We identified 621 genetic variants that were significantly distinct between asymptomatic and acutely symptomatic COVID-19 patients (multiple-testing corrected p-value < 0.001). These variants were found to be associated with pathways governing host immunity, such as interferon, interleukin and cytokine signalling, and known COVID-19 comorbidities, such as obesity and cholesterol metabolism. Further, our ancestry analysis revealed that the asymptomatic COVID-19 patients possess discernibly higher proportions of the Ancestral North Eurasian (ANE) and Eastern Hunter-Gatherer (EHG) ancestry, which was introduced to Europe through Bell Beaker culture (Yamnaya related) and lower fractions of Western Hunter-Gatherer (WHG) ancestry, while severely symptomatic patients have higher fractions of WHG and lower ANE/EHG ancestral components, thereby delineating the likely ancestral differences between the two groups.

SUBMITTER: Upadhyai P

PROVIDER: S-EPMC8470085 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceIndividuals of African descent have been reported to be at higher risk for becoming visually impaired from glaucoma compared with individuals of European descent.ObjectiveTo investigate racial differences in longitudinal visual field variability and their impact on time to detect visual field progression.Design, setting, and participantsThis multicenter prospective observational cohort study included 236 eyes of 173 individuals of European descent and 235 eyes of 171 individuals of African descent followed up for a mean (SD) time of 7.5 (3.4) years.Main outcomes and measuresDifferences in test-retest variability and simulated time to detect progression in individuals of African descent and of European descent with glaucoma. Standard automated perimetry mean deviation values were regressed over time for each eye, and SD of the residuals was used as a measure of variability. Distributions of residuals were used in computer simulations to reconstruct "real-world" standard automated perimetry mean deviation trajectories under different assumptions about rate of change and frequency of testing. Times to detect progression were obtained for the simulated visual fields.ResultsAmong the 344 patients, the mean (SD) age at baseline was 60.2 (10.0) and 60.6 (9.0) years for individuals of African descent and of European descent, respectively; 94 (52%) and 86 (48%) of individuals of African descent and of European descent were women, respectively. The mean SD of the residuals was larger in eyes of individuals of African descent vs those of European descent (1.45 [0.83] dB vs 1.12 [0.48] dB; mean difference: 0.33 dB; 95% CI of the difference, 0.21-0.46; P < .001). The eyes in individuals of African descent had a larger increase in variability with worsening disease (P < .001). When simulations were performed assuming common progression scenarios, there was a delay to detect progression in eyes of individuals of African descent compared with those of European descent. For a scenario with baseline mean deviation of -10 dB and rate of change of -0.5 dB/y, detection of progression in individuals of African descent was delayed by 3.1 (95% CI, 2.9-3.2) years, when considered 80% power and annual tests.Conclusions and relevancePatients of African descent with glaucoma showed increased visual field variability compared with those of European descent, resulting in delayed detection of progression that may contribute to explain higher rates of glaucoma-related visual impairment in individuals of African descent compared with those of European descent with glaucoma.

Project description:OBJECTIVES:We have previously reported a top-ranked risk gene [i.e., serine incorporator 2 gene (SERINC2)] for alcohol dependence in individuals of European descent by analyzing the common variants in a genome-wide association study. In the present study, we comprehensively examined the rare variants [minor allele frequency (MAF)<0.05] in the NKAIN1-SERINC2 region to confirm our previous finding. MATERIALS AND METHODS:A discovery sample (1409 European-American patients with alcohol dependence and 1518 European-American controls) and a replication sample (6438 European-Australian family participants with 1645 alcohol-dependent probands) were subjected to an association analysis. A total of 39,903 individuals from 19 other cohorts with 11 different neuropsychiatric and neurological disorders served as contrast groups. The entire NKAIN1-SERINC2 region was imputed in all cohorts using the same reference panels of genotypes that included rare variants from the whole-genome sequencing data. We stringently cleaned the phenotype and genotype data, and obtained a total of about 220 single-nucleotide polymorphisms in individuals of European descent and about 450 single-nucleotide polymorphisms in the individuals of African descent with 0<MAF<0.05 for an association analysis. RESULTS:Using a weighted regression analysis implemented in the program SCORE-Seq, we found a rare variant constellation across the entire NKAIN1-SERINC2 region that was associated with alcohol dependence in European-Americans (Fp: overall, P=1.8×10(-4); VT: overall, P=1.4×10(-4); Collapsing, P=6.5×10(-5)) and European-Australians (Fp: overall, P=0.028; Collapsing, P=0.025), but not in African-Americans, and not associated with any other disorder examined. Association signals in this region came mainly from SERINC2, a gene that codes for an activity-regulated protein expressed in the brain that incorporates serine into lipids. In addition, 26 individual rare variants were nominally associated with alcohol dependence in European-Americans (P<0.05). The associations of five of these rare variants that lay within SERINC2 showed region-wide significance (P<?=0.0006) and 25 associations survived correction for a false discovery rate (q<0.05). The associations of two rare variants at SERINC2 were replicated in European-Australians (P<0.05). CONCLUSION:We concluded that SERINC2 was a replicable and significant risk gene specific for alcohol dependence in individuals of European descent.

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Genomic and Ancestral Variation Underlies the Severity of COVID-19 Clinical Manifestation in Individuals of European Descent.

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