EDITORS CHOICE

Epigenetics: the next big thing

Shah Ebrahim
Corresponding author. E-mail: shah.ebrahim@lshtm.ac.uk
The theme of this issue of International Journal of
Epidemiology is epigenetics. Perhaps, we are rather
late as TIME magazine featured an article Why your
DNA isnt your destiny in January 2010.
1
The TIME
article focused on transgenerational effects of the
cycles of famine and plenty affecting Norrbotten,
northern Sweden in the 19th century and studied
more recently by Lars Byrgen. Byrgen found a
marked reduction in longevity of grandchildren
whose grandparents had been exposed to abundant
food in childhood. Could this be due to inheritance
of an epigenetic effect provoked by glut? Or might
socio-cultural transmission of environmental factors
across generations be a more plausible explanation?
Or could it just be a chance finding? Animal experi-
ments may help sort this out. The article cited an
agouti mouse (it has a mutant gene that codes for
yellow coat, increased body weight and an increased
risk of diabetes) experiment that showed that preg-
nant agouti mice given folic acid and vitamin B12 had
offspring with brown coats and normal weight and
did not develop diabetes, to illustrate epigenetic ef-
fects. One of the mechanisms by which epigenetic
changes occur is through methylation of DNA that
alters gene expression. Folic acid and vitamin B12
are involved in the methyl donation pathway, leading
to methylation of the agouti gene and altering its ex-
pression in the offspring. However, such effects are
actually within generation (i.e. the fetus and its de-
velopment into a pup) and do not provide evidence of
transgenerational transmission. Undeterred, the TIME
article extrapolated from this work to a range of
human conditions (autism, memory, longevity and
obesity) raising the flag for Lamarckismthe inherit-
ance of acquired characteristics. Popular science wri-
ters always find it hard to resist a good story. There is
very little evidence in mammals, let alone humans,
that epigenetic effects are transmitted through the
germ line across subsequent generations in a quanti-
tatively important manner.
2
As with most modern scientific discoveries, epigen-
etics has its roots in the past. Conrad Waddington
used the term epigenome in the 1930s to define the
developmental processes by which the genotype gives
rise to the phenotype of an organism. In this issue, we
reprint his 1943 paper that gives a brief overview of
his understanding of the complex processes by which
development is controlled by multiple genes, but says
nothing about environmental modifiers of gene ex-
pression.
3
Jablonka and Lamm
4
highlight how epigen-
etics now has a more specific meaningthe study of
the mechanisms that lead to persistent developmental
changes in gene activities and effects, but do not in-
volve altered DNA base sequences from one gener-
ation to the next. David Haig,
5
also commenting on
Waddington, identifies two epigenetic traditions: first
Waddingtons and second David Nanneyswhich
distinguish genetic from epigenetic causes of variation
in phenotype, and he notes that both traditions are
united in an interest in how a constant genotype
can produce different phenotypes. Scott Gilbert
6
pro-
vides essential context to Waddingtons ideas, arising
as they did during the Second World War, and as a
product of his expertise in both genetics and embry-
ology, resulting in the paradigm-changing idea that
genes are responsible for guiding the mechanics of
development.
The impact of new biotechnology on our under-
standing of human genetics and its associations
with disease has been dramatic in terms of publica-
tions. For example, the Human Genome Epidemiology
Network (HuGE) established an electronic archive
that enables publication trends to be determined
(Figure 1) and archives publications on specific
genes and diseases.
7
Haig
5
notes the dramatic rise of
papers with the term epigenetics in the title; as a
proportion of all genetics papers there has been a
10-fold increase since 1999. He suggests that the
lack of an agreed precise definition of epigenetics
has enabled scientists from different disciplines to
feel they are at the cutting edge of science as their
work is epigenetic. The hype will likely continue to
fuel the rise in publications, and contribute to diffi-
culties for epidemiologists in keeping up with the ex-
ponential growth of knowledge.
To help jobbing epidemiologists to keep up, our edi-
torial by Relton and Davey Smith
8
provides an access-
ible overview of the field and focuses on what
epidemiologists can offerin particular our methods
for causal inference that have been rather unimport-
ant in the design and interpretation of studies of the
influence of germline genetic variation. In a methodo-
logical paper in this issue on two-stage Mendelian
randomization to determine the cause role of
Published by Oxford University Press on behalf of the International Epidemiological Association
The Author 2012; all rights reserved.
International Journal of Epidemiology 2012;41:13
doi:10.1093/ije/dys015
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epigenetic processes, Relton and Davey Smith provide
some very useful background on epigenetic inherit-
ance and methods of measuring DNA methylation,
which will help the novice get to grips with the
basics of epigenetics.
9
The International Journal of Epidemiology encourages
researchers to submit their epigenetic papers for con-
sideration here. But before doing so, authors are
strongly advised to read Heijmans and Mills
10
excel-
lent commentary, The seven plagues of epigenetic
epidemiology, which catalogues important limitations
in the conduct, analysis and interpretation of epigen-
etic epidemiology studies. As they note, the notion of
what we do and how we live our own lives having
adverse effects on our childrens lives provides good
but often misleadingmedia stories.
The scientific contributions on epigenetics reflect the
current state of the field. Two of them focus on asso-
ciations between socio-economic position and epigen-
etic differences using different methods to assess
epigenetic patterns and different study designs. The
first study examines the idea that the higher chronic
disease prevalence in disadvantaged populations is
explained by underlying high levels of chronic inflam-
mation that in turn leads to aberrant DNA methyla-
tion.
11
Using a small (n 666) cross-sectional study
from Glasgow, UK, the investigators obtained
DNA from 239 participants and carried out a global
DNA methylation assay to assess differences in epi-
genetic patterns between socio-economic groups.
Hypomethylation was found in the most socially
deprived participants and associations were also
found with inflammatory markers. The second study
using the 1958 birth cohort included only 40 men
drawn from extremes of low and high socio-economic
positions in childhood and adulthood.
12
DNA methy-
lation was assessed on adult blood samples using a
genome-wide approach examining the methylation
status of 20 000 genes and 400 microRNAs. In con-
trast to the first study, it was possible to examine
DNA methylation patterns by functional pathways:
extra-cellular signalling, intra-cellular signalling,
DNA signalling and metabolism. Stronger associations
were found with childhood than adult socio-economic
position and different patterns of hyper- and
hypomethylation were found for the different func-
tional pathways. What does it all mean? Both sets
of investigators make some good suggestions but
ultimately much bigger studies are needed with
more focused hypotheses that will become feasible
as the costs of measuring DNA methylation fall and
our understanding of how epigenetic patterns influ-
ence development and disease increases.
Now, if you think epigenetics is too complicated,
take a deep breath in, count to five and turn to
Chris Wilds
13
piece The exposome: from concept to
utility. He defines it as follows: The exposome is
composed of every exposure to which an individual
is subjected from conception to death. Wilds idea is
to capture the most important pieces of the jigsaw
puzzle of the causal mechanisms from genes to dis-
ease. Attempting to catalogue the dynamic patterns of
exposure, ranging from social to biological processes
(and including epigenetic processes), is a daunting
but necessary task if we are ever going to be able to
make sense of the findings from the current gener-
ation of genetic and epigenetic studies.
Finally, for those of us working in Europe please
read a rapid response on the International
Association of Epidemiology website (http://www
.ieaweb.org/). The European Union will replace their
Directive on Data Protection with a new General Data
Protection Regulation.
14
Consultations on the previous
drafts did not result in public health and epidemi-
ology interests gaining sufficient support to ensure
our research can easily continue in its present form.
For example, studies published in this issue of the
Journal would likely require informed consents from
study participants for conducting epigenetic tests if
not previously requested and cohort participants
would be required to give regularly updated consents.
We now need some sustained lobbying to revise the
current draft.
References
1
Cloud J. Why DNA Isnt Your Destiny. TIME Magazine,
6 January 2010. http://www.time.com/time/magazine/art-
icle/0,9171,1952313,00.html#ixzz1jbJjxmzy (17 January
2012, date last accessed).
2
Davey Smith G. Epidemiology, epigenetics and the
Gloomy Prospect: embracing randomness in population
health research and practice. Int J Epidemiol 2011;40:
53762.
3
Waddington CH. The epigenotype. Endeavour 1942;1:
1820. Reprinted in Int J Epidemiol 2012;41:1013.
4
Jablonka E, Lamm E. The epigenotype a dynamic net-
work view of development. Int J Epidemiol 2012;41:1620.
5
Haig D. The epidemiology of epigenetics. Int J Epidemiol
2012;41:1316.
Figure 1 Trends in HuGE publications 19972010
6
2 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY

