# Genomic and ancestral variations linked to the development of post-acute sequelae of SARS-CoV-2 infection in Indian populations

## TL;DR

This study explores genetic factors in Indian populations linked to severe COVID-19 and long-term effects, identifying genes involved in neurological and cardiovascular functions.

## Contribution

The study presents the first exploratory GWAS on PASC in Indian populations, identifying shared genetic risk factors for severe disease and post-viral complications.

## Key findings

- Candidate genes like CNTNAP2, WWOX, and ADAMTS17 are linked to both severe COVID-19 and PASC.
- Shared molecular pathways in neurological and cardiovascular dysfunction were identified through GWAS and transcriptomic data integration.
- Polygenic risk analysis revealed population-specific genetic predisposition to PASC in Indian populations.

## Abstract

Susceptibility to infectious diseases is a result of complex interactions between genomic, environmental, and clinical factors. COVID-19 severity and post-acute sequelae of COVID-19 (PASC) vary widely among individuals, yet its genetic determinants remain underexplored in Indian populations. In this article, we undertake an exploratory analysis to investigate candidate genetic variants and biological pathways underlying the clinical outcomes in COVID-19 severity and PASC.

Sixty individuals with a history of COVID-19 were genotyped, and their data were supplemented with publicly available datasets from the Genome Asia 100K and Gujarat Biotechnology Research Centre. Two case–control genome-wide association study (GWAS) models were analyzed: (i) COVID-19 severity (mild/asymptomatic vs. severe) and (ii) an exploratory, hypothesis-generating GWAS for PASC (presence vs. absence of post-COVID-19 complications). Candidate genes identified here were further compared with RNA-sequencing datasets derived from brain and lung tissues of SARS-CoV-2-infected hamsters. The population-specific genetic risk for PASC was estimated using the polygenic risk score algorithm PRSice-2.

GWAS identified candidate genes common to both COVID-19 severity and PASC, including CNTNAP2, WWOX, and ADAMTS17, which are implicated in extracellular matrix remodeling and neurological and cognitive development. We identified 806 candidate genes shared between the severity and PASC cohorts. Of these, 30 protein-coding genes were associated with neuropsychiatric disorders, and 23 were linked to cardiovascular conditions. Notably, CACNA1C, SLC8A1, GRK5, PDE4B, and LRRK2 were identified in both categories, suggesting potential convergence of molecular pathways underlying neurological and cardiovascular dysfunction. Integration with transcriptomic data reinforced the involvement of shared molecular pathways disrupted by SARS-CoV-2 infection. Polygenic risk analysis revealed significant population-specific variation in genetic predisposition to PASC.

Genetic susceptibility to severe COVID-19 and PASC in Indian populations appears to be linked to dysregulation of pathways central to cardiac and neurological function. These findings, derived from an exploratory PASC GWAS, provide preliminary insights into the molecular mechanisms that may underlie the post-viral sequelae. These emphasize the need for population-wide genomic studies to validate the candidate associations, better understand PASC risk, and facilitate the development of precision diagnostics and therapeutics.

Diagram illustrating the genetic analysis workflow for COVID-19. It shows two pathways: on the left, the progression from SARS-CoV-2 exposure to genetically heterogeneous groups, leading to severe COVID-19, with GWAS identifying risk loci. On the right, it details the progression from exposure to PASC and its controls, also leading to risk loci identification.