Impact of Host Genome
on COVID-19 clinical variability

GEN-COVID is a network of more than 40 Italian Hospitals, 16 Continuity Assistance Special Unit (USCA) and 8 Departments of Preventive Medicine led by Professor Alessandra Renieri of the University of Siena in Italy. Physicians of several specialties from Infectious Diseases to Anesthesiology, Respiratory Diseases, Cardiology, Rheumatology, Neurology ENT specialty and Medical Genetics will prove the basis for a detailed patient Registry and Biobank of samples. The network started its activity on March 16, 2020 after IRB approval and since then more than 3000 patients have been collected and sequenced, in order to develop a genetic-based approach to understand the clinical variability of COVID-19 public health emergency.

The project collected and organized high-quality samples and data whose integrity was assured and could be readily accessed and processed for COVID-19 research using existing interoperability standards and tools. To this end, a GEN-COVID Biobank (GCB) and a GEN-COVID Patient Registry (GCPR) were established utilizing already existing biobanking and patient registry infrastructure. The collection of samples and data are now utilized in the GEN-COVID Multicenter Study for generating Genotyping (GWAS) and whole-exome sequencing (WES) results. The data resulting from these studies are then stored and made available through the GEN-COVID Genetic Data Repository (GCGDR).

The GEN-COVID study is connected with the HGI Human Genetic Iniziative (


This project aims to rapidly respond to the current COVID-19 outbreak, at time of writing worldwide cases now reach >700,000 and are rapidly rising as testing becomes more widespread. Healthcare systems are threatened and, in some instances, failing. GEN-COVID will bring a strong evidence-based approach through the most advanced science, making use of the widest possible sets of patient data and genetic material in order to identify genetic cause of clinical variability useful for the diagnosis, prognosis and personalized treatment of COVID-19.

To achieve this overall aim, we will address the following specific objectives:

  1. to perform genotyping (GWAS) on 3.000 COVID-19 patients at Institute for Molecular Medicine of Finland (FIMM)

  2. to perform sequencing (WES) on 3.000 COVID-19 patients at University of Siena (UNISI)

  3. to associate the host genetic data obtained on 3.000 COVID-19 patients with severity and prognosis

  4. to share phenotypic data and samples across the GEN-COVID network platform as well as in cooperation research institutions and national platforms through the GEN-COVID Disease Registry and Biobank;

  5. to share genetic data through Network of Italian Genome (NIG) at CINECA, the largest Italian computing center, and one of the most important worldwide.


  • Source: Fondo Integrativo Speciale per la Ricerca (FISR) - Ministero dell'Università e della Ricerca

Title: “Editing dell'RNA contro il Sars-CoV-2: hackerare il virus per identificare bersagli molecolari e attenuare l'infezione (HACKTHECOV)”

Duration: 2021-2022;

  • Source: Istituto Buddista Italiano Soka Gakkai

Title: “Host genetics and pathogenetic mechanisms of COVID-19 (PAT-COVID)”

Duration: 2021-2022

  • Source: Bando Ricerca COVID-19 Toscana

Title: "Identification of the genetic bases determining the clinical variability of COVID-19 in the Italian population (GEN-COVID)"

Duration: 2021-2022

  • Source: EU project H2020-SC1-FA-DTS-2018-2020

Title: "International consortium for integrative genomics prediction (INTERVENE)" - Grant Agreement No. 101016775

Duration: 2021-2025

  • Source: Intesa San Paolo

Title: "Identificazione delle basi genetiche del COVID-19 nella popolazione italiana"

Duration: 2020-2021

The Expertise of the GEN-COVID Network

This network in built on the expertise of leading physicians in Italy. The network is led by Alessandra Renieri (UNISI), renowned medical geneticist with outstanding expertise in massive parallel sequencing and inventor of 2 CRISPR/Cas9 gene-editing patents.

Click here for opening the list of physicians

Key Public Health Deliverables of the GEN-COVID Network

The key deliverables of the project are:

  1. to develop a state-of-the-art Patient Registry and Biobank for COVID-19 clinical research with access for academic and industry partners;

  2. to understand the genetic and molecular basis of susceptibility to SARS-CoV-2 infection and (susceptibility to a potentially more severe clinical outcome [prognosis] within 12 months);

  3. to understand the genetic profile of patients allowing for the repurposing of medicines for specific therapeutic approaches that demonstrate greater efficacy against the COVID-19 virus and can be rapidly developed (within 12 months);

Publications related to the project:

  • Multiomic analysis reveals cell-type-specific molecular determinants of COVID-19 severity

Zhang S ., et al.

Cell Syst . 2022 June.

  • Host genetic basis of COVID-19: from methodologies to genes

Zguro K., et al.

Eur J Hum Genet . 2022 May.

  • Rare variants in Toll-like receptor 7 results in functional impairment and downregulation of cytokine mediated signaling in COVID-19 patients

Mantovani S. , et al.

Genes Immun. 2021 Dec 24:1–6.

  • Age-dependent impact of the major common genetic risk factor for COVID-19 on severity and mortality

Nakanishi T , et al.