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6
Gilbert SF. The Epigenotype by C.H. Waddington. Int J
Epidemiol 2012;41:2023.
7
Yu W, Wulf A, Yesupriya A, Clyne M, Khoury MJ,
Gwinn M. HuGE watch: tracking trends and patterns of
published studies of genetic association and human
genome epidemiology in near-real time. Eur J Hum
Genet 2008;16:115558.
8
Relton CL, Davey Smith G. Is epidemiology ready for epi-
genetics? Int J Epidemiol 2012;41:59.
9
Relton CL, Davey Smith G. Two step epigenetic
Mendelian randomization: a strategy for establishing
the causal role of epigenetic processes in pathways to
disease. Int J Epidemiol 2012;41:16176.
10
Heijmans BT, Mill J. The seven plagues of epigenetic epi-
demiology. Int J Epidemiol 2012;41:7478.
11
McGuinness D, McGlynn L, MacIntyre A et al. Socio-
economic status is associated with epigenetic differences
in the pSoBid cohort. Int J Epidemiol 2012;41:15160.
12
Borghol N, Suderman M, McArdle W et al. Associations of
early-life socio-economic position in adult DNA methyla-
tion. Int J Epidemiol 2012;41:6274.
13
Wild CP. The exposome: from concept to utility. Int J
Epidemiol 2012;41:2432.
14
Proposal for a Regulation of the European Parliament and of the
Council on the Protection of Individuals with Regard to the
Processing of Personal Data and on the Free Movement of
Such Data (General Data Protection Regulation). http://www
.statewatch.org/news/2011/dec/eu-com-draft-dp-reg-inter-
service-consultation.pdf (17 January 2012, date last
accessed).
EDITORS CHOICE 3

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