Download The use of the twin model to investigate the genetics and

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DOI: 10.1111/j.1468-3083.2011.04444.x
REVIEW ARTICLE
The use of the twin model to investigate the genetics and
epigenetics of skin diseases with genomic, transcriptomic
and methylation data
V. Bataille,†,‡,* M. Lens,† T.D. Spector†
†
Twin Research and Genetic Epidemiology Unit, Kings College, London SE1 7EH, UK
Dermatology Department, West Herts NHS Trust, Herts, UK
*Correspondence: V. Bataille. E-mail: [email protected]
‡
Abstract
Twins have always fascinated medical research even before the discovery of DNA and the understanding of the
differences between identical and non-identical twins. Dermatology with the benefit of being able to visualize
phenotypes was one of the first specialities reporting on the fascinating concordance in identical (MZ) twins in the
1920’s. Over the last 20 years, the heritability of skin diseases using twins has been clearly demonstrated, across a
wide variety of traits including melanoma, polymorphic light eruption, psoriasis, eczema and acne. Other rarer
diseases have also been shown to have a significant genetic basis such as lupus, sarcoidosis and lichen sclerosus.
Following evidence of heritability for many skin disease the next step was Genome-Wide Association Studies
(GWAS) which are uncovering new genes in large twin cohorts. The twin model is also ideal for the new field of
epigenetics, investigating subtle differences in DNA methylation within discordant MZ pairs for a disease, as well as
differences in CNVs. Twins are also valuable for examining differences in gene function via RNA expression in twins
discordant for a skin trait or disease.
Received: 22 July 2011; Accepted: 16 December 2011
Conflict of interest
None declared.
The twin model
The twin study model has always been based on the comparison
of monozygotic (MZ) twins who share almost 100% of their DNA
sequences with dizygotic (DZ) twins who share on average 50% of
their genetic polymorphisms. Although it is now apparent that
MZ twins do not always have completely identical DNA
sequences. These minor differences between identical twins are not
really affecting the heritability estimates in the sense that one can
estimate the relative influence of genetic factors on a disease. Twin
studies allow estimating heritability by comparing concordance of
a disease or trait between MZ and DZ pairs. Path analyses in the
1990s allowed to dissect several components of the variance for a
trait or disease to estimate the relative contribution of genetic,
shared and unique environmental factors on the variance.1 Many
complex traits or diseases have a heritability of roughly 50–80%,
meaning that 50–80% of the variance in the liability to the trait or
diseases can be explained by genetic factors. The rest of the variance is explained by shared family environment and unique environmental factors. However, even for very heritable traits, MZ
twins are often discordant for diseases. Progress made in high
throughput genotyping, transcriptomics, methylation studies and
RNA sequencing are now showing that some of the unexplained
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genetic effect may be explained by epignetic processes that do not
alter DNA sequence, but alter transcription or expression of proteins. Again, twins have proven to be invaluable to examine these
epigenetic effects, as MZ twins with the same DNA sequence can
be compared for epigenetics differences explaining trait or disease
discordance.
Twin studies in dermatology
Dermatologists have an important place in twin research as they
were the first to report on the similarities in many skin traits
including naevi in MZ twins. Herman Werner Siemens, a German
dermatologist, was one of the inventors of the twin study design.
In 1924, he published ‘Zwillingspathologie’ (Twin Pathology) and
introduced the widely used ‘classical twin method’.2 Siemens
reported higher concordance in naevus counts in MZ twins compared with siblings amongst many other dermatological traits.
Already in the 1920s, he commented ‘twins of one egg origin will
be of immense value for geneticists and psychologists’. Siemens’
work was very instrumental in highlighting the scientific value of
MZ and DZ twins with very detailed collection of various skin
phenotypes, well before DNA was discovered. Twin experts recognize the contribution of Siemens in discovering the twin model
ª 2012 The Authors
Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology
Bataille et al.
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Table 1 Heritability estimates in skin
Heritability (%)
Reference
Freckle counts
91
9
Varicose veins
86
45
Polymorphic light eruption
84
43
Acne
81
31
Androgenic alopecia (female)
80
44
Naevus counts below age 45 (UK)
36
9
Naevus count above 45 years (UK)
84
9
Naevus counts in adolescents (UK)
65
10
Naevus counts in adolescents
(Australia)
68
8
Eczema (adults)
61
23
Eczema (children)
90
28
Psoriasis
66
36
that we still use today.3 In the following 50 years from the discovery of the twin model, studies were mainly focused on behavioural
traits and psychiatric diseases. Not until the 1980s, twin studies
restarted to look at non-behavioural traits and common diseases.
Several teams have collected very large and well documented twin
datasets including the UK Twin Registry (TwinsUK cohort), the
Netherlands Twin Registry (NTR), the Queensland Twin Registry
as well as national twin registries in Sweden, Denmark and
Finland4–6 (Table 1).