J Clin Invest. 2021 Oct 1:e152386.

  • Common, low-frequency, rare and ultra-rare coding variants contribute to COVID-19 severity

Fallerini C., et al.

Hum Genet 2021 Dec 10;1-27.

  • C9orf72 Intermediate Repeats Confer Genetic Risk for Severe COVID-19 Pneumonia Independently of Age.

Zanella I, et al.

Int J Mol Sci. 2021, 22(13), 6991

  • Mapping the human genetic architecture of COVID-19

COVID-19 Host Genetics Initiative

Nature 2021.

  • Severe COVID-19 in Hospitalized Carriers of Single CFTR Pathogenic Variants

Baldassarri M, et al

J. Pers. Med. 2021, 11(6), 558

  • Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males

Isidori AM, et al

EBioMedicine. 2021 Jun;68:103426. doi: 10.1016/j.ebiom.2021.103426

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

Fallerini C, et al

J Hematol Oncol 2021, 14, 123.

  • The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males.

Croci S, et al.

Autophagy. 2021 Dec 29:1-11.

  • Protective Role of a TMPRSS2 Variant on Severe COVID-19 Outcome in Young Males and Elderly Women

Monticelli M., et al.

Genes 2021, 12(4), 596:

  • Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study

Fallerini C, Daga S, Mantovani S et al.

eLife. 2021 Mar 2;10:e67569.

  • Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in males.

Baldassarri M, Picchiotti N, Fava F, et al.

EBioMedicine. 2021 Mar;65:103246.

  • Post-Mendelian genetic model in COVID-19

Picchiotti N. et al.

Cardiol Cardiovasc Med 2021; 5 (6): 673-694

  • Employing a systematic approach to biobanking and analyzing clinical and genetic data for advancing COVID-19 research.

Daga S, Fallerini C. et al.

Eur J Hum Genet. 2021 Jan 17:1-15.

  • Genetic mechanisms of critical illness in Covid-19.

Pairo-Castineira E, et al.

Nature. 2020 Dec 11.

  • The effect of angiotensin-converting enzyme levels on Covid-19 susceptibility and severity: a Mendelian randomization study.

Butler-Laporte G, et al.

Int J Epidemiol. 2020 Dec 8:dyaa229.

  • Clinical and molecular characterization of COVID-19 hospitalized patients.

Benetti E, et al.

PLoS One. 2020 Nov 18;15(11):e0242534.

  • Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.

Zhang Q, et al.

Science. 2020 Oct 23;370(6515):eabd4570.

  • Autoantibodies against type I IFNs in patients with life-threatening COVID-19.

Bastard P, et al.

Science. 2020 Oct 23;370(6515):eabd4585.

  • ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population.

Benetti E, Tita R. et al.

Eur J Hum Genet. 2020 Nov;28(11):1602-1614.

GEN-COVID Registry and Biobank

The Genetic Biobank of Siena has over 20 years of experience and is certified by over 10, with a consolidated infrastructure of document management and quality management (standard operating procedures, operating instructions, policies). The collection, management and storage of patient data are performed in accordance with applicable regulations (GDPR) and WHO guidelines and standards developed at national and international level by BBMRI, the National Node of the European Research Infrastructure of Biobanks and BioMolecular Resources.

The Biobank aims to make biological samples available to researchers (academia and individuals) working on rare and common diseases including COVID-19. The Biobank collects high quality samples and patient data in a uniform way and ensuring their FAIR management (Reperible, Accessible, Interoperable and Reusable). It is part of the Telethon network of genetic biobanks (TNGB) of EuroBioBank (EBB), RD-Connect an BBMRI-IT.

The biobank belongs to EuroBioBank (EBB), BBMRI-IT and RD-Connect.

The Biobank and the Registry are ISO9001 and ISO15189 certified (certificate 199556-2016-AQ-ITA-ACCREDIA) and accredited according to SIGU (Italian Society of Human Genetics) requirements (Certificate 204107-2016-AQ-ITA-DNV).

How to Join GEN-COVID Network

The number of Hospitals belonging to GEN-COVID Network is continuously growing with a rate of about 3 per week.

How to join GEN-COVID being an Italian Hospital

Both University Hospitals and Local Health Units enrolling COVID-19 patients can contact Francesca Mari The first step is to enter the new center with an IRB amendment at the Hospital of Siena. Subsequently, all documentation is sent to the new hospital's IRB for approval.

How to join GEN-COVID being an Italian Biobank

The samples are collected centrally in Siena and deposited in the certified BBMRI biobank from which they are available to the whole scientific community. The joining of other biobanks are welcome because they can act as a local node, with primary deposit at the local biobank, sending an aliquot for WES, GWAS and back-up to Siena.

