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Nature Reviews Genetics | AOP, published online 9 July 2013; doi:10.1038/nrg3523

T R A N S L AT I O N A L G E N E T I C S

Bringing genome-wide association

findings into clinical use
Teri A.Manolio

Abstract | Genome-wide association studies (GWASs) have been heralded as a major

advance in biomedical discovery, having identified ~2,000 robust associations with complex
diseases since 2005. Despite this success, they have met considerable scepticism regarding
their clinical applicability; this scepticism arises from such aspects as the modest effect sizes
of associated variants and their unclear functional consequences. There are, however,
promising examples of GWAS findings that will or that may soon be translated into clinical
care. These examples include variants identified through GWASs that provide strongly
predictive or prognostic information or that have important pharmacological implications;
these examples may illustrate promising approaches to wider clinical application.
Heritability
The proportion of the total
phenotypic variation in a trait
that can be attributed to
genetic effects.

Odds ratios
A measure of effect size.
Defined as the ratio of the
odds (that is, the probability of
disease divided by 1 minus the
probability) of a disease being
observed in one group of
genotypes and the odds of a
disease being observed in
another group.

Minor allele frequencies

(MAFs). The frequency of the
less common allele of a
polymorphism. It has a value
between 0 and 0.5 and can
vary between populations.

Division of Genomic Medicine,

National Human Genome
Research Institute, 5635
Fishers Lane, Room 4113,
MSC 9305, Rockville,
Maryland
20892-9305, USA.
email: manolio@nih.gov
doi:10.1038/nrg3523
Published online 9 July 2013

Genome-wide association studies (GWASs) have revolutionized the identification of genomic regions associated with complex diseases. In the past 7years, more
than 1,600 publications have identified ~2,000 robust
associations with more than 300 complex diseases and
traits. These numbers are orders of magnitude greater
than those of replicable linkage and candidate gene
association findings to date for complex diseases. Initial
euphoria at this veritable hoard of reliable associations, totalling nearly 100 or more for some traits1,2, has
dimmed somewhat with the recognition that GWASdefined loci, singly or in aggregate, typically explain
only a small proportion of trait heritability3,4. This missing heritability, which is also reflected in the generally
small odds ratios and limited predictive value5,6 of these
variants, has raised questions about the ultimate applicability of these findings to risk prediction in particular
and to clinical medicine in general7,8.
Impatience with the seemingly slow pace of implementing genomic findings in clinicalcare9,10 may have
been fuelled in part by the frequency and enthusiasm
with which so many new genome-wide associations have
been announced. Optimistic scenarios for the clinical
use of genomic information have no doubt contributed
to high expectations11,12. Most GWAS findings are less
than 3years old, however, whereas clinical adoption of
scientific discoveries in general has been estimated to
take up to 17years13. In addition, these timeframes are
derived from translational experience with proven preventive or therapeutic strategies, however the nature of
GWAS-defined associations may substantially prolong
this lead time. This is because GWAS findings typically

suggest only that a disease-causing variant resides somewhere in a specific genomic region that may include dozens of nearby genes and variants. And although some
GWAS findings have identified previously unknown
pathogenic pathways, such as complement-mediated
inflammation in macular degeneration14 and autophagy
in Crohns disease15,16, these have yet to find major
clinical applications.
Despite the advent of newer technologies, particularly sequencing-based methods for identifying diseaseassociated variants, as discussed below, GWAS-based
findings will continue, for sometime, to be essential for
designing effective clinical applications. This is in part
because of the mass of GWAS data that has already been
accumulated that can continue to be mined for additional trait associations and because of the unflagging
pace with which new GWAS findings are still being
published (FIG.1). More importantly, the continued value
of GWAS comes from the efficiency of the method for
interrogating low-frequency variants (those with minor
allele frequencies (MAFs) of 0.55%) that are initially
identified through sequencing, using dense genotyping
platforms that capture a large proportion of genomic
variation underlying complex traits17,18 (see also Illumina
products for whole-genome genotyping and copy
number variation analysis).
This Review is intended first to summarize briefly
the criticisms and limitations of the GWAS method
and how they affect the potential value of GWAS findings in clinical care. Although several approaches are
available to address these limitations such as imputation, fine mapping and evaluation of genegene and

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1,600

Total number of publications

1,400
1,200
1,000
800
600
400
200
0

2005

2006

2007

2008

2009

2010

2011

2012

Calendar quarter

Figure 1 | Pace of genome-wide association study publications

2005.
Nature since
Reviews
| Genetics
The pace of genome-wide association study (GWAS) publications has increased
dramatically over 7years and shows no signs of slowing. The figure is based on data
from the US National Human Genome Research Institute Catalog of Published
Genome-Wide Association Studies.

geneenvironment interactions these are beyond the

scope of this Review. It next explores several illustrative examples of how, despite these issues, GWAS findings have been or probably will be valuable in disease
prediction, biomarker identification and disease subclassification, treatment selection and drug dosing. This
Review is not intended as a comprehensive nor even as a
representative presentation of all the scenarios in which
GWAS findings may be useful in clinical care, but rather
it is as an exploration of promising findings that can
or should be developed further for clinical translation.
Finally, it identifies several challenges in the clinical translation of GWAS findings that must be resolved before
the GWAS revolution can be integrated into clinicalcare.

