Int. J. Epidemiol. Advance Access published April 17, 2006
Published by Oxford University Press on behalf of the International Epidemiological Association
Ó The Author 2006; all rights reserved.
International Journal of Epidemiology
Make it HuGE: human genome epidemiology
reviews, population health, and the IJE
George Davey Smith,1* Marta Gwinn,2 Shah Ebrahim,3 Lyle J Palmer4 and Muin J Khoury2
The International Journal of Epidemiology is concerned with
scientific evidence that can ultimately form the basis of
strategies for improving population health. Hence, the IJE
would be expected to remain cautious about the technological
advances heralded by the sequencing of the human genome.
The classical epidemiological approaches of examining secular
trends in disease risk, changes in risk consequent upon
migration, and differences in disease rates between populations
indicate that little of the global burden of common disease can
be attributed to simple differences in genetically determined
risk. It is not surprising that many social epidemiologists and
public health practitioners (including, in the past, some of the
authors of this editorial) have pointed this out. More surprising,
perhaps, is that in the spirit of honest accounting, some
geneticists and genetic epidemiologists have also punctured
the inflated claims of genetic epidemiology by emphasizing
that the population-attributable risk of most common genetic
variants will be low and that in any case the influence of genetic
factors is not reversible through changing genetic make-up.
Thus Terwilliger and Weiss 1 point out that alleles identified as
increasing the risk of common diseases ‘tend to be involved in
only a small subset of all cases of such diseases’ and that in any
case ‘while the concept of attributable risk is an important one
for evaluating the impact of removable environmental factors,
for non-removable genetic risk factors, it is a moot point’.
Bearing these criticisms in mind, should the IJE be excited
by the growing Human Genome Epidemiology Network
(HuGENet)?2 This global collaboration launched by the Centers
for Disease Control and Prevention (CDC) and many partners
in 1998, aims to make sense of the implications of gene
discovery for epidemiology and public health. The goals of
HuGENet are to establish an information exchange network
that promotes global collaboration in the development and
dissemination of peer-reviewed epidemiological information
on human genes; develop an updated and accessible knowledge
base on the World Wide Web; and promote the use of this
knowledge base for decision making involving the use of genetic
information for population health. 2 Since 2001, HuGENet has
maintained a searchable, online database of epidemiological
studies of genetic variation
genomics/hugenet). By March 1, 2006, the HuGE Published
and disease (www.cdc.gov/
1 Department of Social Medicine, University of Bristol, BS8 2PR, UK.
2 Centers for Disease Control and Prevention, Atlanta, GA, USA.
3 London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
4 Western Australia Institute for Medical Research, Perth, Australia.
* Corresponding author. E-mail: firstname.lastname@example.org
Literature database contained 20 272 reports of research studies
involving 2252 genes, 2406 health outcomes, and 743 inter
acting factors. 2 However, the implications of these articles for
population health are unclear. To clarify basic issues, such as
the population prevalence of genetic variants, the magnitude of
disease risk associated with these variants (in relative and
absolute terms), the contribution of these variants to the
occurrence of disease in different populations (i.e. attributable
risk), the existence of gene–environment and gene–gene
interactions, the validity of genetic tests based on such variants
in predicting disease risk, and the impact of genetic tests on
morbidity, disability, and mortality in different populations,
HuGE Net has promoted the completion of reviews (HuGE
reviews),3 which are peer-reviewed, systematic synopses of the
epidemiological aspects of variation in particular genetic
variants and health outcomes. By March 1, 2006 44 HuGE
reviews have been published in various journals, with journal
choice partially reflecting the focus of the review and editorial
preferences. HuGE reviews are conducted with specific guide
lines;4 the key aspects of which are outlined in Box 1. In
addition the first detailed guidance for conducting HuGE
Reviews has been published in March 2006 (HuGENet
handbook of systematic reviews, available at http://www.cdc.
