Inherited burden for disease predisposition in diverse populations

Inherited burden for disease predisposition in diverse populations is an open question. American College of Medical Genetics and Genomics (ACMG) guidelines for variant classification, combined with large population variation databases, promise to provide valuable answers. We recently developed a robust ACMG-based automated variant classification tool and categorized the exome sequencing variants of 730,947 individuals from gnomAD.

We leveraged the allele frequency information of variants in 3895 Genomics England PanelApp genes and identified 76,677 pathogenic (P) and 295,356 likely-pathogenic (LP) variants, expanding the ClinVar submissions nearly fivefold.

We found that, on average, an individual is born with 4.31 P or LP variants, of which 1.59 are compatible with a Mendelian condition, 1 in 12 presents with an actionable genotype, and a total of 372 genes are candidates for carrier screening. Furthermore, a genome-first approach revealed that the likelihood of having a genotype compatible with a disease is highest for congenital (1 in 2.24 individuals; 3.37 billion worldwide) followed by nervous (1 in 3.01; 2.39 billion), blood/immune (1 in 3.29; 2.04 billion), musculoskeletal/connective (1 in 3.65; 1.87 billion), skin (1 in 4.46; 1.62 billion), endocrine/metabolic (1 in 4.53; 1.62 billion), circulatory (1 in 7.26; 994 million), eye (1 in 7.62; 961 million), ear (1 in 8.39; 880 million), genitourinary (1 in 10.15; 750 million), neoplasm (1 in 16.01; 410 million), digestive (1 in 18.26; 312 million) and respiratory (1 in 47.72; 155 million) disorders.

Evidence-based genetic epidemiology demonstrates the potential of personalized medicine for the implementation of early preventive measures and incentivization of lifestyle changes to enhance healthspan and lifespan. From a societal standpoint, this research demonstrates the importance of informing the public to decrease discrimination and social stigmatization associated with inherited diseases, as an overwhelming majority of individuals are expected to carry germ-line risk variants on average.