Enhancer elements

Controversy over potential clinical value

Common versus rare polymorphisms. Criticisms of
the GWAS approach include its emphasis on common
polymorphisms (that is, those with an MAF of 5% or
more) and consequent incomplete tagging of rarer,
potentially causal variants, particularly among people
of non-European ancestry 19,20. Both characteristics tend
to obscure associations with variants that have a lower
frequency but a potentially higher phenotypic impact,
in which much of genomically mediated risk is believed
to reside21,22. As genomic technologies improve, detection of associations with variants of lower frequency is
increasingly becoming possible, as discussedbelow.

A regulatory DNA element

that usually binds several
transcription factors and can
activate transcription from a
promoter at great distance and
in an orientation-independent
manner.

Small effect sizes and missing heritability. A substantial surprise that was evident from some of the earliest GWAS findings for complex diseases was that their
associated odds ratios were small (often less than 1.3).
In addition, even in combination, they explained very

Negative selection
A form of natural selection that
suppresses alternative genetic
variants in favour of the
ancestral type.

little (often 10% or less) of the complex trait heritability

that is estimated from familial clustering 3,23. Small effect
sizes present particular problems for clinical applications that might involve disease prediction or risk classification, as very large odds ratios are typically needed
to improve predictive accuracy above that provided by
clinical information5,7.
Some of this missing heritability has been attributed to imperfect tagging (such that a weak GWAS
signal might be indicating a variant that is much more
strongly associated and that lies some genomic distance
away 21, as noted above) or to a lack of ascertainment of
potentially important underlying structural variation24,25
(see below). A not uncommon view is that GWAS was a
useful early technology that should largely be supplanted
by sequencing approaches to detect rarer variants of
large effect 22. Deeper sequencing-based characterization of genomic variation17,18, fine mapping 26,27, imputation28,29 and denser single-nucleotide polymorphism
(SNP) arrays are extending the reach of GWAS to ever
lower ranges of minor allele frequency. At the same time,
the costs and interpretive challenges of whole-genome
sequencing currently put it out of reach for all but the
smallest association studies. In addition, sequencing is
best suited to detecting rare variants underlying conditions that have been under strong negative selection,
which acts to keep their frequencies low. By contrast,
many complex diseases of clinical importance occur
later in life when selection is less likely to have been
operative. Increases in effect sizes, heritability explained
and risk prediction accuracy based on GWAS findings
may be hoped for with improved understanding of noncoding variation, in which the vast majority of GWAS
associations are localized30.
Assessment of structural variation. Although GWAS
arrays are extraordinarily efficient at genotyping SNPs,
they are less effective at capturing structural variation,
such as insertions, deletions, inversions and copy number variants, which commonly occur in the human
genome 24. Such variants have been shown to have
strong associations with several conditions, particularly neurodevelopmental diseases, such as autism and
schizophrenia31, and they clearly have a role in interindividual variations in drug metabolism32 but can be
challenging to detect by GWAS methods25. Clinical
applications of GWAS findings will thus be limited to
the degrees that structural variants have a role in disease
diagnosis, prevention and treatment and that they are
under-represented in GWASarrays.
Signals in non-coding regions. The high proportion (80%
or more) of GWAS-defined signals falling in non-coding
regions of the genome30 has frustrated efforts to identify
their potential causal roles and has slowed attempts to
build on these findings for clinical use. Recent data demonstrating strong correlations of GWAS-defined signals
with enhancer elements and other regulatory regions33,34
(FIG.2), however, have renewed enthusiasm for exploring
functional implications of these signals that at present
are but dimly understood.

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(LD). The nonrandom

association of alleles at two
or more loci. The pattern of
LD in a given genomic region
reflects the history of natural
selection, mutation,
recombination, genetic drift
and other demographic and
evolutionary forces.

Expression quantitative
trait locus
(eQTL). A locus at which
genetic allelic variation is
associated with variation
in gene expression levels.

Sensitivity
The proportion of true
positives that are accurately
identified as such (for example,
the percentage of cases
that are diagnosed using a
questionnaire). A sensitivity
of 100% means that all cases
are correctly identified.

Specificity
The proportion of true
negatives that are classified
as negatives. For example,
a diagnostic test with a
specificity of 100% means that
all healthy people have been
identified as healthy.

Positive predictive value

(PPV). The probability that an
individual who tests positive
truly has the condition (true
positive). A measure of how
well a screening or diagnostic
test distinguishes true positives
from false positives that do not
have the disease.

Assessment and prediction of risk. Despite the numerous

terms used to describe and to quantify disease risk, few
are interpreted in the same way by each patient or clinician, and none captures the concept entirely. Several of
these, such as sensitivity, specificity and positive predictive
value, have repeatedly been described (for example, see
REF.40). The metric most often used for assessing the
added value of a predictive factor is the increase in area
under the receiver operator characteristic (ROC) curve41.
The ROC curve plots the true-positive fraction (sensitivity) of various cut points of a continuous measure, such
as fasting glucose to detect a disease such as diabetes,
against their false-positive fractions (1 minus the specificity). The area under this curve (AUC) is frequently
used to describe the ability of a measure to discriminate
between those with and without disease. Ideal classifiers
would have a high true-positive rate, even at low rates of
false positives and would produce almost square curves,
whereas poor classifiers would increase true positives at
about the same rate as false positives, looking more like
a diagonal curve. AUC thus ranges from 0.5 (providing
no discrimination between those with and without the
condition) to 1.0 (perfect discrimination).