It would also be worth considering the principles that govern
another international group—The Cochrane Collaboration—that
is attempting to deal with an almost infinite amount of
information and assimilating it into systematic reviews of the
effects of interventions (see http://www.cochrane.org/docs/
descrip.htm). Of particular relevance to genetic epidemiology is
the current duplication of effort that is apparent, with several
groups conducting meta-analyses of the same associations. In
a well-organized collaboration it may be possible to reduce this
trend for the common good, allowing resources to be diverted
to other areas. Practical issues that are worth considering are
the mechanisms for updating of reviews, the standardization of
search methods and reporting formats, and the identification
and reduction of sources of bias in systematic reviews.
Why should the IJE be concerned with such a movement?
We contend that, contrary to some of the outright dismissals of
the public health importance of genetic epidemiology, the field
can contribute not just to ‘genomic medicine’ (which currently
we believe has been oversold with respect to common chronic
diseases 5) but also to strengthening causal inferences regarding
environmentally modifiable causes of disease. Confirmed asso
ciations, which are not distorted by the usual problems of
residual confounding and measurement error, between genetic
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Box 1 Key aspects of HuGE reviews
What is a HuGE review?
Systematic review of epidemiological data on specific human
genetic variants at one or more loci in relation to diseases or
other health outcomes
What are the types of HuGE reviews?
1.? Full review: includes prevalence of genetic variants, disease
associations, interactions, implications for population testing
and public health impact, knowledge gaps, and research
2.? Gene–disease association review: as above without preval
3.? Mini review: review of different outcomes in relation to
genetic variant reviewed previously
4.? Prevalence review: review limited to prevalence of genetic
variants in populations
What are the defining characteristics of a HuGE review?
Systematic, specifying methods used to capture all available
data, preferably employing quantitative methods of synthesis
(e.g. meta-analysis or pooled analysis of individual-level data)
variants of known function and disease outcomes provide
strong evidence of a causal link between the biological processes
that the genetic variants are related to and the disease
outcomes. Such evidence implies that modification of biological
processes by non-genetic means can reduce disease risk and
strengthens our conviction that we are indeed focusing
environmental intervention efforts on factors that are truly
causal. Several existing HuGE reviews illustrate this point.
For example, a HuGE review summarized evidence on the
association between the MTHFR 677C!T polymorphism and
risk of neural tube defects (NTDs).6 The polymorphism is
associated with increased blood levels of homocysteine and
lower folate activity; in the HuGE meta-analysis of case–control
studies it was shown that infants with the TT vs CC variants
have a relative risk of 1.75 (95% CI 1.41–2.18). 6 However,
when the parental genotypes were examined, the increased
risk of NTD associated with the TT variant was only seen
when the mother was the carrier. In this case, it appears that
the intra-uterine environment—influenced by maternal TT
genotype—rather than the genotype of offspring, increases the
risk of NTD, as has been discussed previously in more detail.
Thus, this evidence from a systematic HuGE review of genetic
association studies provides further evidence that folate levels
among mothers influences NTD risk in their offspring. In this
case, of course, we have additional evidence from randomized
controlled trials that periconceptional maternal folate intake
influences NTD risk. In other situations, however, robust
evidence from genetic associations may point to yet-to-be
established causes of disease.
Consider, for example, the controversial idea that infections
increase the risk of preterm birth. A HuGE review summarized
the evidence on genetic variants related to inflammation
found that polymorphisms that increase the magnitude or
duration of the inflammatory response were associated with
increased risk of preterm birth. Thus, the evidence from genetic
association studies strengthens the inference that maternal
infection increases the risk of preterm delivery. In both cases—
maternal MTHFR, and maternal inflammation-related genetic
variants—the implication is not that screening for genetic
variants is the key to prevention but that public health
initiatives to increase periconceptional maternal folate and to
prevent infections during pregnancy would produce health
Why utilize genetic association studies to strengthen infer
ences about environmental causes of disease? Is it not more
straightforward to study these factors directly using conven
tional epidemiological techniques? In many cases the answer
may be in the negative. As is increasingly evident, observa
tional epidemiological studies have produced seriously mis
leading findings in areas such as vitamin E supplement use and
coronary heart disease (CHD), beta carotene intake and lung
cancer, or hormone replacement therapy and CHD.
these cases randomized controlled trials (RCTs) demonstrated
the fallacious nature of causal inferences drawn from obser
vational studies; in other areas where RCTs have not or cannot
be performed it is hardly credible that the success of
observational epidemiology has been greater. The considerable
advantage of studying genetic variants is that these variants are
not generally susceptible to the confounding experienced by
dietary patterns or other lifestyle-related risk factors.
studying genetic variants that provide evidence on environ
mentally modifiable risk factors—as MTHFR does about folate
intake and inflammatory variants do about infection in the
examples discussed above—can, paradoxically, provide more
evidence of the ability to modify disease risk through environ
mental change than can the direct study of the environmental
factors of interest.
