Trans-ancestry analysis reveals genetic and nongenetic associations with COVID-19

susceptibility and severityAnálise trans- ancestral revela associações genéticas e não genéticas com suscetibilidade e

gravidade do COVID-19

Presented By:Lucas Garcia Rufino

Marina Vieira Lima de CandiaPedro Henrique Moreli Porceban

Vanessa de Oliveira Silveira

Overview

IntroductionAbstract & Respondent

characteristics

03The study

Methods, GWAS & Main results

04Non genetic

associations with COVID-19

Socioeconomic status, ancestry & preexisting

conditions

08

ABO blood groupThe role of the ABO group

in susceptibility to infection

15Chromosome

3p21.31Multiple genes that could be functionally implicated

in COVID-19 pathology

23Conclusion

Bibliography

28

About the articleAuthor information

Janie F. Shelton & Anjali J. Shastri

Affiliations

23andMe Inc., Sunnyvale, CA, USA: Janie F. Shelton, Anjali J. Shastri, Chelsea Ye, Catherine H. Weldon, Teresa Filshtein-Sonmez, Daniella Coker, Antony Symons, Adrian Chubb, Alison Fitch, Alison Kung, Amanda Altman, Andy Kill, Jason Tan, Jeff Pollard, Jey McCreight, Jess Bielenberg, John Matthews, Johnny Lee, Lindsey Tran, Michelle Agee, Monica Royce, Nate Tang, Pooja Gandhi, Raffaello d’Amore, Ruth Tennen, Scott Dvorak, Scott Hadly, Sungmin Park, Taylor Morrow, Trung Le, Yiwen Zheng, Stella Aslibekyan & Adam Auton

Human Genetics-R&D, GSK Medicines Research Centre, Target Sciences-R&D, Stevenage, UK: Jorge Esparza-Gordillo

Article link: https://rdcu.be/czAka

Abstract

Based on a study of 1,051,032 23andMe research participants, the authors report genetic and

nongenetic associations with testing positive for SARS-CoV-2, respiratory symptoms and

hospitalization

Introduction

ABOUT THE RESEARCH:

Based on a study of 1,051,032 23andMe research participants, it was reported genetic and nongenetic associations with testing positive for SARS-CoV-2, respiratory symptoms and hospitalization.

WHAT WAS FOUND:

A strong association between blood type and COVID-19 diagnosis was identified, as well as a gene-rich locus on chromosome 3p21.31 that is more strongly associated with outcome severity.

Hospitalization risk factors -> advancing age, male sex, obesity, lower socioeconomic status, non-European ancestry and preexisting cardiometabolic conditions.

Lucas Garcia Rufino

IntroductionPARTICIPANTS

Lucas Garcia Rufino

IntroductionPARTICIPANTS

Note: the study participants were 63% female with a median age of 51 years.

15.434 individuals (from the total of 1.051.032) reported a positive COVID-19 test, of whom 1.131 reported hospitalization with COVID-19 symptoms.

Lucas Garcia Rufino

The Genome-wide association study (GWAS)

“A genome-wide association study (GWAS) is an approach used in genetics research to associate specific genetic variations with particular diseases. The method involves scanning the genomes from many different people and looking for genetic markers that can be used to predict the presence of a disease”

- National Human Genome Research Institute

Note: The GWAS can see if any variant is associated with other traits too.

Source: Research Gate, shorturl.at/apwU1

Lucas Garcia Rufino

Nongenetic risk factors - Methods

•Direct-to-consumer research platform

•Explored age, sex, ancestry, median household income of the residential zip code, educational attainment, body mass index (BMI) and preexisting conditions as risk factors

•Ancestry- algorithm

•Final models estimating the relationship between the preexisting condition and COVID-19 hospitalization were adjusted for age

•Separately by US regions

Marina Vieira Lima de Candia

Analysis

•Lower socioeconomic status, African American ancestry, obesity and preexisting conditions were associated with a higher risk of hospitalization

•Those reporting a positive SARS-CoV-2 test were more likely to be male, younger on average and less likely to be of European ancestry

•Living in an urban environment was associated with a higher likelihood of reporting a positive test as was employment as a healthcare professional

Marina Vieira Lima de Candia

While the proportion of individuals reporting a positive SARS-CoV-2 test declined as a function of age, hospitalization rates increased dramatically

with age

Marina Vieira Lima de Candia

Generally, non-European ancestry was associated with higher rates of self-reported SARS-CoV-2 infection and higher proportions of

hospitalization.

Marina Vieira Lima de Candia

The most significant risk factor for hospitalization within the population reporting a positive test for COVID-19 was obesity

Marina Vieira Lima de Candia

Social symptoms

•Socioeconomic status was inversely associated with hospitalization risk, with a 4% decrease in hospitalization per US$10,000 increase in median income in the zip code of residence (coronavirus- uma sindemia? https://cee.fiocruz.br/?q=node/1264)

•High school and lower education conferred a 38% increased risk in hospitalization

•These results highlight the central importance of systemic social factors in altering the risk of severe outcomes within minority communities.