For many common conditions, even multiple GWASdefined variants considered together often fail to increase
the AUC much over clinical risk factors42,43. This is
because, as noted above, SNPs associated with common
diseases typically have small odds ratios (<1.3) and thus
have minimal impact on overall risk classification, particularly in comparison to well-established environmental
factors for these diseases. The situation is little better for
conditions for which there are GWAS-defined variants
that are associated with two- to threefold increased risk
of disease5. Well before the GWAS era, it was argued that

0.35

Fraction of SNPs that overlap feature

Linkage disequilibrium

Difficulty dissecting linkage disequilibrium. Linkage

disequilibrium (LD) presents another formidable obstacle
to the interpretation and application of GWAS findings.
Although LD made the GWAS approach possible (by
allowing a single tag SNP to serve as a proxy for much of
the surrounding genetic variation with which it is inherited), parsing such signals to a single causative variant (if
one exists) can require substantial additional research. An
early GWAS for childhood-onset asthma, for example,
identified associations with multiple markers in a 206kb
region on chromosome 17q21 that contains 19 genes35.
Expression data implicated a gene of unknown function,
ORM1like 3 (ORMDL3), as potentially responsible for
the asthma association signal because the SNPs that
underlie the GWAS signal were most strongly associated
with ORMDL3 expression in relevant immune tissues35.
Subsequent GWASs, however, showed that the strongest association signal in this region lies in the nearby
gasdermin B (GSDMB) gene and also implicated by LD
both ORMDL3 and the neighbouring GSDMA gene.
Furthermore, the expression quantitative trait locus (eQTL)
in the region that had been previously associated with
ORMDL3 expression was found also to influence the
expression of GSMDB36,37. This signal has yet to be isolated to one of these plausible and tightly linked genes in
the 17q21 locus, delaying the understanding of the potential role, if any, of these genes in asthma pathogenesis and
the potential application of this finding to diagnostic
or therapeutic decisionmaking.
LD in GWAS-defined associations can sometimes,
however, be used to implicate or to exclude strong
candidate genes. An example is the case of the strong
GWAS associations with inflammatory bowel disease
that were found to be clustered around interleukin 23
receptor (IL23R) and not in the neighbouring IL12RB2
locus16,38,39. Specific inhibitors of IL23 are currently
under development and clinical investigation.

0.30
0.25
0.20
0.15
0.10
0.05
0

DNase I peaks

Transcription factor
binding sites

Figure 2 | Correlations of presumed regulatory regions

Nature Reviews | Genetics
with signals defined from genome-wide association
studies. Findings from the ENCODE project indicate that
single-nucleotide polymorphisms (SNPs) that are found to
be associated with disease in genome-wide association
studies (GWASs) often lie in enhancers or other putative
regulatory elements. Such elements are inferred from
DNase I peaks, indicating regions of open chromatin
accessible to the transcription apparatus and transcription
factor binding sites, where this apparatus attaches to the
DNA. The red bars show data for SNPs associated with
a disease phenotype at P<5108 in the US National
Human Genome Research Institute (NHGRI) Catalog of
Published Genome-Wide Association Studies (as accessed
by the authors of REF. 34 in June 2011). Overlap of these
SNPs with DNase-hypersensitive sites is shown on the left
and overlap with transcription factor binding sites is shown
on the right. Also shown are data from various control SNP
sets (blue bars). From left to right, these are: SNPs on the
Illumina 2.5M chip, as an example of a SNP genotyping
panel that is widely used for GWAS; SNPs from the 1000
Genomes Project; and SNPs from 24 personal genomes. A
further control is also shown, indicated by light blue points
with bounds at 1.5 times the interquartile range, for
pseudo-associated SNPs. These are sets of SNPs selected
from 1,000 random samplings from the genotyping SNP
panel that match each NHGRI catalogue SNP for allele
frequency and distance to the nearest transcription start
site (TSS). For both types of presumed regulatory region,
there is a larger proportion of overlap with SNPs that have
been implicated in GWASs than for any of the controls
sets. The figure is reproduced from REF.34.