Figure 1 Similar naevus types and distribution in a pair of MZ
twins.
Naevi
Siemens was the first one who tried to determine the role of genes
over environment in for the appearance of naevi. In 1991, almost
seventy years after the reports by Siemens, a UK research group
published the results of the study examining the concordance of
naevus counts in 23 MZ and 22 DZ twin pairs.7 This study demonstrated a higher concordance in the number of common naevi
in MZ twins compared with DZ twins, which suggested that total
naevus count has a strong inherited basis. In 1999, the Queensland
Twin Registry reported a significantly higher concordance for naevus counts in 153 MZ adolescent twins (0.94) compared with the
concordance observed in 199 DZ twins (0.60).8 Analysis of linkage
to a highly polymorphic marker D9S942, located adjacent to
CDKN2A gene, a detected quantitative-trait-loci (QTL) effects
accounting for 27% of variance in total naevus count. Longer
alleles at D9S942 were associated with flat naevi, but not with
raised naevi. In 2000, the UK Twin Registry reported on the heritability of naevus counts based on 127 MZ twin pairs and 323 DZ
twin pairs: the intraclass correlation for total body naevus counts
was 0.83 in MZ twins compared with 0.51 in DZ twins9 (Fig. 1).
Using quantitative genetic analyses, this study showed the importance of age. The contribution of additive genetic factors on naevus count increased significantly with age, with more than 80% of
the variance on naevus attributed to genes in twins aged 45 years
or over compared with only 36% in those aged less than 45 years.
Freckle counts were also highly heritable in the same study
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Figure 2 Freckle counts and photoageing in MZ twins.
(Fig. 2). In 2005, another UK twin study examining gene–environment interactions for nevi was published included 103 MZ and
118 DZ twin pairs from Yorkshire and Surrey using the same protocol as in the large Australian study conducted by Zhu et al.8
and10 Correlations in nevus density were higher in MZ pairs
(0.94) than in DZ pairs (0.61). The reported heritability of 65%
for total body naevus counts in the UK adolescent twins was comparable to the 68% heritability reported for the Australian adolescent twins.
The number of naevi decrease with age which is one of the most
important confounders in naevi studies. Why naevi undergo a
senescence process remains unknown, but studies investigating
ª 2012 The Authors
Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology
Twins in genetics of skin diseases
senescence in melanocytes have shown that patients with an excess
of naevi have a delayed senescence in vitro.11 This finding suggests
that different genes may have an effect on the appearance of naevi
in early adulthood compared with the senescence process which
occurs from the age of 40 years onwards. It has been observed
clinically that the senescence of naevi appears to be delayed in
patients with multiple atypical naevi, especially in those belonging
to susceptible melanoma families. The individuals with multiple
atypical naevi also appear to have delayed photoageing with less
solar elastosis and a lower prevalence of solar keratoses (VB personal observation). The UK Twins Registry already looking at the
genetics of ageing took the opportunity to investigate whether an
excess of naevi may be a marker of delayed ageing. A study of
1897 twins on whom white cell telomere length data were available
was performed to establish the correlation between telomere
length and naevus counts.12 Telomere length is regarded as a surrogate biological clock, as it slowly decreases with age until the cell
undergoes apoptosis. The speed at which this process occurs is in
part genetic.13 Naevus counts were found to be positively correlated with telomere length.12 Longer telomeres were observed in
twins with an excess of naevi compared with those with few naevi.
This equates to roughly 6 years of chronological ageing between
twins with more than 100 naevi compared with those having less
than 25 naevi. These findings suggest that the delayed senescence
observed in melanocytes in patients with a large number of naevi
may not be melanocyte-specific and may also affect other cell
types. This may also explain why patients with an excess of naevi
have delayed photoageing. Another study from the same group
reported that twins with an excess of naevi have higher Bone
Mineral Density (BMD) and are relatively protected against
osteoporosis than those with few naevi. The results from this study
support the hypothesis that the reduced ageing in these individuals
affects other systems.14
The increased heritability of an ageing phenotype with increasing age is supported by studies of longevity using twin models.
These studies show that the genetic influence on longevity
increases with age. The chance of reaching old age is becoming
more concordant in MZ pairs with age (vB15). Genetic influences
on lifespan are minimal prior to age 60, but increase thereafter
(vB15). The Department of Twin Research & Genetic Epidemiology at Kings’ College in London, UK, will use telomere length
assays and transcriptome sequencing integrated with genome-wide
association studies in a systems genetics framework to infer causal
interactions between telomere length, skin ageing and naevus
counts. (EuroBATS project). These unique datasets will provide
novel insights to ageing process.
