Post-Mendelian genetic model in COVID-19

Abstract

Host genetics is an emerging theme in COVID-19 and few common polymorphisms and some rare variants have been identified, either by GWAS or candidate gene approach, respectively. However, an organic model is still missing. Here, we propose a new model that takes into account common and rare germline variants applied in a cohort of 1,300 Italian SARS-CoV-2 positive individuals. Ordered logistic regression of clinical WHO grading on sex and age was used to obtain a binary phenotypic classification. Genetic variability from WES was synthesized in several boolean representations differentiated according to allele frequencies and genotype effect. LASSO logistic regression was used for extracting relevant genes. We defined about 100 common driver polymorphisms corresponding to classical “threshold model”. Extracted genes were demonstrated to be gender specific. Stochastic rare more penetrant events on about additional 100 extracted genes, when occurred in a medium or severe background (common within the family), simulate Mendelian inheritance in 14% of subjects (having only 1 mutation) or oligogenic inheritance (in 10% having 2 mutations, in 11% having 3 mutations, etc).The combined effect of common and rare results can be described as an integrated polygenic score computed as: (nseverity − nmildness) + F (mseverity − mmildness)where n is the number of common driver genes, m is the number of driver rare variants and F is a factor for appropriately weighing the more powerful rare variants. We called the model “post-Mendelian”. The model well describes the cohort, and patients are clustered in severe or mild by the integrated polygenic scores, the F factor being calibrated around 2, with a prediction capacity of 65% in males and 70% in females. In conclusion, this is the first comprehensive model interpreting host genetics in a holistic post-Mendelian manner. Further validations are needed in order to consolidate and refine the model which however holds true in thousands of SARS-CoV-2 Italian subjects.

SELP Asp603Asn and severe thrombosis in COVID-19 males: implication for anti P-selectin monoclonal antibodies treatment

“…A cohort of 1,186 SARS-CoV-2-infected subjects was recruited during the first pandemic wave within the Italian GEN-COVID Study (https://sites.google.com/dbm.unisi.it/gen-covid) 1 . ORL model was applied to the clinical WHO gradings, stratified by sex and adjusted by age, as described elsewhere 20 . The male subset consists of 513 COVID-19 male patients: 236 severe COVID-19 patients (cases) and 277 SARS-CoV-2 PCR-positive oligo-asymptomatic subjects (controls).…”

“…WES with at least 97% coverage at 20x was performed using the NovaSeq6000 System (Illumina, San Diego, CA, USA) as previously described 1 . WES data were represented in a binary mode on a gene-by-gene basis 20 . LASSO logistic regression model was applied to a synthetic boolean representation under recessive model of genetic combinations 20 .…”

Cross-GWAS coherence test at the gene and pathway level

“…Hence, modulo potential confounders, a causal relation from predisposition to take M05B to a protective property towards severity of Covid-19 via HOXC4 is sug-gested. We note that HOXC4 has been discussed before in the Covid-19 context [47]. The gene is related to an enhanced antibody response under the regulation of estrogens.…”

“…We have p V 0.27 under calcium and p V 0.06 under vitamin D, hence, a potential confounding role of vitamin D is possible. We note that HOXC4 has been discussed before in the COVID-19 context [75]. The gene is related to an enhanced antibody response under the regulation of estrogens.…”

“…Our causal analysis using the ratio test (cf., eq. ( 19)) suggests that the genes HOXC4 and DPP9, which have already been associated with severe COVID-19 [75,76], may contribute to the protective role of conditions leading to M05B medication prescription, and that the genes MED23 and GATA4 may play a role in the causal link between vitamin D deficiencies and severe COVID-19. Note that the novel aspect of our method is its capacity to identify candidate genes mediating the causal effects, but we cannot exclude potential confounders in this causal analysis.…”