Harnessing GWAS for Insights, in Alzheimer’s and in General
What's Hot in Biology 2011
By Dr. Jeremy Cherfas
Genome-wide association studies (GWAS) are the hot new tool for getting to grips with genes and diseases. Look at enough people, in enough detail, and researchers can detect genetic associations with weak effects that may nevertheless point the way to a deeper understanding. Latest to succumb to this kind of scrutiny and enter the Top Ten is Alzheimer's disease, with papers at #7 and #8. Coincidentally—or not—just ahead of them at #6 is a valuable overview of the GWAS phenomenon.
A GWAS generally takes the following form: Researchers identify two matched groups of people, one that has the condition of interest, one that does not. Ideally, both groups number in the thousands, to allow the technique to detect small effects. The DNA of each individual is mapped to look at more than half a million single nucleotide polymorphisms (SNPs). SNPs that are significantly more likely to be present in the cases than in the controls are then examined in other batches of cases and controls drawn from different populations. Finally, researchers look at the genes around the SNP to see whether they might plausibly be part of the causal chain that results in the disease.
APOE (apolipoprotein E)
Figure: Wiki Commons, public domain.
For non-familial Alzheimer's, the clearest genetic association hitherto has been with a gene called APOE (apolipoprotein E), which accounts for an estimated 50% of the genetic risk for the diseases. The papers at #7 and #8 both strongly confirmed this link and identified another three interesting genes. Julie Williams, from the Medical Research Council in Britain, led a large group that studied 3,941 cases and 7,848 controls from Germany, the U.K., and the U.S. At #7, they report two new associations for Alzheimer's, one in a locus called clusterin (CLU, also known as APOJ) and the other in a locus called PICALM.
These associations were confirmed in a further 2,023 cases and 2,340 controls from Greece, Belgium, the U.K., and Germany. Philippe Amouyel's team, based at the Institut Pasteur in Lille, France, studied 2,032 French cases and 5,328 controls, followed up with 3,978 cases and 3,297 controls from Belgium, Finland, Italy, and Spain. Their paper, at #8 confirmed the link with CLU and detected another with a complement-receptor gene called CR1.
All three genes fit neatly into the prevailing view of Alzheimer's disease, a characteristic feature of which is the presence of myeloid plaques in the brain, composed largely of the protein amyloid-ß (Aß). Although researchers do not understand how amyloid plaques contribute to neurodegeneration or the loss of cognitive function, it seems that a failure to remove Aß from the brain is what leads to the build-up of amyloid plaques. Clusterin is very similar to APOE; both proteins are present in amyloid plaques, and are active in converting Aß into insoluble forms and regulating its movement across the blood-brain barrier.
CR1 is part of the immune system and also plays a role in removing Aß from the brain; a recent study (L.B. Chibnik, et al., Annals Neurol., DOI: 10.1002/ana.22277) confirms a link with cognitive decline and pathology associated with Alzheimer's disease. PICALM is a bit more mysterious. It is involved in the movement of neurotransmitters across synapses, and so was thought possibly to be associated with some of the declines in brain functions seen in Alzheimer's.
"Genome-wide association studies (GWAS) are the hot new tool for getting to grips with genes and diseases."
A more recent study suggests that PICALM may be more important in controlling the uptake of Aß into vesicles and its transport across blood-vessel walls and away from the brain (S. Baig, et al., J. Neuropath. Exp. Neurol., doi: 10.1097/NEN.0b013e3181f52e01).
It is a long way from positive results in a GWAS to improved therapy—and there is still no effective treatment for Alzheimer's disease. But the ability to identify quite widespread genetic variants that make a small but significant contribution to the etiology of the disease certainly helps researchers to understand what might be going on, as the Alzheimer examples indicate.
That is why the paper at #6 is so important. Francis Collins, former Director of the National Human Genome Research Institute, and Teri Manolio, Director of the Office of Population Genomics at the NHGRI, and their colleagues announce an online catalog of associations between SNPs and traits derived from published GWAS papers.
The paper outlines the methods used to construct and curate the database, ways in which GWAS can be used, and some of the methodological difficulties posed by large GWAS. Perhaps its most significant feature, however, is the database itself.
The paper, published in May 2009, examined 151 published GWAS papers and 531 SNP-trait associations. When examined on 3 December 2010, the database contained 3,593 SNPs culled from 718 publications. Quite apart from the phenomenal growth of GWAS, the database is now allowing meta-reviews that promise to uncover even more subtle associations between genes and traits. That may be why it is ahead in citations.
Dr. Jeremy Cherfas is Science Writer at Bioversity International, Rome, Italy.
What's Hot in Biology | |||
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Rank | Paper |
Cites This Period Jul-Aug 10 |
Rank Last Period May-Jun 10 |
1 | D. Baek, et al., "The impact of microRNAs on protein output," Nature, 455(7209): 64-71, 4 September 2008. [Whitehead Inst., Cambridge, MA; Howard Hughes Med. Inst., MIT, Cambridge; Harvard Med. Sch., Boston, MA] *343XS | 44 | 7 |
2 | M. Selbach, et al., "Widespread changes in protein synthesis induced by microRNAs," Nature, 455(7209): 58-63, 4 September 2008. [Max Delbruck Ctr. Molec. Med., Berlin, Germany; U. Glasgow, U.K.] *343XS | 41 | 6 |
3 | D.R. Bentley, et al., "Accurate whole genome sequencing using reversible terminator chemistry," Nature, 456(7218): 53-9, 6 November 2008. [7 European and U.S. institutions] *369DH | 37 | 9 |
4 | R.C. Friedman, et al., "Most mammalian mRNAs are conserved targets of microRNAs," Genome Res., 19(1): 92-105, January 2009. [MIT, Cambridge, MA; Whitehead Inst., Cambridge, MA; Howard Hughes Med. Inst., Cambridge, MA] *390YQ | 37 | † |
5 | F. Soldner, et al., "Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors," Cell, 136(5): 964-77, 6 March 2009. [Whitehead Inst., Cambridge, MA; MIT, Cambridge; McLean Hosp./Harvard Med. Sch., Belmont, MA] *415JU | 33 | † |
6 | L.A. Hindorff, et al., "Potential etiologic and functional implications of genome-wide association loci for human diseases and traits," PNAS, 106(23): 9362-7, 9 June 2009. [NIH, Bethesda, MD] *456CN | 33 | 10 |
7 | D. Harold, et al., "Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer’s disease," Nature Genetics, 1088-93, October 2009. [44 institutions worldwide] *500UG | 33 | † |
8 | J.-C. Lambert, et al., "Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer’s disease," Nature Genetics, 1094-9, October 2009. [34 institutions worldwide] | 33 | † |
9 | E. Lieberman-Aiden, et al., "Comprehensive mapping of long-range interactions reveals folding principles of the human genome," Science, 326(5950): 289-93, 9 October 2009. [5 U.S. institutions] *504EX | 33 | † |
10 | I.H. Park, et al., "Disease-specific induced pluripotent stem cells," Cell, 134(5): 877-86, 5 September 2008. [9 U.S. and German institutions] *344SL | 29 | † |
SOURCE: Thomson Reuters Hot Papers Database. Read the Legend. |