AI Article Synopsis

  • Genome-wide association studies have identified numerous genetic links to complex diseases, but understanding how these links affect the biology of diseases remains difficult.
  • The authors propose that genetic variants influence specific molecular pathways in different patient groups, leading to diverse clinical outcomes.
  • Their new CASTom-iGEx pipeline helps analyze genetic data to uncover individual risk factors and disease mechanisms, showing that genetic variations can create distinct patient profiles linked to different pathways and disease severities.

Article Abstract

Genome-wide association studies have unearthed a wealth of genetic associations across many complex diseases. However, translating these associations into biological mechanisms contributing to disease etiology and heterogeneity has been challenging. Here, we hypothesize that the effects of disease-associated genetic variants converge onto distinct cell type specific molecular pathways within distinct subgroups of patients. In order to test this hypothesis, we develop the CASTom-iGEx pipeline to operationalize individual level genotype data to interpret personal polygenic risk and identify the genetic basis of clinical heterogeneity. The paradigmatic application of this approach to coronary artery disease and schizophrenia reveals a convergence of disease associated variant effects onto known and novel genes, pathways, and biological processes. The biological process specific genetic liabilities are not equally distributed across patients. Instead, they defined genetically distinct groups of patients, characterized by different profiles across pathways, endophenotypes, and disease severity. These results provide further evidence for a genetic contribution to clinical heterogeneity and point to the existence of partially distinct pathomechanisms across patient subgroups. Thus, the universally applicable approach presented here has the potential to constitute an important component of future personalized medicine concepts.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10197798PMC
http://dx.doi.org/10.1101/2023.05.10.23289788DOI Listing

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