This approach to utilizing findings from genetic association
studies to understand modifiable, environmental causes of
disease—a methodology that has been labelled ‘Mendelian
randomization’7,19—has been applied to the study of interme
diate phenotypes influenced by genetic variants. Many biolo
gical markers have been shown to be related to disease, such as
the classic case of blood cholesterol and CHD. In this instance
RCTs of cholesterol lowering therapies have shown that the
association is causal. In other cases, however, this is less clear.
There could be confounding, or the disease could itself
influence the circulating levels of the supposed exposure, i.e.
reverse causation may be generating the apparent predictive
value of the blood borne factor. If the association is causal, then
genetic variants that influence the intermediate phenotype
should be related to the disease to the degree predicted by the
association between the variant and the intermediate pheno
type. In the case of cholesterol and CHD, carriers of an
apolipoprotein B variant (known as familial defective apo B),
who have higher circulating cholesterol levels but are other
wise similar to non-carriers with respect to coronary risk
factors, have an increased risk of CHD,
anticipated by knowledge of the causal influence of circulating
cholesterol. In other cases this is not seen—for example, those
with genetically influenced higher fibrinogen level do not have
an increased risk of CHD, despite fibrinogen being a predictor of
CHD risk. This suggests that the observational association
between fibrinogen and CHD is non-causal and that lowering
fibrinogen level will not, through this means alone, reduce
So, if genetic epidemiology findings are rigorously reviewed
and interpreted to make inferences regarding environmentally
modifiable risk of disease, does this make it more likely that
as would be
the discipline will contribute to the public health enterprise
(and thus the goals of the IJE)? We feel it does. The overly
hasty dismissal of the value of genetic epidemiology that we
started with—on the grounds that the population attributable
risk of genetic variants is low and that the genetic variants are
not modifiable—is rendered moot by considering the potential
contributions these genetic associations can make to knowledge
of disease aetiology, treatment, and prevention. These contri
butions are highlighted in the new field of pharmacogenomics
and by the growing clinical impact of ‘genomic medicine’. 22
The degree to which associations between genetic variants and
disease outcomes can demonstrate the importance of environ
mentally modifiable factors as causes of disease does not
depend on, or even relate to, the population attributable risk of
the genetic variants themselves. Consider, for example, the case
of familial defective apo B. The genetic mutations associated
with this condition will only account for a trivial percentage of
cases of CHD within the population. However by identifying
blood cholesterol levels as a causal factor for CHD the
three-way associations between genotype, blood cholesterol,
and CHD risk more reliably identify a clearly modifiable
factor—circulating cholesterol levels—with a very high popu
lation attributable risk. A similar argument could be made with
respect to maternal MTHFR and NTDs in offspring. Maternal
genotype will account for only a small proportion of cases;
however the association of maternal genotype and offspring
NTDs identifies maternal folate intake as a modifiable influence
on NTDs, with a high population attributable risk.
