Abstract
Genome-wide association studies (GWAS) and rare variant association studies (RVAS) are applied across many areas of complex disease to analyze variation in whole genomes of thousands of unrelated patients. These approaches are able to identify variants and/or biological pathways which are associated with disease status and, in contrast to traditional linkage studies or candidate gene approaches, do so without requiring multigenerational affected families, prior hypotheses, or known genes of interest. However, the novel associations identified by these methods typically have lower effect sizes than those found in classical family studies. In the motor neuron disease amyotrophic lateral sclerosis (ALS), GWAS, and RVAS have been used to identify multiple disease-associated genes but have not yet resulted in novel therapeutic interventions. There is significant urgency within the ALS community to identify additional genetic markers of disease to uncover novel biological mechanisms, stratify genetic subgroups of disease, and drive drug development. Given the widespread and increasing application of genetic association studies of complex disease, it is important to recognize the strengths and limitations of these approaches. Here, we review ALS gene discovery via GWAS and RVAS.
Highlights
In the timeline of gene discovery for hereditary disease, high penetrance genes are historically identified by linkage analysis in multi-generational family studies and subsequently replicated in high-risk case-control studies of independent disease cohorts
Advances in genetic testing and identification of genetic subtypes of disease have been the cornerstone of amyotrophic lateral sclerosis (ALS) research in recent years, marked by widespread genetic testing in larger and more diverse cohorts, bioinformatic and molecular characterization of identified variants, and progress toward clinical trials for genetic subtypes of disease
Gene discovery has been driven by linkage analysis of families with high-penetrance genes, candidate gene approaches and more recently, association studies such as Genome-wide association studies (GWAS) and Rare variant association studies (RVAS)
Summary
In the timeline of gene discovery for hereditary disease, high penetrance genes are historically identified by linkage analysis in multi-generational family studies and subsequently replicated in high-risk case-control studies of independent disease cohorts. Rare variant association studies (RVAS) extend the genome-wide approach by using massively parallel sequencing to identify less-common variants (MAF < 0.5 or 0.1%) that would be missed by GWAS (Lee et al, 2014) This has been made possible by increasing sample sizes in disease cohorts as well as advances in sequencing technology, leading to greater genomic resolution. The typical association study includes four components; (1) accrual of a large group of individuals with the disease of interest as well as a carefully matched control group for comparison; (2) genotyping of hundreds of thousands to millions of variants in disease and control groups, traditionally via SNV arrays in GWAS and sequencing in RVAS; (3) statistical analyses to test for common- or rare-variant association with disease; and (4) prioritizing and replicating significant findings in a non-overlapping, independent cohort or performing functional experiments to examine variant consequences (Pearson, 2008). PRS have shown modest but reliable prediction capability in a number of disease areas (Barrett et al, 2009; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014; Hoffmann et al, 2017; Seibert et al, 2018) as well as the ability to modify risk prediction for monogenic variants (Fahed et al, 2020)
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