Manhattan Plot

A Manhattan plot showing risk loci strongly associated with disease. The dots represent individual SNPs, with the X-axis showing chromosome location and the Y-axis showing level of associateion. This example is from a GWA examining microciruclation: the higher the tops of the bars reach, the greater the correlation between the presence of the allele and the disease state.[1]

A genome-wide association study (GWA study, or a GWAS) is an assessment of variations in multiple genetic variants that aims to determine if a gene variant is linked with a particular trait. In genetic epidemiology, GWAS examine the correlation between the presence of small nucleotide polymorphisms (SNPs) and traits. If a SNP and a disease state are found to be linked the SNP is said to be "associated" with the disease state.

GWAS typically compare the DNA of two groups: individuals afflicted with the disease (cases) and comparable, unaffected individuals (controls). Participants in the GWA study donate a sample of DNA, which is analyzed for millions of genetic variants using SNP arrays. If one allelic variant is found to be more prevalent in the individuals expressing the disease phenotype, that variant is said to be "associated" with the disease. GWAS differ from gene-specific candidate-driven studies in the sense that they investigate the entire genome rather than specifically testing only one, two, or three genetic regions. It is important to note that while GWA studies only identify SNPs correlated with disease states they stop short of determining which variants are significant and which are coincidental.[2][3][4]

The field of genome-wide association studies dates back to the year 2000 when the method was introduced, providing an alternative to the method of studying single gene disorders through genetic linkage in families.[5] The first successful GWAS was published in 2005 and studied the prevalence of SNPs in patients with age-related macular degeneration. The study discovered two alleles that displayed altered frequency in individuals afflicted with age-related macular degeneration when compared with healthy individuals.[6] By the year 2011, more than 1,200 human GWA studies have been conducted, examining the genetic basis of over 200 diseases and traits. Over the years more than 4,000 SNP associations have been discovered.[7] It is worth noting that several GWA studies have recieved criticism for failing to meet certain quality control steps that have rendered the findings invalid. However, more recent publications address these quality control issues directly.

References Edit

  1. Ikram MK, Sim X, Xueling S, et al. (October 2010). "Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo". In McCarthy, Mark I. PLoS Genet. 6 (10): e1001184.
  2. Manolio TA; Guttmacher, Alan E.; Manolio, Teri A. (July 2010). "Genomewide association studies and assessment of the risk of disease". N. Engl. J. Med. 363 (2): 166–76. doi:10.1056/NEJMra0905980. PMID 20647212.
  3. Pearson TA, Manolio TA (March 2008). "How to interpret a genome-wide association study". JAMA 299 (11): 1335–44. doi:10.1001/jama.299.11.1335. PMID 18349094.
  4. "Genome-Wide Association Studies". National Human Genome Research Institute.
  5. "Online Mendelian Inheritance in Man". Retrieved 2014-09-03.
  6. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J (April 2005). "Complement Factor H Polymorphism in Age-Related Macular Degeneration". Science 308 (5720): 385–9. doi:10.1126/science.1109557. PMC 1512523. PMID 15761122.
  7. Johnson AD, O'Donnell CJ (2009). "An Open Access Database of Genome-wide Association Results". BMC Med. Genet. 10: 6. doi:10.1186/1471-2350-10-6. PMC 2639349. PMID 19161620.