Marina Vieira Lima de Candia

Covariates

•Covariates explored but not found to be significant in the final model included alcohol intake, urban/rural residence, red meat intake and current smoking

Marina Vieira Lima de Candia

Blood group analyses

❖ They classified haplotypes into blood groups on the basis of genotypes at three SNPs (rs8176747, rs41302905 and rs8176719) ➢ Os haplótipos foram classificados segundo o genótipo baseado na presença de 3 SNPs

❖ A deletion at rs8176719 confers a type O haplotype, as does a T allele at rs41302905➢ Uma deleção em rs8176719 confere haplótipo do tipo O, assim como um alelo T em rs41302905

❖ If neither rs8176719 nor rs41302905 confers type O, then rs8176747 distinguishes between types A and B➢ Tanto rs8176719 quanto rs4130290 não conferem o tipo O, sendo rs81176747 a responsável por distinguir os tipos

A e B

❖ Individuals were assigned a blood type on the basis of their diploid combination of haplotypes, with type O being recessive➢ Indivíduos tiveram seu grupo definido a partir da combinação dos haplótipos, sendo o tipo O recessivo

(Análise dos grupos sanguíneos)

Vanessa de Oliveira Silveira

Blood group analyses(Análise dos grupos sanguíneos)

❖ The study also used the structural variant esv3585521 to obtain rhesus type➢ O estudo também utilizou a variante estrutura esv3585521 para obter o tipo sanguíneo segundo o sistema Rh

❖ This variant, located within the RHD gene, has a 39.4% frequency in European populations➢ Essa variante se localiza dentro do gene RHD e apresenta uma frequência de 39,4% em populações europeias

❖ They took individuals imputed as homozygous for the deletion as being rhesus-negative➢ Eles consideraram indivíduos homozigotos para deleção nessa variante como sendo Rh negativo

❖ They used these analysis to compare the blood groups reported by the research participants and those genetically assigned➢ Eles usaram essa análise para comparar os grupos sanguíneos afirmados pelos participantes da pesquisa e os que

lhes foram atribuídos geneticamente

❖ No association was found between Covid-19 and the rhesus factor➢ Não foi encontrado nenhuma associação entre o Covid-19 e o fator Rh

Vanessa de Oliveira Silveira

ABO Blood Group

❖ While comparing SARS-CoV-2 test-positive and test-negative individuals, the study identified an association at chromosome 9q34.2, with the index SNP rs9411378➢ Ao comparar indivíduos positivas com negativos para Covid-19, o estudo identificou uma associação no

cromossomo 9q34.2 com a SNP rs9411378

❖ This index SNP rs9411378 is in linkage disequilibrium (LD) with a functional variant in the ABO gene, specifically rs8176719, which is well-known for usually confers a type O blood group when present in the homozygous form➢ Essa SNP rs9411378 está em desequilíbrio de ligação com a variante funcional no gene ABO,

especificamente a SNP rs8176719, que é conhecida por geralmente conferir sangue do tipo O quando em homozigose

❖ They concluded that testing positive was associated with having rs9411378 instead of rs8176719➢ Eles concluíram que testar positivo para a doença estava associado em ter a SNP rs9411378 em vez da

rs8176719

Vanessa de Oliveira Silveira

Chromosome 9

https://www.rarechromo.org/media/information/Chromosome%20%209/9q34%20duplication%20syndrome%20FTNW.pdf

What is the exact association between Covid-19 and the ABO blood group?

❖ For all COVID-19 phenotypes, they found that the O blood group was protective compared to the other blood groups, whereas blood groups A, B and AB were indifferent

➢ Para todos os fenótipos de Covid-19, eles descobriram que o grupo O foi “protetor” em relação aos outros grupos, enquanto A, B e AB foram indiferentes entre si

❖ However, the effect size estimates at the ABO locus with the severity phenotypes appeared somewhat sensitive to choice of control population, which is consistent with a role in susceptibility rather than severity

➢ Contudo,as estimativas do tamanho do efeito no locus ABO com os fenótipos de gravidade pareceram um tanto sensíveis à escolha da população de controle, o que é consistente com um papel na suscetibilidade ao invés da gravidade.