The study of genetic variants and disease can, therefore, add
a perhaps surprising amount of information about environ
mentally modifiable causes of disease, and thus be of major
population health importance. At the IJE we are very
interested in receiving HuGE reviews that follow the HuGE
guidelines4 and explicitly address the implications of the
findings of the genetic epidemiological studies for population
health. We therefore favour reviews of variants that have
functional connotations of relevance to strategies for modifying
disease risk. We feel this can be done without abandoning the
attractive objectivity of the systematic review, and here we
would contrast a HuGE review of several alcohol-metabolism
relevant genetic variants and head and neck cancer 23 with
a later review that explicitly utilized the association of one
particular variant with oesophageal cancer risk to strengthen
the evidence base that alcohol intake increases the risk of this
cancer. 24 Reviews formulated to provide answers to questions
relating to modifiable causes of disease would appear most
appropriate to the IJE. Thus we call for HuGE reviews to be
sent to the IJE if they are systematic and attempt to utilize all
the data for drawing inferences relevant to health improvement
within populations. When appropriate we would like to receive
two-stage reviews that include both genotype ! intermediate
phenotype and genotype ! disease associations to formally
make inferences about the causal association between inter
mediate phenotype and diseases, applying appropriate system
atic review and statistical methods. HuGENet encourages
registration of HuGE reviews with the HuGENet coordinator,
and, at the IJE, we encourage the submission of protocols for
reviews to the journal. Once approved, we guarantee publica
tion of any review that coherently reports and discusses the
findings in line with the protocol. The international readership,
MAKE IT HuGE
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with an interest in population health, together with rapid
turnaround and web-based publication on acceptance should
make the IJE an ideal vehicle for such reports. Let the
1 Terwilliger JD, Weiss WM. Confounding, ascertainment bias, and
the blind quest for a genetic ‘fountain of youth’. Ann Med
2 Human Genome Epidemiology
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3 Little J, Khoury MJ, Bradley L et al. The human genome project is
complete: how do we develop a handle for the pump? Am J Epidemiol
4 HuGENet guidelines for HuGE reviews. Available at: http://www.cdc.
gov/genomics/hugenet/reviews/guidelines2.htm (Accessed February 6,
5 Davey Smith G, Ebrahim S, Lewis S, Hansell AL, Palmer LJ,
Burton PJ. Genetic epidemiology and public health: hope, hype, and
future prospects. Lancet 2005;366:1484–98.
6 Botto LD, Yang Q. 5,10-Methylenetetrahydrofolate reductase gene
variants and congenital anomalies: a HuGE Review. Am J Epidemiol
7 Davey Smith G, Ebrahim S. ‘Mendelian randomization’: can genetic
epidemiology contribute to understanding environmental deter
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8 MRC Vitamin Study Research Group. Prevention of neural tube
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9 Czeizel AE, Duda ´s I. Prevention of the first occurrence of neural-tube
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10 Crider KS, Whitehead N, Buus RM. Genetic variation associated with
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11 Davey Smith G, Ebrahim S. Data dredging, bias, or confounding. BMJ
12 Davey Smith G, Ebrahim G. Folate Supplementation and cardiovas
cular disease. Lancet 2005;366:1679–81.
13 Davey Smith G, Ebrahim S. Mendelian randomization: prospects,
potentials, and limitations. Int J Epidemiol 2004;33:30–42.
14 Katan MB. Apolipoprotein E isoforms, serum cholesterol, and cancer.
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15 Katan MB. Commentary: mendelian randomization, 18 years on.
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17 Tobin MD, Minelli C, Burton PR, Thompson JR. Commentary:
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18 Davey Smith G, Lawlor D, Harbord R, Timpson N, Rumley A, Lowe G
et al. Association of C-reactive protein with blood pressure and
hypertension: lifecourse confounding and Mendelian randomisation
tests of causality. Arterioscler Thromb Vasc Biol 2005;25:1051–56.
19 Youngman LD, Keavney BD, Palmer A et al. Plasma fibrinogen and
fibrinogen genotypes of 4685 cases of myocardial infarction and in
6002 controls: test of causality by ‘Mendelian randomization’.
20 Tybjærg-Hansen A, Steffenson
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21 Davey Smith G, Harbord R, Milton J, Ebrahim S, Sterne JAC. Does
elevated plasma fibrinogen increase the risk of coronary heart
disease?: evidence from a meta-analysis of genetic association studies.
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22 Willard HF, Angrist M, Ginsburg GS. Genomic medicine: genetic
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23 Brennan P, Lewis S, Hashibe M et al. Pooled analysis of alcohol
dehydrogenase genotypes and head and neck cancer: a HuGE review.
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24 Lewis S, Davey Smith G. Alcohol, ALDH2 and esophageal cancer:
a meta-analysis which illustrates the potentials and limitations of
a Mendelian randomization approach. Cancer Epidemiol Biomarkers