Inherited burden for disease predisposition in diverse populations

Area of Science:

• Genetics
• Genomic Medicine
• Computational Biology

Background:

• Genetic variants play a crucial role in Mendelian conditions.
• Large-scale genomic databases are essential for variant interpretation.
• Understanding the burden of pathogenic variants is key for public health.

Purpose of the Study:

• To identify and quantify pathogenic and likely pathogenic variants across a broad spectrum of disease genes.
• To estimate the prevalence of actionable genotypes and carrier screening candidates in the population.
• To explore the genetic predisposition to various disease groups using a genome-first approach.

Main Methods:

• Leveraged allele frequencies from gnomAD, Regeneron Genetics Center Million Exome, and Turkish Variome.
• Utilized data for 4591 disease genes curated by PanelApp and OMIM.
• Employed an American College of Medical Genetics and Genomics (ACMG)-based classifier to identify pathogenic and likely pathogenic variants.

Main Results:

• Identified 97,135 pathogenic and 478,263 likely pathogenic variants, expanding the known catalog nearly six-fold.
• Determined that individuals carry an average of 4.70 pathogenic or likely pathogenic variants, with 1.66 compatible with Mendelian conditions.
• Found that 1 in 11 individuals possess an actionable genotype, and identified 382 candidate genes for carrier screening.
• Revealed significant genetic predisposition across 13 ICD-10 disease groups, including congenital, musculoskeletal/connective, and blood/immune disorders.

Conclusions:

• This study provides a comprehensive catalog of pathogenic and likely pathogenic variants, significantly enhancing genetic variant interpretation.
• The findings highlight the substantial burden of genetic variants and actionable genotypes in the general population.
• Evidence-based genetic epidemiology supports personalized medicine, enabling early preventive strategies and lifestyle modifications for improved healthspan and lifespan.