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a

1.0

1.0

50
0.8

10
True-positive frequency

True-positive frequency

0.8

0.6

1.5
0.4

0.4

Three-gene model
CFH + LOC model
CFH model
LOC model
C2 model
Null model

0.2

0.2

0.6

0.2

0.4

0.6

0.8

1.0

0.2

0.4

0.6

0.8

1.0

False-positive frequency

False-positive frequency

Figure 3 | Use of odds ratios in risk prediction. a | Area under receiver operator characteristic
curve
for
Nature(ROC)
Reviews
| Genetics
predicting a hypothetical condition with variants carrying modest (1.5), sizeable (10) and large (50) odds ratios,
showing false-positive fractions at 80% sensitivity (dotted line; fractions are >75%, >25% and <10%, respectively).
The graph demonstrates that very large odds ratios are needed to provide acceptably low false-positive fractions.
b | Area under ROC curve for risk prediction for age-related macular degeneration. The graph is derived from
combinations of genome-wide association study (GWAS)-defined loci, showing risk prediction for one-, two- and
three-factor models. The complement factor H (CFH)+LOC387715 (LOC) model performs almost as well as the
three-factor model (including complement component 2 (C2)), but even with the three-factor area under the curve
of 79%, false-positive rate at 80% sensitivity is unacceptably high at >40%. The figure is reproduced, with permission,
from REF.5 (2009) Jakobsdottir et al.

odds ratios of 200 or more may be necessary for meaningful risk prediction in individuals44 (FIG.3a), although the
predictive value of multiple genetic variants considered
jointly may improve with identification of a larger number
of SNPs that explain a greater proportion of variance44,45
(FIG.3b). Even for a condition such as age-related macular
degeneration, however, in which the three major variants
produce an AUC of 0.79, the correct detection of 80% of
cases results in a false-positive rate of >40%5.
As noted above, currently known variants typically
explain too little variability in disease occurrence to
be of much predictive value, but it can be anticipated
that as more risk variants are identified, the predictive
value of cumulative genotype scores will increase5. Care
must also be taken when evaluating the predictive value
of genetic models as they often perform best in the
population from which they were developed, and their
performance can be affected by differences between
populations in genotype frequencies, phenotypic effect
sizes and disease incidence46.

Major histocompatibility
complex
(MHC). A large complex of
tightly linked genes on human
chromosome 6, many of which
are involved in the immune
response. The human
leukocyte antigen genes are
located within the MHC.

Clinically relevant GWAS findings

Areas in which GWAS findings are leading to clinical
applications include risk prediction, disease classification,
drug development and drug toxicity. Illustrative examples
first identified by GWAS or that capitalize on the strengths
of this method are discussed in some detail below, and
other examples on the horizon are briefly listed thereafter.
Risk prediction. Clinical scenarios in which GWAS
findings might find ready application in risk prediction

would include those in which early (before disease

onset) identification of high-risk individuals is important owing to the availability of a treatment that either
prevents disease entirely or that is most effective in
improving outcome when it is instituted before clinical
abnormalities are detected or before a firm clinical diagnosis can be made. Type1 diabetes mellitus is a condition of typically childhood onset that may meet these
criteria after promising immune-modulating therapies
have been fully developed. It results from immunemediated destruction of the insulin-producing -islet
cells of the pancreas. It causes substantial morbidity
and mortality, requires life-long insulin treatment and
is highly heritable: it has an estimated sibling relative
risk of 15 (REFS47,48). By the time that the disease is
detected clinically, the -cells are almost completely
destroyed, and no known treatment can restore them.
Prevention by immune-modulating therapies is thus
likely to be the best near-term approach to reducing the
burden of this disease, and such treatments are under
active development 49.
Although nearly half of the sibling relative risk of
type1 diabetes is explained by associations within the
major histocompatibility complex (MHC) locus, which
were identified well before the GWAS era, GWAS investigations have increased the number of loci associated
with this condition to over 50 (REFS48,50; see also the
Type1 Diabetes Consortium website). Together with the
MHC, these loci are estimated to explain two-thirds to
three-quarters of familial risk and possibly more if familial risk is over-estimated, as has been suggested48. This is

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a
Before

3739

370

b
Within

3671

68

61

275

123

34
23

100

c
After

3732

366

134

Figure 4 | Reclassification of cardiovascular risk based on genotype score. A cohort of 4,232

was| Genetics
Naturepeople
Reviews
classified into low (<10%; green), medium (>10<20%; yellow) and high (>20%; red) 10year risk of cardiovascular
disease before and after applying genotype risk score. a | Before incorporation of the genotype score, standard risk
factors define 3,739 people as low-risk, 370 as intermediate-risk and 123 as high-risk. b | Of the 3,739 people initially
defined as low-risk, 68 are defined by genotyping score as intermediate risk; of the 370 people initially defined as
intermediate-risk, 61 are defined as low-risk, and 34 are defined as high-risk; and of the 123 initially defined as high risk,
genotyping defines 23 as intermediate-risk. c | After incorporation of the genotype score, reclassification statistics and
outcome data show improvement in classification: 3,732 at low-risk, 366 at intermediate-risk and 134 at high-risk. The
figure is based on data from REF.56.

