The hereditary laws have been postulated 157 years ago by the mathematician and biologist Gregor Mendel. It is pretty astonishing that these laws are still used today in the current clinical practice. In the Mendelian disorders, also known as monogenic or rare diseases, these laws are used in a number of clinical actions from prenatal, to presymptomatic, and preimplantation diagnosis to target treatment by both traditional and advanced therapy, such as gene therapy.
On the other hand, no substantial advances have been made in mathematical rules useful in clinical practice for complex disorders, in which more than one gene is involved together with environmental factors. In the dualism between genetic Variability (gV) and environmental Variability (eV) the environmental factors have been often elusive. For example, in diabetes putative viral infections have been invoked but never fully defined. The same is true for multiple sclerosis, for which, only very recently a subtype of EBV virus has been likely identified as the key environmental factor.
COVID-19 is the first disease in which environmental factors are well defined, misurabile and weighable. Heritability (h2) as calculated by gV/gV+aV is very high in COVID-19, similarly to psychiatric disorders . While media are taking care mainly of the viral genome, the host genome is the real discriminant between severe COVID-19 and asymptomatic SARS-CoV-2 infection. Therefore, while COVID-19 is representing a challenge for the health systems and society, it is the first real opportunity to move forward on understanding mechanisms and new rules useful in clinical practice of complex disorders, as described in the papers of this issue [1,2,3,4,5,6,7,8,9].
This special issue wants to summarize for the EJHG readers the key steps toward these achievements. One can start reading the manuscript of Jemison et al which focuses on the SARS-CoV-2 virus’ mechanism of infection and its change of the intracellular environment  and the manuscript by Redin et al focusing on the host immunological determinant of SARS-CoV-2 infection .
To better understand the pathogenic mechanism of SARS-COV-2 infection and COVID-19 disease, one cannot ignore the HLA system . Zhang Y et al. show an increased allelic expression pattern with overexpression of HLA-B gene in human lung epithelial cells infected by SARS-CoV-2. They also demonstrate that the antiviral cytokine IFN-β contributes to allelic expression of the HLA-B gene in lung cells .
Several useful tools are also presented in this issue  and other issues of this journal  for either updating the readers on loci/genes associated with COVID-19  or genetic data/biological samples availability for running new models .
Bruce J at al. explore how host genetics may impact decisions about vaccine administration. As host genetic factors influence vulnerability, as well as resistance to infection, they evaluate the prioritisation of genetic vulnerability in vaccination schemes, and the potential for ethical de-prioritisation for resistors . Another unexplored area about vaccines is related to the so-called “more common” rare disease with impact on lung function such as α-1 antitrypsin (A1AT) deficiency (AATD) . On one hand, AATD patients have not been included in the COVID-19 vaccine clinical trials and vaccine efficacy is unknown. On the other hand, A1AT could be a promising therapeutic option for patients with COVID-19 .
A different perspective was employed by Kerner and Quintana-Murci . They focused on past selection events relevant for the history of our species. Admixture with Neanderthals was crucial for modern human adaptation to the threats of pathogens during evolution. They show how ancient genetic adaptation contributes to the observed population differences in the susceptibility to SARS-CoV-2 infection and the severity of COVID-19.
Finally, Zguro et al. focus on new methods for understanding the host genetics determinants of COVID-19 . A new method named “post-Mendelian model” has been developed combining for the first time both common and rare genetic variability and using a gene-based machine learning approach with the support of GEN-COVID (https://sites.google.com/dbm.unisi.it/gen-covid). Data are shared through NIG - Network of Italian Genomes (http://nigdb.cineca.it/). Therefore, we are looking beyond Mendelian rules, making a real step forward in understanding and predicting complex disorders.
Zguro K, Fallerini C, Fava F, Furini S, Renieri A. Host genetic basis of COVID-19: from methodologies to genes. Eur J Hum Genet. 2022. https://doi.org/10.1038/s41431-022-01121-x.
Jamison DA Jr, Anand Narayanan S, Trovão NS, Guarnieri JW, Topper MJ, Moraes-Vieira PM, et al. A comprehensive SARS-CoV-2 and COVID-19 review, Part 1: Intracellular overdrive for SARS-CoV-2 infection. Eur J Hum Genet. 2022. https://doi.org/10.1038/s41431-022-01108-8.
Redin C, Thorball CW, Fellay C. Review on human genomics of SARS-CoV-2 infection. Eur J Hum Genet. 2022. https://doi.org/10.1038/s41431-022-01136-4.
Zhang Y, Sun Y, Zhu H, Hong H, Jiang J, Yao P, et al. Allelic imbalance of HLA-B expression in human lung cells infected with coronavirus and other respiratory viruses. Eur J Hum Genet. 2022. https://doi.org/10.1038/s41431-022-01070-5.
Barmania F, Mellet J, Ryder MA, Ford G, Herd CL, Tamuhla T, et al. Coronavirus Host Genetics South Africa (COHG-SA) database-a variant database for gene regions associated with SARS-CoV-2 outcomes. Eur J Hum Genet. 2022. https://doi.org/10.1038/s41431-022-01089-8.
Daga S, Fallerini C, Baldassarri M, Fava F, Valentino F, Doddato G, et al. Employing a systematic approach to biobanking and analyzing clinical and genetic data for advancing COVID-19 research. Eur J Hum Genet. 2021;29:745–59. https://doi.org/10.1038/s41431-020-00793-7
Bruce J, Johnson SB. Exploring the ethics of genetic prioritisation for COVID-19 vaccines. Eur J Hum Genet. 2022. https://doi.org/10.1038/s41431-022-01058-1.
Yang C, Zhao H, Tebbutt SJ. Leave no one behind: inclusion of alpha-1 antitrypsin deficiency patients in COVID-19 vaccine trials. Eur J Hum Genet. 2022. https://doi.org/10.1038/s41431-022-01047-4.
Kerner G, Quintana-Murci L. The genetic and evolutionary determinants of COVID-19 susceptibility. Eur J Hum Genet. 2022. https://doi.org/10.1038/s41431-022-01141-7.
This study is part of the GEN-COVID Multicenter Study, https://sites.google.com/dbm.unisi.it/gen-covid, the Italian multicenter study aimed at identifying the COVID-19 host genetic bases. We thank private donors for the support provided to AR (Department of Medical Biotechnologies, University of Siena) for the COVID-19 host genetics research project (D.L n.18 of March 17, 2020). We also thank the COVID-19 Host Genetics Initiative (https://www.covid19hg.org/). This work was funded by MIUR project “Dipartimenti di Eccellenza 2018-2020” to Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020). Private donors for COVID-19 research. “Bando Ricerca COVID-19 Toscana” project to Azienda Ospedaliero-Universitaria Senese (CUP I49C20000280002). Charity fund 2020 from Intesa San Paolo dedicated to the project N. B/2020/0119 “Identificazione delle basi genetiche determinanti la variabilità clinica della risposta a COVID-19 nella popolazione italiana”. the Istituto Buddista Italiano Soka Gakkai for funding the project “PAT-COVID: Host genetics and pathogenetic mechanisms of COVID-19” (ID n. 2020-2016_RIC_3); the Italian Ministry of University and Research for funding within the “Bando FISR 2020” in COVID-19. We thank EU project H2020-SC1-FA-DTS-2018-2020, entitled “International consortium for integrative genomics prediction (INTERVENE)” – Grant Agreement No. 101016775.
The author declares no competing interests.
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Renieri, A. COVID-19: a challenge and an opportunity. Eur J Hum Genet 30, 870–871 (2022). https://doi.org/10.1038/s41431-022-01142-6