Project 2: Gene x Environment Interactions
Overview
Growing evidence indicates that SARS-CoV-2 infection causes neurological complications of short-term consequence including acute neuropathy, encephalopathy, anosmia, and hypoxic/ischemic brain injury, and longer-term consequences including cognitive impairment and neuropsychiatric disturbances. The interindividual variation in the neurobiological responses to SARS-CoV-2 is marked. As with most complex phenotypes, causal determinants likely include both genetic and environmental factors. However, no genetic epidemiological study has yet considered differential neurophenotypic response to infection. Thus, delineating the genetic architecture of ADRD-relevant neurophenotypic responses to SARS-CoV-2 ffers important biological insights, which in turn could provide strategies for fostering healthy brain aging in the presence of future infectious challenges. Project 2 assesses the genetic basis of ADRD-relevant endophenotypic response to SARS-CoV-2 infection in a set of older (>60 years of age) adults from diverse populations (Amerindians from Argentina [ n=3000], US Native Americans [n=250], Mexican Americans [n=500], Puerto Ricans [n=125], African Americans [n=125], and Africans [n=300]) using whole genome sequence (WGS) data in a case/control design (75% post-infection cases, 25% never infected controls). The data generated enables estimating the importance of genetics in disease response and the identification of key genes involved in the response. Through Project 2, we are identifying causal genetic factors that underly differential response in ADRD risk to COVID-19.
Participating Institutions
- UT Rio Grande Valley
Aim 1
Detect Genetic Influences on Endophenotypic Responses to COVID-19 Infection. Using WGS data, we will estimate the overall heritability of ADRD-relevant phenotypic response to infection in the two larger cohorts (Amerindians and Mexican Americans). A significant heritability is a formal test of a genotype × infection interaction hypothesis. Phenotypes include three-year changes in neurocognitive measures, neuroimaging measures, and blood-based biomarkers of AD-related pathology, neurodegeneration, and neuronal damage.
Aim 2
Test Sequence Variation in Genes and Gene Pathways Influencing Response to COVID-19. Using a variety of statistical genetic methods, we will initially search for evidence that variation at the gene level differentially (i.e., showing different magnitudes of effects in cases versus controls) influences response. We also will perform genome-wide gene- and pathway-based association searches focused separately on protein altering variation (weighted using functional prediction) and regulatory variation (using imputed genetic values of gene expression). Joint tests across all populations will be performed allowing for between-population heterogeneity in the genetic basis of response to infection.
Aim 3
Genetics of Between-Population Variation in Mean Responses to Infection. Just as individuals differ in response, we anticipate population differences in response. Using a hierarchical mixed model and between population estimates of expected identity-by-descent (or identity-by-state) genetic covariances derived from allele frequency differences, we will formally test ADRD-related phenotypes for a genetic component influencing observed between-population differences in response to COVID-19 infection.
Core Leadership
- Dr. John Blangero – UT Rio Grande Valley
- Dr. Sarah Williams-Blangero – UT Rio Grande Valley
- Dr. Gladys Maestre – UT Rio Grande Valley
Data and Resource Sharing
The AC oversees sharing study resources with external investigators, promoting collaborations. Resource transfer agreements are managed through the Data Management & Statistics Core and deposited in NIH-maintained repositories, including NACC, NCRAD, and NIAGADS.