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This JAMA Guide to Statistics and Methods reviews the use of whole genome association studies to quantify the association between single-nucleotide polymorphisms (SNPs) and human disease, and the importance of using the information to identify the actual effector transcripts responsible for the underlying pathophysiology.

Each individual’s genetic makeup influences the presence of, manifestation of, and susceptibility to disease. The identification of specific genetic regions that influence disease for mendelian genetic conditions, such as cystic fibrosis and Huntington disease, have often been elucidated through familial linkage studies, combining familial patterns of disease with a limited set of genomic markers. In contrast, many diseases have very complex underlying mechanisms with many genes and the environment influencing risk. Understanding the influence of genetics on risk for these diseases requires approaches beyond familial linkage studies.

A candidate gene association study begins by identifying the candidate genes—either 1 gene or multiple genes thought to belong to a common pathway. The association between genetic variations in the candidate genes and the presence of disease is investigated. The success of this strategy is highly dependent on the correct choice of genes to study, although the overall experience with candidate gene association studies has been disappointing.1

In contrast to a candidate gene association study, a genome-wide association study (GWAS) is based on a hypothesis-free strategy with no need to specify target genes in advance, and can be used to survey the entire genome to elucidate susceptibility to common heritable human diseases. A GWAS quantifies the association between the presence of disease and genetic variations at known positions in the genome, referred to as single-nucleotide polymorphisms (SNPs), to pinpoint relatively smaller areas of the genome that may contribute to the risk of disease.

In this issue of JAMA, Hauser et al2 report a GWAS that evaluated genetic disposition for primary open-angle glaucoma (POAG) in individuals with African ancestry. SNP rs59892895∗C in the amyloid β A4 precursor protein-binding family B member 2 (APBB2) gene was found to be significantly associated with POAG in this population, while no association between this gene and POAG was found in European or Asian populations. The authors conclude that there are differences in genetic mechanisms underlying glaucoma in African ancestry populations compared with European and Asian ancestry populations.


Why Is the Method Used?

GWASs take advantage of variation in the millions of known SNPs, occurring in known locations across the entire genome, to determine whether one genetic variant (ie, allele) at the location of each SNP occurs more often than expected in individuals with a particular disease than in those without the disease. The associated SNPs are then considered to mark a region of the human genome that influences the risk of disease. The approach allows identification of small genetic regions that contain potential effector ...

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