Rationale for Correct Answer

The correct answer is: GWAS have identified differences in the allele frequency of genetic variants between individuals who have LOAD and those who do not

Genome-wide association studies (GWAS) are a powerful tool for identifying genetic variants that may be associated with Alzheimer's disease (AD). GWAS compare genomes and identify variants that are significantly more common in the disease population than in the control population. Significant variants are then explored in more detail. These gene variants may be useful in nominating candidate genes that are potentially associated with Alzheimer’s disease,1 but typically are unable to establish disease causality (due to genetic linkage, lack of statistical power, and multiple causative variants or genes).2

GWAS need to be conducted separately for individual racial and ethnic groups due to differences in linkage disequilibrium and allele frequency patterns. GWAS typically report clusters of correlated single-nucleotide polymorphisms (SNPs or variations in the genetic code) that all show a statistically significant correlation with the trait of interest. These clusters of associated SNPs provide hints about the disease’s biology.3 When novel disease-associated variants cluster in specific pathways, they help disentangle the genetic causes and pathways underlying Alzheimer’s disease.4

GWAS studies require large populations to get enough statistical power to identify significant genetic differences between populations. The data from multiple GWAS can be compiled to develop a polygenic risk score, but GWAS are not pertinent at the individual level.3

1. Karch CM et al. Biol Psychiatry. 2015;77:43-51.
2. Flister M et al. Genome Res. 2013;23:1996-2002.
3. Uffelmann E. Nat Rev Methods Primers. 2012;1.
4. Reitz C. Ann Translat Med. 2016;4:107.