scholarly journals A genomic region associated with protection against severe COVID-19 is inherited from Neandertals

2021 ◽  
Vol 118 (9) ◽  
pp. e2026309118 ◽  
Author(s):  
Hugo Zeberg ◽  
Svante Pääbo
Keyword(s):  
Genetic Risk ◽  
Association Studies ◽  
Severe Disease ◽  
Genetic Association Studies ◽  
Genomic Region ◽  
Risk Haplotype ◽  
The Past ◽  
Human Genomes ◽  
Using Data ◽  
Western Eurasia

It was recently shown that the major genetic risk factor associated with becoming severely ill with COVID-19 when infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is inherited from Neandertals. New, larger genetic association studies now allow additional genetic risk factors to be discovered. Using data from the Genetics of Mortality in Critical Care (GenOMICC) consortium, we show that a haplotype at a region on chromosome 12 associated with requiring intensive care when infected with the virus is inherited from Neandertals. This region encodes proteins that activate enzymes that are important during infections with RNA viruses. In contrast to the previously described Neandertal haplotype that increases the risk for severe COVID-19, this Neandertal haplotype is protective against severe disease. It also differs from the risk haplotype in that it has a more moderate effect and occurs at substantial frequencies in all regions of the world outside Africa. Among ancient human genomes in western Eurasia, the frequency of the protective Neandertal haplotype may have increased between 20,000 and 10,000 y ago and again during the past 1,000 y.

scholarly journals A genetic variant protective against severe COVID-19 is inherited from Neandertals

2020 ◽  
Author(s):  
Hugo Zeberg ◽  
Svante Pääbo
Keyword(s):  
Genetic Risk ◽  
Genetic Variant ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Risk Haplotype ◽  
Additional Risk ◽  
Genome Wide ◽  
The World ◽  
Moderate Effect ◽  
Using Data

AbstractIt was recently shown that the major genetic risk factor associated with becoming severely ill with COVID-19 when infected by SARS-CoV-2 is inherited from Neandertals. Thanks to new genetic association studies additional risk factors are now being discovered. Using data from a recent genome-wide associations from the Genetics of Mortality in Critical Care (GenOMICC) consortium, we show that a haplotype at a region associated with requiring intensive care is inherited from Neandertals. It encodes proteins that activate enzymes that are important during infections with RNA viruses. As compared to the previously described Neandertal risk haplotype, this Neandertal haplotype is protective against severe COVID-19, is of more moderate effect, and is found at substantial frequencies in all regions of the world outside Africa.

scholarly journals Fine scale human genetic structure in three regions of Cameroon reveals episodic diversifying selection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kevin K. Esoh ◽  
Tobias O. Apinjoh ◽  
Steven G. Nyanjom ◽  
Ambroise Wonkam ◽  
Emile R. Chimusa ◽  
...  
Keyword(s):  
Genetic Structure ◽  
Ethnic Groups ◽  
Genetic Association ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Genomic Region ◽  
Sub Saharan Africa ◽  
Genome Wide Association Studies ◽  
Fine Scale ◽  
Sub Saharan

AbstractInferences from genetic association studies rely largely on the definition and description of the underlying populations that highlight their genetic similarities and differences. The clustering of human populations into subgroups (population structure) can significantly confound disease associations. This study investigated the fine-scale genetic structure within Cameroon that may underlie disparities observed with Cameroonian ethnicities in malaria genome-wide association studies in sub-Saharan Africa. Genotype data of 1073 individuals from three regions and three ethnic groups in Cameroon were analyzed using measures of genetic proximity to ascertain fine-scale genetic structure. Model-based clustering revealed distinct ancestral proportions among the Bantu, Semi-Bantu and Foulbe ethnic groups, while haplotype-based coancestry estimation revealed possible longstanding and ongoing sympatric differentiation among individuals of the Foulbe ethnic group, and their Bantu and Semi-Bantu counterparts. A genome scan found strong selection signatures in the HLA gene region, confirming longstanding knowledge of natural selection on this genomic region in African populations following immense disease pressure. Signatures of selection were also observed in the HBB gene cluster, a genomic region known to be under strong balancing selection in sub-Saharan Africa due to its co-evolution with malaria. This study further supports the role of evolution in shaping genomes of Cameroonian populations and reveals fine-scale hierarchical structure among and within Cameroonian ethnicities that may impact genetic association studies in the country.

