(Stroke. 2005;36:1879.)
© 2005 American Heart Association, Inc.
Original Contributions |
Editorial Comment—Epistasis Is Coming
Are We Ready?
Vascular and Critical Care Neurology, and the Center for Human Genetic Research, Massachusetts General Hospital, Boston, Mass
Key Words: amyloid • angiography • genetics • intracerebral hemorrhage
For physicians and patients, the central challenge of human genetics is unraveling the genetic architecture of human diseases. Depending on the disease, this architecture can range from simple to complex. In the so-called mendelian diseases, 1 mutation in a single gene is sufficient to cause disease, whereas more complex diseases may involve changes in single genes, multiple genes, or even combinations of alleles within the same gene. The payoff for successful disease-gene discovery is likely to be enormous, leading to novel biologic discoveries and innovative interventions that can alleviate human suffering. The search so far, however, has been slower than we would all like. The nagging problem is that for most common diseases, the culprit gene variants contribute only a small proportion of disease risk. Successful studies must therefore detect relatively weak associations, and finding weak associations requires very large samples of patients.
Epistasis, broadly defined, is the interaction between alleles at different loci, or positions, in the genome. Most simply, a variant at 1 locus can prevent a variant at another locus from manifesting its effect.1,2 These combinations of variants may be in different genes, or they may be within the same gene, eg, within the regulatory and coding regions. Ultimately, epistatic interaction is synergistic, with an effect that differs from the simple sum of the effects of each individual allele.
The analysis of haplotypes has become a widely used technique in the search for disease genes because it allows investigators to assess the disease contribution of large sections of a chromosome without having to test all of the single-nucleotide polymorphisms (SNPs) contained in those sections. Haplotypes, sets of SNPs contained within a given stretch of DNA along a chromosome, may hold the key to discovery of the gene variants that cause disease. When there is extensive linkage disequilibrium across a region containing a haplotype, it is likely that this region of DNA has been passed down from generation to generation nearly unchanged. As a result, large numbers of individuals across the population can share a small number of haplotype variants. When this is the case, genotyping a few "tag" SNPs may serve to identify a large proportion of the genetic variation in the region of the haplotype. The genotype of a "tag" SNP will predict genotypes at multiple nearby SNPs. Theoretically, then, one can start by genotyping the "tag" SNPs in a region first, determine the haplotypes formed by the "tags," and then assess whether a particular haplotype or set of "tags" is more commonly found among cases or controls. Once the culprit haplotype is found, investigators can then focus on finding the variants embedded within the haplotype.
Although the theoretical underpinning of this approach is far from straightforward or without controversy, it is nonetheless the basis of the International HapMap Project, which aims to develop a haplotype map of the human genome that can, among other things, supply information on all of the "tags" necessary to capture a large proportion of the variation across most of the genome (http://www.hapmap.org). The hope is that with these "tags" in hand, clinician scientists can then efficiently examine long stretches of the genome, or even the entire genome, in their study population by sticking to the "tags."
The analysis of Woo et al3 uses haplotypes to ask a different question. Rather than picking "tags" as a means of efficiently discovering new gene regions of interest, they focused on the region of DNA containing the apolipoprotein E gene (APOE) and asked whether particular sets of SNPs might play a role in risk for the development of lobar intracerebral hemorrhage (ICH). In particular, they sought to determine whether regulatory variants that might influence gene expression interact with the coding variants responsible for the 
2 and 4 alleles that have been well studied by their group and others.4–8
This is an epistatic analysis. Woo et al are the first to ask such a question in lobar ICH, a disease that they have shown has both a strong genetic component and an important element of family aggregation.3 With just >200 chromosomes from cases for analysis, however, power is limited, particularly given the large number (26) of haplotypes studied. Furthermore, the small numbers make the haplotype results unstable—the frequency of any studied 2 or 4 haplotype among white subjects, for example, never exceeds 4.3%, and among controls the highest value is 5.1% (Table 2 in Woo et al).
So, could variation in regulatory sequences influence the effect of 2 or 4 on the risk of lobar ICH, perhaps through modulation of gene expression? If so, could a treatment that alters APOE gene expression reduce the risk of lobar ICH? Experiments in transgenic mice demonstrate that human apo 4 promotes the development of cerebral amyloid angiopathy, a leading cause of ICH in the elderly,8 although similar studies of 2 have not been reported. The confirmation of epistatic interactions at the level of human APOE, however, requires further study involving many more patients.
