Genes for covid-19 resilience: identification of DNA markers corresponding to coronavirus resistance and susceptibility

Dr. Timothy Sexton

Coronavirus Genetic Markers: An Overview of Their Role in Diagnosis and Treatment.


Coronaviruses (CoVs) (order Nidovirales, family Coronaviridae, subfamily Coronavirinae) are responsible for respiratory disease outbreaks in many vertebrate species. They are a large family of single-stranded RNA enveloped viruses (+ssRNA) that can be isolated in different animal species. They have genome sizes ranging between 26 to 32 kilobases (kb) in length, being the largest genomes for RNA viruses (consequently increasing the effectiveness of facemasks). COVID-19 also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or "novel coronavirus 2019" is a new virus and we are just beginning to understand resistance and susceptibility in humans.


COVID-19 is similar to severe acute respiratory syndrome (SARS) in the respect that both viruses infect their human hosts via the same receptor, the angiotensin-converting enzyme 2 (ACE2 receptor), and cause similar clinical and pathological features. Interestingly the spike protein which is responsible for receptor binding is highly similar between 2019-nCoV and SARS-CoV, this is a result of significant selection for the same receptor (Wu., 2020). Research into how our bodies defend against SARS might reveal how our bodies could defend against covid-19.


Several recent Genome Wide Association Studies (GWAS) have provided a much deeper insight into the genetic variations that can help to explain why some individuals are virtually unaffected by COVID-19, and for others the virus is life threatening or even fatal.

In this post, we provide a review of the peer reviewed literature and present information about candidate genes for SARS-CoV resistance. If you have taken an at home DNA test like those available from 23andMe, Ancestry DNA, Dante labs, you can evaluate your raw DNA data and see how your DNA sequence compares with the research findings.


How to analyze your DNA for coronavirus resistance or susceptibility?


Step 1) Download your raw autosomal DNA file and save it to a safe and secure location

To analyze your DNA data, start by downloading your raw autosomal DNA and save it to a safe location. Here are instructions to download your raw DNA file from: 23andMe, Ancestry DNA, Family Tree DNA, Dante Labs, My Heritage, Genes For Good, Vitagene, and Living DNA.


Step 2) Analyze your raw DNA file


Search your raw DNA data using a text editor such as "text wrangler" or "notepad" using the "find" function, or using command line.

Open your raw DNA file and you will notice the headers of unique SNP ID (rs# or i#), chromosome, position and genotype. The formats differ slightly between each direct to consumer DNA testing company.


To evaluate your risk of poor recovery from the COVID-19 have a look for these DNA markers described below:

Several Genome Wide Association Study (GWAS) were recently published that describe loci associated with respiratory failure in patients infected with SARS-CoV-2 and three studies identified SNP markers in the same ~50 kb genomic segment that is inherited from Neandertals (Ellinghaus D et al., 2020, Zeberg & Pääbo, and Blokland et al., 2020). In addition these GWAS studies also identified a number of other DNA markers that are associated with COVID-19, and each of these are presented in the tabel below.


In addition, other DNA markers covered in this post include rs4804803 which was associated with SARS, and those positioned in the angiotensin-converting enzyme-2 (ACE2) receptor which was proved to be the same receptor for the human respiratory coronavirus NL63, , SARS-coronavirus (SARS-CoV), and the novel coronavirus 2019-nCoV/SARS-CoV (Li et al., 2017; Lu et al., 2019). Since the spike protein of the coronavirus has evolved to match the ACE2 receptor, it's likely that individuals with variations that alter the protein sequence would result in a degree of resistance to covid-19. Below are non-synonymous SNPs from the ACE2 transcript NM_021804.2 and of particular interest are SNPs that cause major changes like rs199951323 which results in a premature stop codon.


