From Ethnic Diversity to Variant Actionability

The level of ethnic diversity is believed to have significant consequences on population structure and genetic architecture. Large consortium-based sequencing studies using next-generation whole-genome sequencing provide insights into ethnic diversity and its application in pharmacogenetics. Indeed, recent pharmacogenetic studies of admixed ethnic groups showed that individuals from different ethnic groups experience variable responses to specific therapeutic agents. In addition, there is robust evidence from clinical trials showing that differences in genetic ancestries may impact the frequency of genetic variations that have the potential to alter the therapeutic efficacy of commonly used therapies. These studies include candidate gene studies, genome-wide association studies, and whole-genome admixture-based approaches which account for ancestral genetic structure, complex haplotypes, gene-gene interactions, and rare variants to detect and replicate novel pharmacogenetic loci.

Many studies investigated the in-silico prediction of variants in African genomes and propose recommendations for re-evaluating the pathogenicity of actionable variants used in research and clinical practice and the actionable pathogenic variants in European and African descent using exome data. Their results showed major disparities in Africans. Some studies reported on patients that were misdiagnosed with some diseases due to a lack of access to patients in the study population from different or unspecified ancestry. This leads to misclassifications of many variants as pathogenic.

This raises two important questions to be considered in an ethnic context:

1. How could we assess the pathogenicity of a genetic variant and classify it in public databases as either pathogenic or benign?

2. What is the impact of genetic diversity on variant classification and its clinical relevance?

We believe that these questions can be addressed by investigating the variant frequency in diverse populations of different ethnicity and through well-designed studies of ethnically diverse populations to identify genetic risk factors for monogenic and polygenic diseases and the clinical relevance for diagnosis and/or therapeutic intervention plans.

Based on this, we would like to suggest this topic: “From ethnic diversity to variant actionability” and ask contributors mainly from underrepresented populations to share the topic-related results of their studies in order to bring new insights on the impact of ethnic-based genetic diversity on the clinical relevance of genetic variations.