Genetic Methodologies and Applications

2017 ◽  
Author(s):  
Shaun M. Purcell
Keyword(s):  
Mental Illness ◽  
Genetic Risk ◽  
Genetic Basis ◽  
Common Mental Disorders ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
The Past ◽  
Genome Wide ◽  
Experimental Approaches ◽  
Large Families

Mental illness is highly heritable, yet it has been difficult historically to identify the specific genes that comprise that risk. This difficulty resides in the fact that the genetic risk for all common mental disorders is polygenic, with perhaps hundreds of genetic variations, each of small effect, contributing to the overall risk. Despite these challenges, the field has made dramatic advances over the past decade in beginning to understand the genetic basis of mental illness. This chapter provides an overview of the experimental approaches used, beginning with epidemiology and population genetics to define the heritability of an illness, to classic studies of large families and linkage disequilibrium analysis, to genome-wide investigations including genome-wide association studies (GWAS), exome sequencing, and whole genome sequencing. Increasingly, these genetic advances are being understood within the biological context of disease pathophysiology.

scholarly journals Concordance of genetic risk across migraine subgroups: Impact on current and future genetic association studies

Cephalalgia ◽  
2014 ◽  
Vol 35 (6) ◽  
pp. 489-499 ◽  
Author(s):  
Dale R Nyholt ◽  
Verneri Anttila ◽  
Bendik S Winsvold ◽  
Tobias Kurth ◽  
Hreinn Stefansson ◽  
...  
Keyword(s):  
Genetic Risk ◽  
Association Studies ◽  
Meta Analysis ◽  
Genetic Association Studies ◽  
Population Based ◽  
Significant Heterogeneity ◽  
Single Nucleotide ◽  
Disease Spectrum ◽  
Genome Wide ◽  
Genetic Overlap

Background There has been intensive debate whether migraine with aura (MA) and migraine without aura (MO) should be considered distinct subtypes or part of the same disease spectrum. There is also discussion to what extent migraine cases collected in specialised headache clinics differ from cases from population cohorts, and how female cases differ from male cases with respect to their migraine. To assess the genetic overlap between these migraine subgroups, we examined genome-wide association (GWA) results from analysis of 23,285 migraine cases and 95,425 population-matched controls. Methods Detailed heterogeneity analysis of single-nucleotide polymorphism (SNP) effects (odds ratios) between migraine subgroups was performed for the 12 independent SNP loci significantly associated ( p < 5 × 10−8; thus surpassing the threshold for genome-wide significance) with migraine susceptibility. Overall genetic overlap was assessed using SNP effect concordance analysis (SECA) at over 23,000 independent SNPs. Results Significant heterogeneity of SNP effects ( phet < 1.4 × 10−3) was observed between the MA and MO subgroups (for SNP rs9349379), and between the clinic- and population-based subgroups (for SNPs rs10915437, rs6790925 and rs6478241). However, for all 12 SNPs the risk-increasing allele was the same, and SECA found the majority of genome-wide SNP effects to be in the same direction across the subgroups. Conclusions Any differences in common genetic risk across these subgroups are outweighed by the similarities. Meta-analysis of additional migraine GWA datasets, regardless of their major subgroup composition, will identify new susceptibility loci for migraine.

scholarly journals Genetic Association Studies of Suicidal Behavior: A Review of the Past 10 Years, Progress, Limitations, and Future Directions

2016 ◽  
Vol 7 ◽  
Author(s):  
Bojan Mirkovic ◽  
Claudine Laurent ◽  
Marc-Antoine Podlipski ◽  
Thierry Frebourg ◽  
David Cohen ◽  
...  
Keyword(s):  
Genetic Association ◽  
Suicidal Behavior ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Future Directions ◽  
The Past

scholarly journals COVID-19 genetic risk and Neanderthals: A case study highlighting the importance of scrutinizing diversity

2020 ◽  
Author(s):  
Inken Wohlers ◽  
Verónica Calonga-Solís ◽  
Jan-Niklas Jobst ◽  
Hauke Busch
Keyword(s):  
Genetic Risk ◽  
World Wide ◽  
Association Studies ◽  
Genomic Region ◽  
Human Populations ◽  
Genome Wide Association Studies ◽  
Single Nucleotide Variants ◽  
Genetic Risk Assessment ◽  
Genome Wide ◽  
Highly Correlated

AbstractRecent genome wide association studies (GWAS) have identified genetic risk factors for developing severe COVID-19 symptoms. The first published study reported a 1bp insertion rs11385942 on chromosome 3 (1) and subsequent studies single nucleotide variants (SNVs) such as rs35044562, rs67959919 (2) and rs13078854 (3), all highly correlated with each other. Zeberg and Pääbo (4) subsequently traced them back to Neanderthal origin. They found that a 49.4 kb genomic region including the risk allele of rs35044562 is inherited from Neanderthals of Vindija in Croatia. Here we add a differently focused evaluation of this major genetic risk factor to these recent analyses. We show that (i) COVID-19-related genetic factors of three previously assessed Neanderthals deviate from those of modern humans and that (ii) they differ among world-wide human populations, which compromises risk prediction in non-Europeans. Currently, caution is thus advised in the genetic risk assessment of non-Europeans during this world-wide COVID-19 pandemic.