Gene dbsnp Chromosome (GRCh37) POS REF ALT Risk Alleles Marker Effect Reference
IVNS1ABP rs6668622 1 185414582 T C Susceptibile Variant T:T and T:C in males odds ratio 1.44 Roberts., 2020;
SRRM1 rs111972040 1 24999361 A G risk genotypes G:G and A:G, 3_prime_UTR_variant odds ratio for hospitalization = 8.29
LZTFL1 rs35044562 3 45909024 A G risk genotypes G:G and A:G, intron_variant,genic_upstream_transcript_variant odds ratio 1.60 Blokland et al., 2020; Zeberg & Pääbo
LZTFL1 rs11385942 3 45876460 A - or A or AAA InDel, A:A and A:- have higher respiratory failure susceptibility, intron_variant odds ratio 1.77 Ellinghaus et al., 2020; Roberts., 2020
LZTFL1 rs10490770 *LD with rs11385942 3 45864732 T C risk genotypes T:C and C:C, intron_variant odds ratio for heterozygous carriers 1.7 Zeberg and Pääbo., 2020;
LZTFL1 rs67959919 *LD with rs11385942 3 45871908 G A risk genotypes G:A and A:A, intron_variant odds ratio for heterozygous carriers 1.7
LZTFL1 rs35624553 *LD with rs11385942 3 45867440 A G risk genotypes G:A and G:G, intron_variant odds ratio for heterozygous carriers 1.7
LZTFL1 rs71325088 *LD with rs11385942 3 45862952 T C risk genotypes C:T and C:C, intron_variant odds ratio for heterozygous carriers 1.7
ABO rs657152 9 136139265 A C or T A risk allele, intron_variant odds ratio 1.77 Ellinghaus et al., 2020; Roberts., 2020
Intergenic rs5798227 12 53120100 C - Risk allele is the deletion p = 2.2x10-7 Blokland et al., 2020;
IGHV3-7 rs11844522 14 106522576 C T Susceptibile variations T:T, C:T p=1.9x10-7
Immunoglobulin Lambda Locus (IGL) rs73166864 22 23340580 T C or G Susceptibile variations T:T and T:C odds ratio 1.7 Roberts., 2020;
TLR7 rs200553089 ChrX 12906010 G T risk genotypes T:G and T:T, missense_variant Made et al., 2020;
Synonymous SNPs positioned in ACE2
ACE2 rs373153165 chrX 15580093 C T or A missense_variant p.Asp785Asn/c.2353G>A Cao et al., 2020
ACE2 rs140016715 chrX 15582154 G A missense_variant p.Arg768Trp/c.2302C>T
ACE2 rs147311723 chrX 15582265 G A missense_variant p.Leu731Phe/c.2191C>T
ACE2 rs41303171 chrX 15582298 T C missense_variant p.Asn720Asp/c.2158A>G
ACE2 rs370187012 chrX 15582327 C T missense_variant p.Arg710His/c.2129G>A
ACE2 rs776995986 chrX 15582334 G A missense_variant p.Arg708Trp/c.2122C>T
ACE2 rs149039346 chrX 15584416 A G missense_variant p.Ser692Pro/c.2074T>C
ACE2 rs200180615 chrX 15584488 C T missense_variant p.Glu668Lys/c.2002G>A
ACE2 *rs199951323 chrX 15585879 A C stop_gained p.Leu656*/c.1967T>G
ACE2 rs183135788 chrX 15585933 T C missense_variant p.Asn638Ser/c.1913A>G
ACE2 rs748163894 chrX 15588434 G A missense_variant
ACE2 rs202137736 chrX 15591485 T C splice_region_variant+intron_variant c.1541+5A>G
ACE2 rs140473595 chrX 15591530 C T missense_variant p.Ala501Thr/c.1501G>A
ACE2 rs191860450 chrX 15593829 T C missense_variant p.Ile468Val/c.1402A>G
ACE2 rs758142853 chrX 15609868 A G missense_variant p.Val184Ala/c.551T>C
ACE2 rs754511501 chrX 15609902 C T missense_variant p.Gly173Ser/c.517G>A
ACE2 rs746034076 chrX 15609943 T C missense_variant p.Asn159Ser/c.476A>G
ACE2 rs373252182 chrX 15609973 T C missense_variant p.Asn149Ser/c.446A>G
ACE2 rs2285666 chrX 15610348 C T splice_region_variant+intron_variant c.439+4G>A
ACE2 rs768736934 chrX 15612963 C T splice_region_variant+intron_variant c.345+5G>A
ACE2 rs4646116 chrX 15618958 T C missense_variant p.Lys26Arg/c.77A>G
ACE2 rs73635825 chrX 15618980 A G missense_variant p.Ser19Pro/c.55T>C
SNPs associated with SARS
CD209 rs4804803 19 7812733 A G Susceptibile genotype A:A, upstream_transcript_variant NC_000019.10:7747846 Sakuntabhai et al., 2005; Chan et al., 2010


One interesting observation to note is that the ACE2 gene is positioned on the X chromosome, meaning that men will only inherit one copy of this gene. The additional diversity provided by the females 2nd copy of the ACE2 gene on their 2nd X chromosome could in part help to explain why women are less susceptible to covid-19.


Step 3) Compare your genotype/SNPs with additional research findings

There are a wealth of resources describing information for relating to this SNP check out dbSNP and SNPedia


dbSNP

dbSNP contains human single nucleotide variations, microsatellites, and small-scale insertions and deletions along with publication, population frequency, molecular consequence, and genomic and RefSeq mapping information for both common variations and clinical mutations.


SNPpedia

SNPedia is a wiki investigating human genetics. They share information about the effects of variations in DNA, citing peer-reviewed scientific publications. It is used by Promethease to create a personal report linking your DNA variations to the information published about them.



**If you are concerned about anything you see in your DNA results, please speak to your doctor, or a genetics councillor




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