Gene-Environment Interaction Analysis Incorporating Sex, Cardiometabolic Diseases, and Multiple Deprivation Index Reveals Novel Genetic Associations With COVID-19 Severity

Increasing evidence indicates that specific genetic variants influence the severity of outcomes after infection with COVID-19. However, it is not clear whether the effect of these genetic factors is independent of the risk due to more established non-genetic demographic and metabolic risk factors such as male sex, poor cardiometabolic health, and low socioeconomic status. We sought to identify interactions between genetic variants and non-genetic risk factors influencing COVID-19 severity via a genome-wide interaction study in the UK Biobank. Of 378,051 unrelated individuals of European ancestry, 2,402 were classified as having experienced severe COVID-19, defined as hospitalization or death due to COVID-19. Exposures included sex, cardiometabolic risk factors [obesity and type 2 diabetes (T2D), tested jointly], and multiple deprivation index. Multiplicative interaction was tested using a logistic regression model, conducting both an interaction test and a joint test of genetic main and interaction effects. Five independent variants reached genome-wide significance in the joint test, one of which also reached significance in the interaction test. One of these, rs2268616 in the placental growth factor (PGF) gene, showed stronger effects in males and in individuals with T2D. None of the five variants showed effects on a similarly-defined phenotype in a lookup in the COVID-19 Host Genetics Initiative. These results reveal potential additional genetic loci contributing to COVID-19 severity and demonstrate the value of including non-genetic risk factors in an interaction testing approach for genetic discovery.

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Gene-environment interaction analysis incorporating sex, cardiometabolic diseases, and multiple deprivation index reveals novel genetic associations with COVID-19 severity

10.1101/2021.08.13.21261910 ◽

2021 ◽

Author(s):

Kenneth E. Westerman ◽

Joanna Lin ◽

Magdalena Sevilla-Gonzalez ◽

Beza Tadess ◽

Casey Marchek ◽

...

Keyword(s):

Risk Factors ◽

Genetic Variants ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Deprivation Index ◽

European Ancestry ◽

Cardiometabolic Health ◽

Multiple Deprivation ◽

Genome Wide ◽

Interaction Test

AbstractIncreasing evidence indicates that specific genetic variants influence the severity of outcomes after infection with COVID-19. However, it is not clear whether the effect of these genetic factors is independent of the risk due to more established non-genetic demographic and metabolic risk factors such as male sex, poor cardiometabolic health, and low socioeconomic status. We sought to identify interactions between genetic variants and non-genetic risk factors influencing COVID-19 severity via a genome-wide interaction study in the UK Biobank. Of 378,051 unrelated individuals of European ancestry, 2,402 were classified as having experienced severe COVID-19, defined as hospitalization or death due to COVID-19. Exposures included sex, cardiometabolic risk factors (obesity and type 2 diabetes [T2D], tested jointly), and multiple deprivation index. Multiplicative interaction was tested using a logistic regression model, conducting both an interaction test and a joint test of genetic main and interaction effects. Five independent variants reached genome-wide significance in the joint test, one of which also reached significance in the interaction test. One of these, rs2268616 in the PGF gene, showed stronger effects in males and in individuals with T2D. None of the five variants showed effects on a similarly-defined phenotype in a lookup in the COVID-19 Host Genetics Initiative. These results reveal potential additional genetic loci contributing to COVID-19 severity and demonstrate the value of including non-genetic risk factors in an interaction testing approach for genetic discovery.

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P6017 A high density genome-wide scan for genetic risk factors of insect bite hypersensitivity (IBH): A Horsegene Project Initiative

Journal of Animal Science ◽

10.2527/jas2016.94supplement4156a ◽

2016 ◽

Vol 94 (suppl_4) ◽

pp. 156-157

Author(s):

B. D. Velie ◽

M. Shrestha ◽

L. Francois ◽

A. Schurink ◽

A. Stinckens ◽

...

Keyword(s):

Risk Factors ◽

Genetic Risk ◽

Genetic Risk Factors ◽

High Density ◽

Genome Wide ◽

Insect Bite Hypersensitivity ◽

Genome Wide Scan

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Cross-disorder analysis of schizophrenia and 19 immune-mediated diseases identifies shared genetic risk

Human Molecular Genetics ◽

10.1093/hmg/ddz145 ◽

2019 ◽

Vol 28 (20) ◽

pp. 3498-3513 ◽

Cited By ~ 15

Author(s):

Jennie G Pouget ◽

Buhm Han ◽

Yang Wu ◽

Emmanuel Mignot ◽

Hanna M Ollila ◽

...

Keyword(s):

Risk Factors ◽

Ulcerative Colitis ◽

Crohn’S Disease ◽

Crohn's Disease ◽

Genetic Risk ◽

Genetic Risk Factors ◽

Phenotypic Correlation ◽

Biliary Cirrhosis ◽

Genome Wide ◽

Shared Genetic

Abstract Many immune diseases occur at different rates among people with schizophrenia compared to the general population. Here, we evaluated whether this phenomenon might be explained by shared genetic risk factors. We used data from large genome-wide association studies to compare the genetic architecture of schizophrenia to 19 immune diseases. First, we evaluated the association with schizophrenia of 581 variants previously reported to be associated with immune diseases at genome-wide significance. We identified five variants with potentially pleiotropic effects. While colocalization analyses were inconclusive, functional characterization of these variants provided the strongest evidence for a model in which genetic variation at rs1734907 modulates risk of schizophrenia and Crohn’s disease via altered methylation and expression of EPHB4—a gene whose protein product guides the migration of neuronal axons in the brain and the migration of lymphocytes towards infected cells in the immune system. Next, we investigated genome-wide sharing of common variants between schizophrenia and immune diseases using cross-trait LD score regression. Of the 11 immune diseases with available genome-wide summary statistics, we observed genetic correlation between six immune diseases and schizophrenia: inflammatory bowel disease (rg = 0.12 ± 0.03, P = 2.49 × 10−4), Crohn’s disease (rg = 0.097 ± 0.06, P = 3.27 × 10−3), ulcerative colitis (rg = 0.11 ± 0.04, P = 4.05 × 10–3), primary biliary cirrhosis (rg = 0.13 ± 0.05, P = 3.98 × 10−3), psoriasis (rg = 0.18 ± 0.07, P = 7.78 × 10–3) and systemic lupus erythematosus (rg = 0.13 ± 0.05, P = 3.76 × 10–3). With the exception of ulcerative colitis, the degree and direction of these genetic correlations were consistent with the expected phenotypic correlation based on epidemiological data. Our findings suggest shared genetic risk factors contribute to the epidemiological association of certain immune diseases and schizophrenia.

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Genetics of Keratoconus: Where Do We Stand?

Journal of Ophthalmology ◽

10.1155/2014/641708 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 27

Author(s):

Khaled K. Abu-Amero ◽

Abdulrahman M. Al-Muammar ◽

Altaf A. Kondkar

Keyword(s):

Risk Factors ◽

Candidate Gene ◽

Genetic Risk ◽

Current Knowledge ◽

Genetic Risk Factors ◽

Factors Associated ◽

Genetic Components ◽

Genome Wide ◽

Molecular Etiology

Keratoconus is a progressive thinning and anterior protrusion of the cornea that results in steepening and distortion of the cornea, altered refractive powers, and reduced vision. Keratoconus has a complex multifactorial etiology, with environmental, behavioral, and multiple genetic components contributing to the disease pathophysiology. Using genome-wide and candidate gene approaches several genomic loci and genes have been identified that highlight the complex molecular etiology of this disease. The review focuses on current knowledge of these genetic risk factors associated with keratoconus.

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