far greater than the proportion of heritability explained

for any other complex disease, making type1 diabetes
unique in this regard. Predictive models incorporating
all of these loci have AUCs close to 0.9 (REFS51,52), the
highest known for any condition.
Although highly predictive biomarkers are also
available in the form of islet cell autoantibodies 53,
screening the population at large for such a rare condition using genetic variation or biomarkers is not feasible, as false positives would vastly outnumber true
positives. Targeting autoantibody screening, however,
to those with a known genetic predisposition measured
by a genetic risk score or positive family history, or both,
narrows the screening population and substantially
increases positive predictive value and yield48. When
effective immune-modulating therapies become available, type1 diabetes would meet the criteria that are
noted above for effective genetic risk prediction: early
identification is important owing to effective preventive or disease-altering therapies, heritability is high,
identified genetic loci explain a large portion of the
risk, and genotyping scores show high discriminative
value53. The only weakness in type1 diabetes as a model
for clinical application at present is in the availability of
effective therapies; although immune modulation has
shown promise in animal models and transient preservation of -cell function has been achieved in human
studies54, definitive therapies have yet to be developed.
When they become available, combining a genetic risk
score with family history (which is often predictive
above and beyond identified variants55) could be used in
clinical care to identify a high-risk group of individuals
in whom interventions could be considered. At present
genetic findings are being used to select participants
with high-risk type1 diabetes alleles for prevention and
treatment studies and to exclude those with protective
alleles, which is an important prelude to use of these
variants in clinicalcare.

Another potential application of GWAS-defined risk

variants is in reclassification of subjects who are initially
assigned to a low-risk category on the basis of established
risk factors (such as age, sex and hypertension for cardiovascular disease risk). Subjects can be reclassified to
a higher or lower category after the inclusion of an additional measure such as a genetic variant. Reclassification
can be particularly important for clinical settings in
which risk thresholds have been defined and guidelines
for intervention have been developed, with the recognition that such thresholds, although useful clinically,
are by nature arbitrary and debatable7. In a cohort that
had been classified for risk of cardiovascular events, a
combination of genetic variants was used to develop a
genotype score for reclassification56. As a result, of the
26% of the study cohort that was initially estimated to be
at intermediate risk, 35% (that is, 9% of the total cohort)
were reclassified into low- or high-risk categories; this
showed significant improvement in reclassification statistics compared to established risk factors alone (FIG.4).
Reclassification can be of particular value in clinical decision making in people defined as intermediate risk by
standard guidelines, although actual reclassification typically involves only minor increments in risk score that
shift borderline subjects between adjacent categories7.
Disease classification. Genetic variants can also help
to identify useful biomarkers, which can themselves be
used as risk or prognostic indicators in certain circumstances. Genetic or biomarker risk information may
be particularly valuable when its assessment is easier,
cheaper, more available, more reliable and/or more sensitive than other clinical indicators of risk; these are conditions that to date have rarely been met, in part because
of the small effect sizes and limited predictive value of
GWAS findings discussed earlier.
Monogenic forms of diabetes often known collectively as maturity-onset diabetes of the young (MODY)

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Missense variant
A variant that results in the
substitution of an amino
acid in a protein.

Splice variant
A variant, usually found at the
intronexon boundary, that
alters the splicing of an exon
to its surrounding exons.

account for 12% of all diabetes cases, but they are commonly misdiagnosed as type1 or type2 diabetes57. These
typically non-insulin-dependent disorders of -cell
function are dominantly inherited but are clinically
heterogeneous in regard to age of onset, severity and
causative genes and mutations. One of the most common forms is due to mutations in HNF1 homeobox A
(HNF1A)58,59. Identification of mutations in this gene
has important implications for patients and their relatives, as many patients with HNF1AMODY are better
managed with low-dose sulphonylureas than with metformin or insulin, and their first-degree relatives are
at a 50% risk of inheriting the same mutation. Genetic
testing remains difficult, however, because of the high
cost and limited availability of tests, the low prevalence
of the condition (and hence low predictive value), the
lack of familiarity with available genetic tests and their
interpretation among clinicians, and highly debated
ethical concerns about the risks of genetic information.
Patients are typically selected for molecular testing on
the basis of atypical course or parental history, but such
criteria tend to be poor discriminators, and many cases
are missed57. As -cell dysfunction is present in all forms
of diabetes, availability of a biomarker that is specific to
non-pancreatic manifestations may be most useful in
indicating the presence of HNF1A mutations59.
Although mutations in HNF1A that underlie MODY
were first identified through linkage studies rather than
through GWASs, the GWAS approach also demonstrated associations of common variants in HNF1A
with levels of Creactive protein (CRP)60, which is a
potential biomarker of the condition. HNF1A encodes
the transcription factor HNF1, binding sites for which
are present in the CRP promoter. Variants resulting in
loss of HNF1 binding lead to loss of CRP expression61.
CRP levels are in fact markedly lower in patients with
HNF1AMODY than in other forms of diabetes and
are indeed significantly lower than in non-diabetics59,62.
A recent multi-centre meta-analysis demonstrated
AUCs of 0.79 to 0.91 across centres for distinguishing
HNF1AMODY from young-adult-onset type2 diabetes with high sensitivity (78%) and specificity (80%)62.
Combining low CRP and the clinical criterion of age at
diagnosis <25years produced sensitivities near 90% and
specificities up to 81%62. Using these criteria to screen
for patients who need further investigation would limit
sequencing to 20% of type2 diabetics diagnosed at ages
up to 45years and would detect HNF1A mutations in
16% of those sequenced; this constitutes a substantial
enrichment over the ~1% prevalence of these mutations
among unselected type2 diabetics59. Prospective studies of CRP to identify HNF1AMODY will be needed
to evaluate its clinical utility and cost-effectiveness,
but this initial work provides strong evidence for the
value of this GWAS-defined biomarker in distinguishing these patients and in directing them towards more
effective modes of treatment62. It is imaginable that other
biomarkers related to disease subtypes particularly
metabolic conditions in which a specific gene product
affects a measurable metabolite in specific ways could
lend themselves to rapid translation and improvedcare.

