Genetic interactions affecting human gene expression identified by variance association mapping.
Non-additive interaction between genetic variants, or epistasis, is a possible explanation for the gap between heritability of complex traits and the variation explained by identified genetic loci. Interactions give rise to genotype dependent variance, and therefore the identification of variance quantitative trait loci can be an intermediate step to discover both epistasis and gene by environment effects (GxE). Using RNA-sequence data from lymphoblastoid cell lines (LCLs) from the TwinsUK cohort, we identify a candidate set of 508 variance associated SNPs. Exploiting the twin design we show that GxE plays a role in ∼70% of these associations. Further investigation of these loci reveals 57 epistatic interactions that replicated in a smaller dataset, explaining on average 4.3% of phenotypic variance. In 24 cases, more variance is explained by the interaction than their additive contributions. Using molecular phenotypes in this way may provide a route to uncovering genetic interactions underlying more complex traits.DOI: http://dx.doi.org/10.7554/eLife.01381.001.
Human Genetics, Wellcome Trust Sanger Institute, Cambridge, United Kingdom NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Andrew Anand
AA
Brown
Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland Institute of Genetics and Genomics in Geneva, University of Geneva Medical School, Geneva, Switzerland Swiss Institute of Bioinformatics, Geneva, Switzerland.
Alfonso
A
Buil
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
Ana
A
Viñuela
Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland Institute of Genetics and Genomics in Geneva, University of Geneva Medical School, Geneva, Switzerland Swiss Institute of Bioinformatics, Geneva, Switzerland.
Tuuli
T
Lappalainen
Department of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal, Canada.
Hou-Feng
HF
Zheng
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom Department of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal, Canada.
J Brent
JB
Richards
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
Kerrin S
KS
Small
Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.
Timothy D
TD
Spector
Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland Institute of Genetics and Genomics in Geneva, University of Geneva Medical School, Geneva, Switzerland Swiss Institute of Bioinformatics, Geneva, Switzerland.
Emmanouil T
ET
Dermitzakis
Human Genetics, Wellcome Trust Sanger Institute, Cambridge, United Kingdom rd@sanger.ac.uk.
Richard
R
Durbin
D056808:Biostatistics; D004843:Epistasis, Genetic; D006801:Humans; D020412:Multifactorial Inheritance; D019655:Quantitative Trait, Heritable
epistasis; gene expression; gene-environment interactions