Importance of Diversity in Precision Medicine: Generalizability of Genetic Associations Across Ancestry Groups Toward Better Identification of Disease Susceptibility Variants

Abstract

Genome-wide association studies (GWAS) revolutionized our understanding of common genetic variation and its impact on common human disease and traits. Developed and adopted in the mid-2000s, GWAS led to searchable genotype–phenotype catalogs and genome-wide datasets available for further data mining and analysis for the eventual development oftranslational applications. The GWAS revolution was swift and specific, including almost exclusively populations of European descent to the neglect of the majority of the world's genetic diversity. In this narrative review, we recount the GWAS landscape of the early years that established a genotype–phenotype catalog that is now universally understood to be inadequate for a complete understanding of complex human genetics. We then describe approaches taken to augment the genotype–phenotype catalog, including the study populations, collaborative consortia, and study design approaches aimed to generalize and then ultimately discover genome-wide associations in non-European descent populations. The collaborations and data resources established in the efforts to diversify genomic findings undoubtedly provide the foundations of the next chapters of genetic association studies with the advent of budget-friendly whole-genome sequencing. Expected final online publication date for the Annual Review of Biomedical Data Science, Volume 6 is August 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

A Genetic Analysis of Current Medication Use in the UK Biobank

“…In general, the majority of participants in existing GWASs are of European descent, despite the European population only accounting for 16% of the global population [ 61 ]. This constitutes a great inequity challenge, as it limits the discovery of novel causal genetic variants, which are exclusive to certain populations due to genetic drift [ 62 ]. Moreover, because the discovery GWASs lack ancestral diversity, the polygenic scores translate into poor generalisability across diverse ancestries and cohorts [ 63 ].…”

Associations between the New DNA-Methylation-Based Telomere Length Estimator, the Mediterranean Diet and Genetics in a Spanish Population at High Cardiovascular Risk

“…A few GWAS studies have been published on DNAmTL, such as an investigation including European Americans and African Americans [51], as well as a study focusing on participants recruited in Canada [109]. Considering that linkage disequilibrium and other population characteristics may affect the specific variants most significantly associated in GWASs, it is necessary to conduct studies on multiple populations to assess the level of consistency or heterogeneity in the findings [118]. Similar to the detection of genetic heterogeneity in GWASs, there is also an observed heterogeneity in DNA methylation research based on the ethnic background of the participants [119,120].…”