Drug development. Genetic variants related to drug

response are likely to have largely escaped the negative
selection pressures that act to suppress both allele frequencies of large-effect variants and effect sizes of common variants. This is in part owing to the recent and
selective entry of modern therapeutic agents into any
given persons environment. Pharmacogenetic variants
may thus be more amenable to the GWAS discovery
approach with its focus on common variants, as demonstrated by the common variants recently identified as
being associated with anaemia induced by the antiviral
agent ribavirin in the treatment of hepatitisC63.
Hepatitis C is a common chronic viral infection and
a major cause of severe cirrhosis that results in the need
for liver transplant 64. Pegylated interferon plus ribavirin is the treatment of choice, but treatment can be
complicated by ribavirin-induced haemolytic anaemia,
which can be dose-limiting; dose reduction significantly
reduces rates of viral clearance and treatment response65.
A GWAS of quantitative change in haemoglobin levels
during ribavirin treatment in hepatitis C identified several associated SNPs at genome-wide significance levels63.
One of the genes implicated inosine triphosphatase
(ITPA) encodes an enzyme that hydrolyses inosine
triphosphate (ITP). Several ITPA variants are known to
produce ITPA deficiency, which is a benign red cell enzymopathy that leads to accumulation of ITP in red cells
and increased toxicity of purine analogue drugs, such as
mercaptopurine63. This makes ITPA a strong biological
candidate, and a database search for known variants identified a missense variant (rs1127354) and a splice variant
(rs7270101) that have been validated as being functional
variants in patients with ITPA deficiency 65.
The presumed mechanism of ribavirin-induced anaemia is depletion of guanosine triphosphate (GTP), leading
to reduced ATP biosynthesis and loss of ATP-dependent
oxidative metabolism66. The ITPA deficiency induced
by these two functional variants causes accumulation
of ITP in red cells, where it can substitute for guanosine triphosphate (GTP) in the biosynthesis of ATP via
adenylosuccinate synthase, thereby restoring ATP production. Although ITPA deficiency in the absence of
ribavirin is associated only with benign elevations in red
cell ITP levels, when ribavirin is present, these elevations
can provide the substrate needed to avoid haemolysis66.
Elucidation of the mechanism by which lossoffunction
ITPA variants protect against ribavirin-induced anaemia
points not only to a potential biomarker of this adverse
treatment response but also to possible novel therapeutics
to avoid ribavirin-induced anaemia in patients without
these protective variants66. Such therapeutics have yet to
be developed, but pharmacological inhibition of a gene or
gene product, in this case ITPA, is often easier than other
forms of therapeutic manipulation.
It is notable that these two functional variants were
found almost exclusively on chromosomes carrying the minor allele of rs6051702, with which they are
in strong linkage disequilibrium (r 2=0.65), and that
they entirely explain the association signal detected for
rs6051702 and the other genome-wide-significant SNPs
in the region63. This again demonstrates the power of

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Cumulative percentage of patients who have had a myopathy

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20

15

CC genotype
CT genotype
TT genotype

10

Years since starting 80 mg of simvastatin

Figure 5 | Risk of myopathy in chronic simvastatin use. Estimated

cumulative
risk
Nature Reviews
| Genetics
of myopathy associated with high-dose simvastatin by solute carrier organic anion
transporter family member 1B1 (SLCO1B1) rs4149056 genotype. The figure is modified
from REF.71 (2008) Massachusetts Medical Society.

the GWAS approach, in which a common SNP (MAF

for rs6051702=19%) tags less common functional variants. It also demonstrates the large effect sizes that may
be detected for pharmacogenetic variants, as the combination of these two functional alleles explained 1929%
of the variability in haemoglobin decline across three
major ethnic groups63. The potential clinical applications of these recently identified associations and causal
relationships in prognostication and drug development
have yet to be explored, but they could be substantial.
As the genetic basis of action and toxicity of other drugs
becomes better understood through GWAS of treatment
response and other techniques, it might be anticipated
that similar lossoffunction variants could be attractive
targets for pharmacological manipulation to avoid or to
reduce toxicity.

Rhabdomyolysis
The rapid breakdown of
skeletal muscle tissue due
to injury, drugs, toxins or
metabolic disease. This leads
to electrolyte release and high
concentrations of myoglobin in
plasma and urine that are toxic
to the kidneys and can cause
renal failure and death.

Methotrexate
A folic acid antagonist used
as a chemotherapeutic and
immunosuppressant drug.

