From Linkage to GWAS: The Evolution of Genetic Variant Association in Clinical Diagnostics

The history of genetic variant association and its use as a diagnostic tool in the clinic has evolved significantly over the years. Early efforts focused on linkage analysis in multiplex pedigrees to identify high-penetrance variants responsible for Mendelian diseases. However, this approach was largely unsuccessful for common, later-onset traits with complex multifactorial etiologies, such as asthma, diabetes, and depression. The shift towards association-based methods and the advent of genome-wide association studies (GWAS) marked a turning point in the field. The HapMap Consortium's characterization of genome-wide patterns of genomic variation and the development of massively parallel genotyping arrays enabled genome-wide surveys of association, leading to the discovery of robust associations across a range of diseases.

The first GWAS, conducted in the mid-2000s, uncovered common variants with subtle effects on disease risk. Subsequent efforts expanded the size of studies, used denser genotyping arrays, and applied novel strategies for imputation, leading to the identification of tens of thousands of robust associations. The advent of exome and whole-genome sequencing extended discovery to low-frequency and rare alleles previously inaccessible to GWAS.

Clinical translation of these findings has been facilitated by the development of information resources such as ClinVar and ClinGen, which provide clinically interpreted variants, and databases like ExAC and gnomAD, which catalog genetic variation across populations. These resources have helped reduce the contamination of databases with variants erroneously interpreted as causal for disease and have improved the recognition of the variable penetrance of many 'monogenic' disease alleles.

Despite the progress, challenges remain in establishing the causal role of individual variants within genes and in resolving the penetrance of variants with established causality. Aggregation of sequencing data and the development of functional assays are key to addressing these challenges. Additionally, extending GWAS and sequencing studies to diverse populations is crucial for uncovering novel risk alleles and understanding the genetic basis of common diseases across different population groups.

Reference:

Claussnitzer, M., Cho, J. H., Collins, R., Cox, N. J., Dermitzakis, E. T., Hurles, M. E., ... & McCarthy, M. I. (2020). A brief history of human disease genetics. Nature, 577(7789), 179-189.