The biobanks must also be included among the participating centers with an IRB amendment (contact Ilaria Meloni

How to join GEN-COVID being a SME or a Research Center

The role of SME and research centers can be valuable for possible integration of the main analyzes. Once the candidate genes have been identified, there will certainly be a need for validation analysis (contact Elisa Frullanti

How to join GEN-COVID being BE

The network GEN-COVID is looking for Big Enterprise who may contribute to research development, using the Registry and Biobank for developing products meeting clinical needs in the COVID-19 outbreak. BE interested can contact the PI Alessandra Renieri,

May 2021 Accademia Scienze, Torino

General public, Italian

It is uor genes, in addition to age, that determine wether we will fall sickwith severe life-threatening COVID-19 ora have a simple cold. It is the GEN-COVID study involving 40 italian hospitals to prove this. The genes that determine severity are different between males and females and therefore the drugs that could help in severe COVID must also be different. Some males get sick because there is a defective gene that does not "feel" the presence of the virus (TLR7). The gene is on the X chromosome and females are protected by the second copy of gene. In these cases, the administration of the interferon ( whose production is stimulated by the normal gene) could help overcome the disease. In other cases, different pathogenic mechanisms due to the sum of genes that are a little less functional than they should, lead to serious disease. Also in these cases, in males, testosterone (a powerful natural inflammatory molecule ) or drugs that limit the complement cascade, a system that is activated in inflammation, could help. So knowing our genes could help us cure COVID-19 and also predict its severity.

February 2021 Accademia Fisiocritici, Siena

General public, Italian

It is clear to everyone that the disease caused by Sars- CoV-2 virus does not have the same intensity and symptoms in the people who contract it. The reasons are explained by Professor Alessandra Renieri, geneticist and physiocritical Academic, in the appointment of the "today's Medicine" cycle entitled "Why does COVID-19 affect in different ways? Individual genetics determine the severity of the disease".

Machine Learning approach to untangle host genetics complexity in COVID-19_long.mp4.mp4
COVID-19 and dehumanisation 2021.mp4

October 2021 ASHG meeting

Scientific, English

Common, low frequency, rare and ultra-rare variants contribute to COVID-19 severity

Host genetics is an emerging theme in COVID-19. A handful of common polymorphisms and some rare variants have been identified, either through GWAS or candidate gene approach. However, an organic model is still missing. We applied a gene-based approach to Whole Exome Sequencing data of 2,200 SARS-CoV-2 infected subjects with different clinical expressivity, from very severe to oligo-asymptomatic, within the GEN-COVID cohort. Common, low frequency, rare and ultra-rare variants were tested separately. Autosomal genes were tested separately from genes on the X chromosome. LASSO logistic regression was applied under the assumption of either dominant or recessive phenotype. Both sexes were tested together and separately. Among 18,347 tested genes, about 2,000 genes were found to be contributing after multiple train-test splits. Among these, ¼ of genes was sex specific. These latter genes are under sexual hormone control, such as the testosterone down-regulated TLR3 gene or the estrogen down-regulated TLR5 gene, and exert their effect in one sex only. Integrated PolyGenic Score (IPGS) was calculated as (nmildness - nseverity common) + F1 (mmildness - mseverity low-frequency) + F2 (xmildness - xseverity rare) + F3 (ymildness - yseverity ultra-rare), where F is a weighting factor taking into account the assumption that the impact of protein function inversely correlates with frequency. The weighting factor for ultra-rare is so high that, when the ultra-rare is present, the model simulates Mendelian inheritance such that it happens in TLR7 ultra-rare variants, which we and others proved to be an inherited X-linked form of COVID-19. IPGS is able to improve prediction of clinical outcome in addition to the already known powerful factors, such as age and comorbidities, and profiles a specific genetic signature for adjuvant therapy. A platform of clinical trials based on genetic markers has been submitted to Italian Drug Agency AIFA. This is the first modelling of a genetic complex disease taking into account whole variability from common to ultra-rare variant and it can be translated to many other complex disorders.

October 2021 COVID-19 and dehumanisation meeting Siena

General public, English

COVID-19, the disease originated by the Sar-CoV-2 virus, does not have the same intensity and symptoms in every infected people. In addition to age, our genes determine whether we will get serious life-threatening COVID-19 or have a simple cold. The GEN-COVID multicenter study, coordinated by prof. Alessandra Renieri and involving more than 40 Italian hospitals, proved this. One of the most relevant results is that the genes that determine severity are completely different between males and females. Therefore the drugs that could help in severe COVID-19 must also be different. Some males get sick because there is a defective gene that does not "feel" the presence of the virus (TLR7 gene). This gene is on the X chromosome and females are protected by the second copy of the normal gene. In these cases, the administration of interferon (whose production is stimulated by the normal gene), in addition to the standard therapy, could help overcome the disease. In other cases, different pathogenetic mechanisms due to a set of less functioning genes lead to a serious disease. Also in these cases, in males, testosterone (a powerful natural inflammatory) or drugs that block leucocyte and platelet adherence to the vessel wall, could help. So knowing our genes helps us cure COVID-19 and also predict severity or transmission in family members.


March 10, 2021 Dìmartedì show, channel La7

General public, Italian

March 23, 2021 Dìmartedì show, channel La7

General public, Italian


December 14, 2021 Dìmartedì show, channel La7

General public, Italian