Addition of Epigenetics

RESEARCH HIGHLIGHTS
Nature Reviews Genetics | AOP, published online 12 January 2010; doi:10.1038/nrg2741

COMPLEX DISEASE
Adding epigenetics to the mix

Three recent papers highlight the out, further studies in specific types of In a third study, Feinberg and
importance of considering epigenet- immune cells will be needed to confirm Irizarry suggest a previously unex-
ics in the study of both heritable and effects that are relevant to SLE. plored way in which epigenetics can
non-heritable influences on complex Another recent study indicates influence complex traits, including
human disease. that epigenetic effects also need to human disease. They propose that
Because of the genetic near-identity be taken into account to understand some genetic variants can lead to
between monozygotic twins, cases of the heritability of complex diseases. stochastic variation in epigenetic
discordance provide opportunities Genome-wide association studies status that in turn causes increased
to explore non-genetic factors that have generally identified variants that variability for a phenotype, which
influence phenotypic differences. By account for only a fraction of the her- can be selected for in certain condi-
DNA methylation profiling of DNA itability of a particular disease. Some tions. To test their hypothesis, they
from white blood cells, Javierre and of the ‘missing heritability’ might be investigated DNA methylation pat-
colleagues uncovered epigenetic dif- explained by variants that have dif- terns in mouse and human tissues
ferences that might contribute to dis- ferent phenotypic effects depending and showed that regions that are
cordance among monozygotic twins on whether they have been inherited highly variable for DNA methylation
for the autoimmune disease systemic maternally or paternally. Kong and exist both within and between spe-
lupus erythematosus (SLE). They colleagues extensively genotyped cies. They also showed that loss or
identified a set of genes that differ in 38,167 Icelanders and used the gain of CpG dinucleotides provides
promoter methylation and expression detailed genealogical information a heritable basis for changes in this
between affected and unaffected that is available in Iceland, together variability, which might therefore
twins. These genes are enriched for with long-range phasing of haplo- provide material for evolution.
immune-related functions, which types, to determine the parent of ori- Using a modelling approach,
suggests that epigenetic differences gin for the vast majority of genotyped the authors provided theoretical
arising from, for example, different SNPs. Genomic imprinting — in evidence that increased phenotypic
diets or environmental exposures which differences in epigenetic status variability can lead to increased
might influence the development of cause differential expression between fitness in fluctuating environments.
SLE. However, as the authors point the two parental alleles — is a likely Furthermore, such genetically
cause of parental origin effects. The encoded stochastic epigenetic varia-
authors identified 5 SNPs that lie tion might contribute to the low her-
within 500 kb of imprinted genes itability of some phenotypic effects
and that show associations with — another potential explanation for
disease that depend on the parent the missing heritability tackled by
of origin — 1 SNP is associated Kong and colleagues.
with breast cancer, 1 with basal cell Louisa Flintoft
carcinoma and 3 with type 2 diabetes.
They showed that failing to take the
ORIGINAL RESEARCH PAPERS
parent of origin into account can lead Javierre, B. M. et al. Changes in the pattern of DNA
to underestimates of the size of the methylation associate with twin discordance in
systemic lupus erythematosus. Genome Res.
effect of a SNP on the phenotype and 22 Dec 2009 (doi:10.1101/gr.100289.109) |
that some associations can be missed Kong, A. et al. Parental origin of sequence variants
altogether: for example, they identi- associated with complex diseases. Nature 462,
868–874 (2009) | Feinberg, A. P. & Irizarry, R. A.
fied a parent-of-origin-specific asso- Stochastic epigenetic variation as a driving force
ciation with type 2 diabetes that had of development, evolutionary adaptation, and
FANCY
been overlooked by previous large disease. Proc. Natl Acad. Sci. USA 22 Dec 2009
(doi:10.1073/pnas.0906183107)
genome-wide association studies.
NATURE REVIEWS | GENETICS VOLUME 11 | FEBRUARY 2010
© 2010 Macmillan Publishers Limited. All rights reserved

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RESEARCH HIGHLIGHTS

Nature Reviews Genetics | AOP, published online 12 January 2010; doi:10.1038/nrg2741

Adding epigenetics to the mix

NATURE REVIEWS | GENETICS VOLUME 11 | FEBRUARY 2010

© 2010 Macmillan Publishers Limited. All rights reserved

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