Drug toxicity. Pharmacological inhibitors of 5hydroxy3methylglutaryl coenzyme A (HMG-CoA) reductase,

collectively known as statins, are the most effective
known agents for reducing low-density lipoprotein cholesterol and are widely and increasingly prescribed67. An
important adverse effect of these drugs that can lead to
non-adherence to therapy is myopathy, which is characterized by muscle pain that occurs in 15% of treated
patients68,69, weakness and elevated muscle enzyme levels. Rarely, this myopathy can progress to rhabdomyolysis,
renal failure and death. The mechanism is poorly understood and may involve induction of pro-apoptotic pathways or immune-mediated necrotizing myopathy 70. Risk
is increased with advanced age, low body mass, higher
doses, concomitant drug administration and conditions
that interfere with hepatic metabolism. Risk of myopathy

is highest with simvastatin, which is the most commonly

prescribed member of this drug class and the third most
commonly prescribed drug in the United States in 2010
(REFS69,70).
In 2008, a GWAS was carried out for 85 patients
with myopathy and 90 matched controls from the
12,000patient-strong Study of the Effectiveness of
Additional Reductions in Cholesterol and Homocysteine
(SEARCH) trial. This study detected an association
with a single non-coding SNP in solute carrier organic
anion transporter family member 1B1 (SLCO1B1; which
encodes an organic anion transporting polypeptide
(OATP1B1) that has been shown to regulate the hepatic
uptake of statins)71. This non-coding SNP is in nearly
complete LD with a nonsynonymous SNP (r 2=0.97)
that encodes a valine-toalanine substitution and that
confers a 4.5fold increased risk of myopathy per copy
of the minor C allele (FIG.5). This variant and others in
this highly polymorphic gene have been demonstrated
to reduce hepatic uptake and to increase serum levels of
statins7174. Observed areas under the concentration time
curve, which is a measure of invivo simvastatin exposure,
are 2.2fold greater in rs4149056 CC homozygotes compared with TT homozygotes69. Roughly 25% of the population carry the C allele, either alone or in combination
with other SLCO1B1 variants, all of which appear to affect
simvastatin levels similarly. The effects of these variants
differ quantitatively across the seven clinically available
statins and are greatest for simvastatin75. Although myopathy risk is strongly dose-dependent, the effect of dose
also appears to be greatest for simvastatin.
Interestingly, GWASs have also shown SLCO1B1
variants to be associated with reduced clearance of
methotrexate and increased gastrointestinal toxicity in
children with acute lymphoblastic leukaemia76,77. Here
again effect sizes are large: SLCO1B1 variants explain
10% of methotrexate clearance (only dosage regimen
explained more) and carry a 15fold increased risk of
toxicity. GWASs have also shown SLCO1B1 variants to be
associated with bilirubin levels78, presumably reflecting
the role of this transporter in hepaticuptake.
Guidelines for managing simvastatin-induced myopathy risk in the context of SLCO1B1 genotyping have
recently been published69. Although genotyping is not
currently required in conjunction with treatment, it is
commercially available as a single assay or in combination with other pharmacokinetic variants (see The
Pharmacogenomics Knowledgebase). Heterozygotes
for the C allele are expected to have an intermediate
activity phenotype and to be at intermediate risk of
myopathy, whereas homozygotes have low activity and
are at highest risk (although other variants, concomitant drugs and other factors may modify these expectations). The Clinical Pharmacogenomics Implementation
Consortium has recommended dose reductions or alternative therapy in C allele carriers69. Serial monitoring of
muscle enzymes in CC homozygotes may be beneficial
even at lower doses, although this remains to be proved69.
With the availability of clinical guidelines, genotyping
of SLCO1B1 before initiating simvastatin therapy will
probably gain broader clinical usage. Pilot studies are

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REVIEWS
Table 1 | Characteristics of GWAS findings that make them readily translatable to clinical care
Application

Key characteristics

Example

Risk prediction

Heritability is high

T1DM loci

Large proportion of heritability is explained

Genotyping can be targeted to high-risk group (such as that defined by
positive family history)
Genotyping scores substantially increase predictive value
Early detection is important
Preventive strategies are available
Disease subtyping
or classification

Clinical syndrome has multiple subtypes with varying prognosis or

response to treatment aetiologies

CRP (or HNF1A

typing) for MODY

Subtypes are not readily discernible by clinical examination

Compared to other indicators, assay of biomarker (genetic or non-genetic)
is easier, cheaper, more available, more reliable and more sensitive
Subtyping affects treatment selection
Subtyping identifies increased risk in family members
Drug development

Loss of function variants have a useful biological effect

ITPA variants and

ribavirin toxicity

Drug toxicity

Variants are common

SLCO1B1 variants
and statins

Effect sizes are large

Alternative drugs or increased monitoring are available

CRP, C-reactive protein; GWAS, genome-wide association study; HNF1A, HNF1 homeobox A; ITPA, inosine triphosphatase;
MODY, maturity-onset diabetes of the young; SLCO1B1, solute carrier organic anion transporter family member 1B1; T1DM, type 1
diabetes mellitus.