Genetics of Intracranial Aneurysms

Stroke ◽  
2021 ◽  
Author(s):  
Mark K. Bakker ◽  
Ynte M. Ruigrok
Keyword(s):  
Genetic Risk ◽  
Aneurysmal Subarachnoid Hemorrhage ◽  
Association Studies ◽  
Current Status ◽  
Genome Wide Association Studies ◽  
Genetic Studies ◽  
The Past ◽  
Genome Wide ◽  
Family Based ◽  
Severe Type

Rupture of an intracranial aneurysm leads to aneurysmal subarachnoid hemorrhage, a severe type of stroke which is, in part, driven by genetic variation. In the past 10 years, genetic studies of IA have boosted the number of known genetic risk factors and improved our understanding of the disease. In this review, we provide an overview of the current status of the field and highlight the latest findings of family based, sequencing, and genome-wide association studies. We further describe opportunities of genetic analyses for understanding, prevention, and treatment of the disease.

scholarly journals Human genetics of tuberculosis: a long and winding road

2014 ◽  
Vol 369 (1645) ◽  
pp. 20130428 ◽  
Author(s):  
Laurent Abel ◽  
Jamila El-Baghdadi ◽  
Ahmed Aziz Bousfiha ◽  
Jean-Laurent Casanova ◽  
Erwin Schurr
Keyword(s):  
Human Genetics ◽  
Association Studies ◽  
Single Gene ◽  
Genetic Association Studies ◽  
Epidemiological Studies ◽  
Interferon Γ ◽  
Past Century ◽  
Inborn Errors ◽  
Novel Treatments ◽  
The Past

Only a small fraction of individuals exposed to Mycobacterium tuberculosis develop clinical tuberculosis (TB). Over the past century, epidemiological studies have shown that human genetic factors contribute significantly to this interindividual variability, and molecular progress has been made over the past decade for at least two of the three key TB-related phenotypes: (i) a major locus controlling resistance to infection with M. tuberculosis has been identified, and (ii) proof of principle that severe TB of childhood can result from single-gene inborn errors of interferon-γ immunity has been provided; genetic association studies with pulmonary TB in adulthood have met with more limited success. Future genetic studies of these three phenotypes could consider subgroups of subjects defined on the basis of individual (e.g. age at TB onset) or environmental (e.g. pathogen strain) factors. Progress may also be facilitated by further methodological advances in human genetics. Identification of the human genetic variants controlling the various stages and forms of TB is critical for understanding TB pathogenesis. These findings should have major implications for TB control, in the definition of improved prevention strategies, the optimization of vaccines and clinical trials and the development of novel treatments aiming to restore deficient immune responses.

scholarly journals Quantifying the extent to which index event biases influence large genetic association studies

2016 ◽  
Author(s):  
Hanieh Yaghootkar ◽  
Michael P. Bancks ◽  
Sam E. Jones ◽  
Aaron McDaid ◽  
Robin Beaumont ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Genetic Association ◽  
Genetic Risk ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Population Based ◽  
Uk Biobank ◽  
Index Event ◽  
Risk Alleles

AbstractAs genetic association studies increase in size to 100,000s of individuals, subtle biases may influence conclusions. One possible bias is “index event bias” (IEB), also called “collider bias”, caused by the stratification by, or enrichment for, disease status when testing associations between gene variants and a disease-associated trait. We first provided a statistical framework for quantifying IEB then identified real examples of IEB in a range of study and analytical designs. We observed evidence of biased associations for some disease alleles and genetic risk scores, even in population-based studies. For example, a genetic risk score consisting of type 2 diabetes variants was associated with lower BMI in 113,203 type 2 diabetes controls from the population based UK Biobank study (−0.010 SDs BMI per allele, P=5E-4), entirely driven by IEB. Three of 11 individual type 2 diabetes risk alleles, and 10 of 25 hypertension alleles were associated with lower BMI at p<0.05 in UK Biobank when analyzing disease free individuals only, of which six hypertension alleles remained associated at p<0.05 after correction for IEB. Our analysis suggested that the associations between CCND2 and TCF7L2 diabetes risk alleles and BMI could (at least partially) be explained by IEB. Variants remaining associated after correction may be pleiotropic and include those in CYP17A1 (allele associated with hypertension risk and lower BMI). In conclusion, IEB may result in false positive or negative associations in very large studies stratified or strongly enriched for/against disease cases.

Sign in / Sign up

Export Citation Format

Share Document