Vanessa de Oliveira Silveira

https://media.springernature.com/full/springer-static/image/art%3A10.1038%2Fs41588-021-00854-7/MediaObjects/41588_2021_854_Fig5_HTML.png?as=webp

Comparison of the effect sizes of ABO blood groups across phenotypes

The O blood group❖ ABO blood groups can play a direct role in pathogen

infection by serving as receptors and/or coreceptors➢ Os grupos sanguíneos ABO podem desempenhar um papel direto

na infecção de um patógeno, servindo como receptores ou correceptores

❖ SARS-CoV-2 spike protein interacts with multiple host C-type lectin receptors in a glycosylation-dependent manner➢ As proteínas spike do SARS-CoV-2 interagem com vários

receptores de lectina do tipo C de forma dependente de glicosilação❖ Differential glycosylation of the spike protein or

envelope glycolipids from expression of different ABO glycosyltransferases may then impact the binding and propagation of SARS-CoV-2 viral particles in the host➢ A glicosilação diferencial da proteína spike ou glicolipídeos do

envelope da expressão de diferentes glicosiltransferases ABO pode impactar a ligação e propagação de partículas virais SARS-CoV-2 no hospedeiro

C-Type Lectin Receptors

https://encrypted-tbn0.gstatic.com/images?q=tbn:ANd9GcTHrel9kCQA1Zi6RqS9e2Ebcp5ZuBvzGOVDmA&usqp=CAUVanessa de Oliveira Silveira

The O blood group

❖ There is, also, a speculation that the lower susceptibility of blood type O could be linked to anti-A blood antibodies inhibiting the adhesion of coronavirus to angiotensin converting enzyme 2 (ACE2)-expressing cells, thereby providing protection

➢ Há, também, uma especulação de que a menor suscetibilidade do tipo sanguíneo O poderia estar ligada a anticorpos anti-A sanguíneos que inibem a adesão do coronavírus às células que expressam a enzima conversora de angiotensina 2 (ACE2), proporcionando proteção

❖ However, this idea is questionable because, if the protection against infection were caused by anti-A blood antibodies, blood B should present a differentiated picture, precisely due to the presence of anti-A

➢ No entanto, essa ideia é questionável porque, se a proteção contra a infecção fosse causada por antígenos anti-A, o sangue B deveria apresentar um quadro diferenciado, devido à presença justamente do anti-A

Vanessa de Oliveira Silveira

Association at chromosome 3p21.31● Association shared across all

phenotypes

● Association was strongest in phenotypes related to respiratory symptoms

● Lowest P value observed in the severe respiratory symptom phenotype (index SNP rs13078854, alleles A/G, P= 1.6 X 10-18) and with a relatively large estimated effect size (G allele OR=0.592, 95% CI 0.527-0.665)

Pedro Henrique Moreli Porceban

Pedro Henrique Moreli Porceban

Test-positive versus test-negative

Respiratory symptoms

Association at chromosome 3p21.31● Testing rsl3078854 separately in males and females for the severe respiratory

symptoms phenotype gave an OR=0.49 (95% CI 0.41-0.59) in males and OR=0.69 (95% CI 0.58-0.82) in females, with the difference being moderately significant (P= 0.003; z-test).

● ABO blood type does not modulate the effect at the chromosome 3p21.31 locus (P value=0.8; z-test): conditioning on blood type O, the OR of rs13078854 was estimated to be 0.63 (95% CI 0.52-0.77), whereas conditioning on any other blood type gave an OR of 0.57 (95% CI 0.49-0.66).

Pedro Henrique Moreli Porceban

Multiple genes● CCR9 predominantly regulates T

cell homing to the gut, which may indirectly impact the response in the lung; however, it has also been shown to regulate eosinophil recruitment to the lung

● SLC6A20 potentially forms a complex with ACE2. Increased SLC6A20 levels may lead to increased ACE2 protein levels and greater viral uptake.

● CXCR6 promotes natural killer T cell and tissue-resident memory CD8+ T cells residence in the lungs and plays a role in the trafficking of T lymphocytes to the bronchial epithelia during respiratory infection and inflammatory lung disease

● LZFTL1 has been implicated in ciliogenesis and intracellular trafficking of ciliary proteins, which may impact airway epithelial cell function.

Pedro Henrique Moreli Porceban

Risk variants● The risk variants at the chromosome

3p21.31 locus achieved ORs of approximately 2.0 in their data, which is relatively large in the context of GWAS studies.

● Risk alleles are relatively common

● Little evidence was found to suggest that allele frequency differences at this locus could account for the higher rate of severe outcomes from COVID-19 for non-European ancestry groups.

● The primary risk allele at the chromosome 3p21.31 is most common in European populations.

Pedro Henrique Moreli Porceban

Bibliography● https://www.nature.com/articles/s41588-021-00854-7#Fig10● https://pt.wikipedia.org/wiki/Linkage_disequilibrium#:~:text=Em%20gen%C3%A9tica%20pop

ulacional%2C%20linkage%20disequilibrium,com%20recombina%C3%A7%C3%A3o%20limitada%20entre%20eles.

● https://www.invivogen.com/review-clr