Decision support tools

Software tools providing
intelligently filtered and
appropriately timed medical
information specific to a given
patient to aid in clinical
decision making at the point
of care. Examples include
computerized alerts of
potential adverse effects of
a proposed treatment or
reminders of overdue
screening tests.

underway to examine effective modes of implementation, acceptance by clinicians and patients, and impact
on adherence and lipid-lowering efficacy 69. It is an
instructive example because the genetically mediated
risk is not readily identified by other means, the variants are common and the effects are large, and treatment
modifications in the form of increased monitoring or
alternative therapy are available. What remains to be
tackled before implementation can be effective is wider
availability of clinically licensed testing, more compelling
evidence of efficacy and smoother integration of pharmacogenetic information into clinical decision making.
Smoother integration is probably best achieved through
integration with electronic medical records and decision
support tools that alert clinicians when they are about to
prescribe simvastatin in a patient at genetically increased
risk of myopathy 69. Such tools are currently under development and testing and are likely to be adaptable to a
host of pharmacogenetic indications.
This SLCO1B1 finding demonstrates that GWASs
for treatment response are powerful approaches for
identifying variants signalling increased risk of adverse
effects and that these variants may become indications
for closer monitoring or alternative therapies. Another
interesting recent example is in erectile dysfunction following radiation therapy, in which initial models suggest that GWAS-defined SNPs substantially increase
the AUC for predicting this common side effect of
treatment79. Similarly, a recent report of antipsychoticdrug-induced extreme weight gain associatedwith melanocortin 4 receptor (MC4R) variants may also point the
way towards alternative treatments80.

Other findings on the horizon. This Review focuses on

indepth exploration of fairly mature and illustrative
examples of GWAS findings that are ready for translation
in four specific areas, but several others that are under
development are likely to be applied soon. Findings on
the clinical horizon that relate to risk prediction include
recent reclassification studies in breast cancer 81 and
osteoporotic fractures82, demonstrating increased discrimination of clinical risk with the inclusion of genomic
markers. These findings are similar to those discussed
earlier for coronary disease, whereas predictive models
incorporating GWAS findings are now being formally
tested for their impact on coronary-disease-related
outcomes in a randomized clinical trial83. Other cogent
examples of GWAS findings in risk prediction include
complement-related variants in predicting macular
degeneration5 and APOL1 variants predicting hypertensive renal disease84,85. Given the limitations of genomic
risk measures in the prediction of almost all diseases
except type1 diabetes, in the short term, predictive variants are likely to be used to identify people at particular
genetic risk for targeting or intensifying interventions
proven effective in diseasecases.
In the area of disease classification and subtyping,
GWAS findings have recently been used to develop more
refined molecular taxonomies for breast cancer 86, lung
cancer 87 and inflammatory bowel disease88. More recent
GWAS-augmented efforts that relate to drug development include IL23R inhibition, which has been identified as a potential therapeutic strategy for inflammatory
bowel disease through examination of LD patterns in
some of the earliest GWAS38. Further, because IL23R has

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REVIEWS
multiple variants, some associated with increased risk
and some with decreased risk, identification of specific
variants in a given patient may eventually be useful in
determining the appropriateness of IL23specific therapy.
Complement-related findings are also being therapeutically explored for macular degeneration89. In the area of
drug toxicity, the GWAS approach has recently been used
to identify variants predisposing to paclitaxel-induced
peripheral neuropathy 90 and aspirin-exacerbated respiratory disease91. Additional clinical applications are
expected as the thousands of GWAS results from the past
7years are more deeply explored and as additional GWAS
are conducted. As genomic approaches to clinical care
become more commonplace and disseminate beyond
major medical centres92,93, it may be expected that the
pace of identifying clinically relevant GWAS findings and
translating them to the clinic will accelerate.

Conclusions: pathways to translation

These four examples in risk prediction, disease classification, drug development and drug selection demonstrate the potential for rapid application of selected
GWAS findings in clinical care. Finding unifying characteristics among these four that promote successful
translation is challenging (TABLE1). Indeed, translational
potential may be driven as much by the clinical scenario
(such as importance of early detection, availability of
alternative treatments and accessibility of genotyping) as
by the variants involved or the relevant genetic architecture. The examples cited here tend to share some characteristics, such as moderate allele frequencies and large
effect sizes, but these may be more important in permitting initial identification of the association than for its
translation. The HNF1AMODY variants, for example,
have low allele frequencies, whereas allele frequency

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would largely be irrelevant were an effective treatment

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A key component in translating GWAS findings is
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Competing interests statement

The authors declare no competing financial interests.

FURTHER INFORMATION
1000 Genomes Project: http://www.1000genomes.org
Illumina products for whole-genome genotyping and copy
number variation analysis: http://www.illumina.com/
applications/detail/snp_genotyping_and_cnv_analysis/
whole_genome_genotyping_and_copy_number_variation_
analysis.ilmn
The Pharmacogenomics Knowledgebase: http://www.
PharmGKB.org
National Human Genome Research Institute (NHGRI)
Catalog of Published Genome-Wide Association Studies:
http://www.genome.gov/gwastudies
Nature Reviews Genetics Series on Genome-wide association
studies: http://www.nature.com/nrg/series/gwas/index.html
Nature Reviews Genetics Series on Translational genetics:
http://www.nature.com/nrg/series/translational/index.html
Type1 Diabetes Consortium: https://www.t1dgc.org/
home.cfm
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