Epistasis Blog

From the Computational Genetics Laboratory at Dartmouth Medical School (www.epistasis.org)

Tuesday, October 19, 2010

Biological validation of increased schizophrenia risk with NRG1, ERBB4, and AKT1 epistasis via functional neuroimaging in healthy controls

This study biological validates an epistasis model. Nice.

Nicodemus KK, Law AJ, Radulescu E, Luna A, Kolachana B, Vakkalanka R, Rujescu D, Giegling I, Straub RE, McGee K, Gold B, Dean M, Muglia P, Callicott JH, Tan HY, Weinberger DR. Biological validation of increased schizophrenia risk with NRG1, ERBB4, and AKT1 epistasis via functional neuroimaging in healthy controls. Arch Gen Psychiatry. 2010 Oct;67(10):991-1001. [PubMed]


CONTEXT: NRG1 is a schizophrenia candidate gene and plays an important role in brain development and neural function. Schizophrenia is a complex disorder, with etiology likely due to epistasis.

OBJECTIVE: To examine epistasis between NRG1 and selected N-methyl-d-aspartate-glutamate pathway partners implicated in its effects, including ERBB4, AKT1, DLG4, NOS1, and NOS1AP.

DESIGN: Schizophrenia case-control sample analyzed using machine learning algorithms and logistic regression with follow-up using neuroimaging on an independent sample of healthy controls.

PARTICIPANTS: A referred sample of schizophrenic patients (n = 296) meeting DSM-IV criteria for schizophrenia spectrum disorder and a volunteer sample of controls for case-control comparison (n = 365) and a separate volunteer sample of controls for neuroimaging (n = 172).

MAIN OUTCOME MEASURES: Epistatic association between single-nucleotide polymorphisms (SNPs) and case-control status; epistatic association between SNPs and the blood oxygen level-dependent physiological response during working memory measured by functional magnetic resonance imaging.

RESULTS: We observed interaction between NRG1 5' and 3' SNPs rs4560751 and rs3802160 (likelihood ratio test P = .00020) and schizophrenia, which was validated using functional magnetic resonance imaging of working memory in healthy controls; carriers of risk-associated genotypes showed inefficient processing in the dorsolateral prefrontal cortex (P = .015, familywise error corrected). We observed epistasis between NRG1 (rs10503929; Thr286/289/294Met) and its receptor ERBB4 (rs1026882; likelihood ratio test P = .035); a 3-way interaction with these 2 SNPs and AKT1 (rs2494734) was also observed (odds ratio, 27.13; 95% confidence interval, 3.30-223.03; likelihood ratio test P = .042). These same 2- and 3-way interactions were further biologically validated via functional magnetic resonance imaging: healthy individuals carrying risk genotypes for NRG1 and ERBB4, or these 2 together with AKT1, were disproportionately less efficient in dorsolateral prefrontal cortex processing. Lower-level interactions were not observed between NRG1 /ERBB4 and AKT1 in association or neuroimaging, consistent with biological evidence that NRG1 × ERBB4 interaction modulates downstream AKT1 signaling.

CONCLUSION: Our data suggest complex epistatic effects implicating an NRG1 molecular pathway in cognitive brain function and the pathogenesis of schizophrenia.

Monday, October 18, 2010

Does heritability hide in epistasis between linked SNPs?

This is a very short, but highly relevant, note about the possibility of epistasis between linked loci for complex traits such human height. This is indeed a real possibility.

Haig D. Does heritability hide in epistasis between linked SNPs? Eur J Hum Genet. 2010 Oct 6. [PubMed]

Friday, October 15, 2010

A Simple and Computationally Efficient Sampling Approach to Covariate Adjustment for Multifactor Dimensionality Reduction Analysis of Epistasis

Our new paper on covariate adjustment for MDR has been published. This approach is included in the latest version of our MDR software.

Gui J, Andrew AS, Andrews P, Nelson HM, Kelsey KT, Karagas MR, Moore JH. A Simple and Computationally Efficient Sampling Approach to Covariate Adjustment for Multifactor Dimensionality Reduction Analysis of Epistasis. Hum Hered. 2010 Oct 1;70(3):219-225. [PubMed]


Epistasis or gene-gene interaction is a fundamental component of the genetic architecture of complex traits such as disease susceptibility. Multifactor dimensionality reduction (MDR) was developed as a nonparametric and model-free method to detect epistasis when there are no significant marginal genetic effects. However, in many studies of complex disease, other covariates like age of onset and smoking status could have a strong main effect and may potentially interfere with MDR's ability to achieve its goal. In this paper, we present a simple and computationally efficient sampling method to adjust for covariate effects in MDR. We use simulation to show that after adjustment, MDR has sufficient power to detect true gene-gene interactions. We also compare our method with the state-of-art technique in covariate adjustment. The results suggest that our proposed method performs similarly, but is more computationally efficient. We then apply this new method to an analysis of a population-based bladder cancer study in New Hampshire.

Saturday, October 02, 2010

Random Jungles

This is the latest in a series of paper developing random forest methods for the analysis of high-dimensional data. Note the software is freely available. http://www.randomjungle.org

Schwarz DF, König IR, Ziegler A. On safari to Random Jungle: a fast implementation of Random Forests for high-dimensional data. Bioinformatics. 2010 Jul 15;26(14):1752-8. [PubMed]


MOTIVATION: Genome-wide association (GWA) studies have proven to be a successful approach for helping unravel the genetic basis of complex genetic diseases. However, the identified associations are not well suited for disease prediction, and only a modest portion of the heritability can be explained for most diseases, such as Type 2 diabetes or Crohn's disease. This may partly be due to the low power of standard statistical approaches to detect gene-gene and gene-environment interactions when small marginal effects are present. A promising alternative is Random Forests, which have already been successfully applied in candidate gene analyses. Important single nucleotide polymorphisms are detected by permutation importance measures. To this day, the application to GWA data was highly cumbersome with existing implementations because of the high computational burden.

RESULTS: Here, we present the new freely available software package Random Jungle (RJ), which facilitates the rapid analysis of GWA data. The program yields valid results and computes up to 159 times faster than the fastest alternative implementation, while still maintaining all options of other programs. Specifically, it offers the different permutation importance measures available. It includes new options such as the backward elimination method. We illustrate the application of RJ to a GWA of Crohn's disease. The most important single nucleotide polymorphisms (SNPs) validate recent findings in the literature and reveal potential interactions.

AVAILABILITY: The RJ software package is freely available at http://www.randomjungle.org