Genetic epistasis

A while ago, in a post titled the Missing Heritability, I discussed the fact that some risk alleles (gene copies that have been found to increase the risk for a certain disease) may turn out to be counter-effected by other genes and thus explain why some people with these alleles never develop the particular disease. At the time I did a quick search on PubMed but couldn't come up with anything in the literature. Well, I was missing the keyword: epistasis. The word comes from the Greek "epi", which means "upon," and "stasis," which means to stop (I see my mom gloating out there in the audience!): compositional epistasis is the mechanism by which the effect of one allele is modified, and in some cases even blocked, by other gene alleles. This of course is hard to detect, but intuition tells us that it is a rather diffuse phenomenon. Genes are far from being "push-buttons," rather, they work in concert, initiating complex pathways, and therefore more often than not, a single gene is unlikely to give us a complete picture.

Back to my quest. I searched "genetic epistasis" on PubMed and this time I found a lot of interesting stuff. As a disclaimer I should say that for some of these studies there are contrasting outcomes in the literature (some results weren't reproduced in different populations). Nonetheless, I think that we are just starting to scrape the tip of the iceberg: gene-to-gene interaction are complex and poorly understood, but they certainly hold the key to the mysterious ways in which our genome works. Despite the skepticism expressed by some in the field, I do believe that single-gene studies are limited and should eventually give way to whole-genome studies.

[1] Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depressionEpistasis of BDNF and SLC6A4 in depression.

SERT is a protein whose function is to terminate and recycle the neurotransmitter serotonin. Historically, serotonin has been associated to happiness and well-being, which explains why SERT is the target of numerous drugs addressing psychiatric disorders. SLC6A4, the gene encoding SERT, has been extensively studied and one polymorphism in particular, 5-HTTLPR (which is not a SNP, a single-base mutation, rather some individuals present a long allele with a 44 base-pair insertion, compared to the short allele) has been associated to the efficacy of some antidepressants and also to other psychiatric disorders. On the other hand, the brain-derived neurotrophic factor (BDNF) protein is involved in the growth, proliferation, and differentiation of certain neurons. The gene encoding BDNF has been associated to bipolar disorder and improved general cognitive ability. Two genes, two (apparently) distinct pathways and signaling systems. Using anatomical neuroimaging techniques in a sample of healthy subjects (n=111), Pezawas et al. showed

"that the BDNF MET allele, which is predicted to have reduced responsivity to 5-HT signaling, protects against 5-HTTLPR S allele-induced effects on a brain circuitry encompassing the amygdala and the subgenual portion of the anterior cingulate (rAC). Our analyses revealed no effect of the 5-HTTLPR S allele on rAC volume in the presence of BDNF MET alleles, whereas a significant volume reduction (P<0.001) was seen on BDNF VAL/VAL background. [...] These data provide in vivo evidence of biologic epistasis between SLC6A4 and BDNF in the human brain by identifying a neural mechanism linking serotonergic and neurotrophic signaling on the neural systems level, and have implications for personalized treatment planning in depression."

[2] Renin-angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort: detection of high order gene-gene interaction.

Tsai et al. [2] recruited 1254 patients who underwent cardiac catheterization (735 with documented coronary artery disease and 519 without) and individually matched them with controls based on corresponding risk factors for coronary artery disease. The researchers genotyped several polymorphisms: one in the angiotensin-converting enzyme gene, six in the angiotensinogen gene, and one in the angiotensin II type I receptor gene. In single-locus analyses, no locus was associated with coronary artery disease or acute myocardial infarction. However:

"Significant three-locus (G-217A, M235T and I/D) gene-gene interactions were detected by multifactor-dimensionality reduction method (highest cross-validation consistency 10.0, lowest prediction error 40.56%, P=0.017) and many even higher order gene-gene interactions by multilocus genotype disequilibrium tests (16 genotype disequilibria exclusively found in the controls, all of which included at least two genes among AGT, ACE and AT1R genes). Our study is the first to demonstrate epistatic, high-order, gene-gene interactions between RAS gene polymorphisms and CAD. These results are compatible with the concept of multilocus and multi-gene effects in complex diseases that would be missed with conventional approaches."

I've added below a few more references on epistasis for those interested in researching the topic further.

Photo: Walt Disney Concert Hall, Los Angeles, CA. Shutter speed 1/15, focal length 24mm, F-stop 22, ISO speed 100.

[1] Pezawas, L., Meyer-Lindenberg, A., Goldman, A., Verchinski, B., Chen, G., Kolachana, B., Egan, M., Mattay, V., Hariri, A., & Weinberger, D. (2008). Evidence of biologic epistasis between BDNF and SLC6A4 and implications for depression Molecular Psychiatry, 13 (7), 709-716 DOI: 10.1038/mp.2008.32

[2] Tsai CT, Hwang JJ, Ritchie MD, Moore JH, Chiang FT, Lai LP, Hsu KL, Tseng CD, Lin JL, & Tseng YZ (2007). Renin-angiotensin system gene polymorphisms and coronary artery disease in a large angiographic cohort: detection of high order gene-gene interaction. Atherosclerosis, 195 (1), 172-80 PMID: 17118372

[3] Wiltshire S, Bell JT, Groves CJ, Dina C, Hattersley AT, Frayling TM, Walker M, Hitman GA, Vaxillaire M, Farrall M, Froguel P, & McCarthy MI (2006). Epistasis between type 2 diabetes susceptibility Loci on chromosomes 1q21-25 and 10q23-26 in northern Europeans. Annals of human genetics, 70 (Pt 6), 726-37 PMID: 17044847

[4] Abou Jamra R, Fuerst R, Kaneva R, Orozco Diaz G, Rivas F, Mayoral F, Gay E, Sans S, Gonzalez MJ, Gil S, Cabaleiro F, Del Rio F, Perez F, Haro J, Auburger G, Milanova V, Kostov C, Chorbov V, Stoyanova V, Nikolova-Hill A, Onchev G, Kremensky I, Jablensky A, Schulze TG, Propping P, Rietschel M, Nothen MM, Cichon S, Wienker TF, & Schumacher J (2007). The first genomewide interaction and locus-heterogeneity linkage scan in bipolar affective disorder: strong evidence of epistatic effects between loci on chromosomes 2q and 6q. American journal of human genetics, 81 (5), 974-86 PMID: 17924339

[5] Coutinho AM, Sousa I, Martins M, Correia C, Morgadinho T, Bento C, Marques C, Ataíde A, Miguel TS, Moore JH, Oliveira G, & Vicente AM (2007). Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and in the determination of platelet serotonin levels. Human genetics, 121 (2), 243-56 PMID: 17203304