The Greater Cincinnati–Northern Kentucky investigators have been international leaders in assembling well-phenotyped cohorts of patients with ischemic and hemorrhagic stroke for genetic studies, but even a center as successful as theirs has only been able to assemble just >100 patients with lobar ICH for study. Genetic studies of epistatic interactions within APOE are likely to require 10 times as many patients, making the need for collaboration among centers essential for the future.9 Such collaboration will, of course, require the collection of common phenotypic information. Leaders in the field have recognized the need for this kind of common dataset for the study of another clinical manifestation of cerebrovascular disease, vascular cognitive impairment. A collaborative effort led by the National Institute of Neurological Disorders and Stroke and the Canadian Stroke Network will establish minimal research datasets that can be completed at centers across the globe to facilitate future genetics studies. Initiatives like these are likely to serve future studies of the range of cerebrovascular disease.10
As the cost of genotyping continues to plummet, the challenge of phenotyping becomes more and more pressing. A role for epistatic interactions in the genetic architecture of complex diseases like stroke may well be the rule rather than the exception.11 Thus, the challenge for the field of vascular neurology will be phenotyping large numbers of patients adequately and uniformly.
 |
Acknowledgments |
|---|
This study was supported by grants K23 NS42695-01 and R01 NS042147-02 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md.
|
References |
|---|
 Top References |
|---|
- Cordell HJ. Epistasis: what it means, what it doesn’t mean, and statistical methods to detect it in humans. Hum Mol Genet. 2002; 11: 2463–2468.
[Abstract/Free Full Text] - Moore JH. A global view of epistasis. Nat Genet. 2005; 37: 13–14.[CrossRef][Medline] [Order article via Infotrieve]
- Woo D, Kaushal R, Chakraborty R, Woo J, Haverbusch M, Sekar P, Kissela B, Pancioli A, Jauch E, Kleindorfer D, Flaherty M, Schneider A, Khatri P, Sauerbeck L, Khoury J, Broderick J. Association of Apolipoprotein E4 and Haplotypes of the Apolipoprotein E Gene With Lobar Intracerebral Hemorrhage. Stroke. 2005; 36: 1874–1879.
[Abstract/Free Full Text] - Woo D, Sauerbeck LR, Kissela BM, Khoury JC, Szaflarski JP, Gebel J, Shukla R, Pancioli AM, Jauch EC, Menon AG, Deka R, Carrozzella JA, Moomaw CJ, Fontaine RN, Broderick JP. Genetic and environmental risk factors for intracerebral hemorrhage: preliminary results of a population-based study. Stroke. 2002; 33: 1190–1196;discussion 1196.
- O’Donnell HC, Rosand J, Knudsen KA, Furie KL, Segal AZ, Chiu RI, Ikeda D, Greenberg SM. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage [see comments]. N Engl J Med. 2000; 342: 240–245.
[Abstract/Free Full Text] - Rosand J, Hylek EM, O’Donnell HC, Greenberg SM. Warfarin-associated hemorrhage and cerebral amyloid angiopathy: a genetic and pathologic study. Neurology. 2000; 55: 947–951.
[Abstract/Free Full Text] - Nicoll JA, Burnett C, Love S, Graham DI, Dewar D, Ironside JW, Stewart J, Vinters HV. High frequency of apolipoprotein e
2 allele in hemorrhage due to cerebral amyloid angiopathy. Ann Neurol. 1997; 41: 716–721.[CrossRef][Medline]
[Order article via Infotrieve]
- McCarron MO, Nicoll JA, Ironside JW, Love S, Alberts MJ, Bone I. Cerebral amyloid angiopathy-related hemorrhage: interaction of Apo E 2 with putative clinical risk factors. Stroke. 1999; 30: 1643–1646.
[Abstract/Free Full Text] - Fryer JD, Simmons K, Parsadanian M, Bales KR, Paul SM, Sullivan PM, Holtzman DM. Human apolipoprotein e4 alters the amyloid-ß 40:42 ratio and promotes the formation of cerebral amyloid angiopathy in an amyloid precursor protein transgenic model. J Neurosci. 2005; 25: 2803–2810.
[Abstract/Free Full Text] - Rosand J, Altshuler D. Human genome sequence variation and the search for genes influencing stroke. Stroke. 2003; 34: 2512–2516.
[Abstract/Free Full Text] - Moore JH. The ubiquitous nature of epistasis in determining susceptibility to common human diseases. Hum Hered. 2003; 56: 73–82.[CrossRef][Medline] [Order article via Infotrieve]
Related Article:
- Association of Apolipoprotein E4 and Haplotypes of the Apolipoprotein E Gene With Lobar Intracerebral Hemorrhage
- Daniel Woo, Ritesh Kaushal, Ranajit Chakraborty, Jessica Woo, Mary Haverbusch, Padmini Sekar, Brett Kissela, Arthur Pancioli, Edward Jauch, Dawn Kleindorfer, Matthew Flaherty, Alexander Schneider, Pooja Khatri, Laura Sauerbeck, Jane Khoury, Ranjan Deka, and Joseph Broderick
Stroke 2005 36: 1874-1879.[Abstract] [Full Text] [PDF]
This article has been cited by other articles:
 |
|
 |
|
  A. Baessler, M. Fischer, B. Mayer, M. Koehler, S. Wiedmann, K. Stark, A. Doering, J. Erdmann, G. Riegger, H. Schunkert, et al. Epistatic interaction between haplotypes of the ghrelin ligand and receptor genes influence susceptibility to myocardial infarction and coronary artery disease Hum. Mol. Genet., April 15, 2007; 16(8): 887 - 899. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||