In contrast to naevi, cutaneous melanoma, like many other
cancers, is not highly heritable. Part of this difference may be
methodological, because the naevus as an intermediate phenotype
is a continuous trait, whereas cancer is a dichotomous trait and
rarer, and so, more difficult to study in very large numbers. The
Finish Twin Cohort, as a population-based study, suggested that
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environmental and not hereditary effects are most important in
the development of cutaneous malignancies.16 In 2009, the
Queensland Twins Registry published results of a twin study
determining the proportion of genetic and environmental factors
influencing variation in liability to melanoma.17 Melanoma concordance was higher in MZ twins (4 of 27 pairs) than in DZ twins
(3 of 98 pairs). MZ twins with a co-twin with melanoma were 9.8
more likely to have melanoma than a DZ pairs, where the risk was
only 1.8. This study estimated that 55% of the variation in liability
to melanoma was due to genetic influences.
With the advances in high throughput genotyping, twin data
have now led to valuable genome-wide analyses due to large and
well phenotyped cohorts. The UK Twin Registry published the
first genome-wide linkage analysis on naevi counts in 2006 using
700 markers along the whole genome.18 This study identified
regions linked to total body naevus counts on chromosome 9p21
and 5q31. In 2007, the Queensland Twin Registry reported linkage
to regions on chromosome 2, 9, 8 and 17 for flat naevi using 796
microsatellite markers across the genome.19 In 2009, the UK Twin
Registry published a genome-wide association study on a much
denser marker set of over 300 000 markers using the Illumina Hap
300K duo Chip. A genome-wide association study looks at possible associations between half a million genetic markers across the
whole genome and a disease and a trait. This led to the discovery
of two new naevus genes, MTAP on chromosome 9p21 close to
the CDKN2A locus and PLA2G6 on chromosome 22q13.20 These
two genes were also found to be melanoma genes and were replicated in two case-control melanoma studies in the UK and Australia, respectively, as well as in melanoma families from the
Genomel Melanoma Consortium.20,21 MTAP has already been
implicated in other cancers such as pancreatic cancer, which is
found to cluster in some melanoma families. The fact that MTAP
lies close to the CDKN2A raises the question of possible interactions between these two genes. They appear to often be deleted
together in many cancers, but MTAP has also been reported to
act as an independent tumour suppressor gene. PLA2G6 has
been shown to be involved in cell growth and apoptosis in various
cancers.20
Eczema
Eczema has also been investigated using the twin model. A population-based study conducted in Denmark involving 812 twin
pairs showed that the concordance rate of atopic dermatitis was
0.72 in MZ and 0.23 in DZ twin pairs.22 The atopic phenotype is
associated with increased IgE levels. In a study including 340 MZ
and 533 DZ British adult female twins, Strachan et al.23 found that
IgE levels were under significant heritable control with 60% of the
variance explained by genetic factors. However, MZ twins are
often discordant for atopic disorders, and so gene–environment
interactions or geneti ⁄ epigenetic differences may explain discordant MZ pairs. In a study of 1480 Swedish twin pairs (7–9 year
old), Lichtenstein and Svartengren24 showed that 39–76% of the
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Journal of the European Academy of Dermatology and Venereology ª 2012 European Academy of Dermatology and Venereology
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liability to eczema was due to genetic factors. In 2005, a
Norwegian study based on 3334 twins aged 18–35 years reported a
concordance of 54% for eczema and itch.25 In a population-based
study, Lerbaek et al.26 showed that 41% of the variance in hand
eczema in more than 4000 twins can be explained by genetic
factors. Thomsen et al.27 published the results from a large twin
study based on more than 11 515 twins in Denmark showing a
heritability of 82% for atopic dermatitis with a sevenfold increased
risk of atopic dermatitis for a co-twin of an MZ pair compared
with a threefold increase for a co-twin of a DZ pair. The highest
heritability estimate for eczema (approximately 90%) was reported
in a study enrolling 8633 twins in Holland.28 A very high contribution of genetic factors in the pathogenesis of eczema found in
this study may be explained by the fact that the twins were young
children, and in children, it is possible that the environmental differences on the expression of the diseases may be less significant.
Multicentre genome-wide association studies (GWAS) on eczema
are currently under way.
Acne
Acne was first studied using the twin model in 1984 in a study
including 930 twin pairs in the USA.29 A twin study was conducted in the UK measured sebum excretion and acne scores in
adolescent twins and found a higher concordance of sebum excretion in MZ twins compared with DZ twins.30 In a large twin study
enrolling 458 pairs of MZ and 1099 pairs of DZ twins, Bataille
et al.31 showed that acne is one the most heritable skin phenotypes
with 81% of the variance in acne liability explained by additive
genetic factors. Hormonal factors, reproductive factors, BMI, glucose levels and lipids were not found to be associated with acne.
Acne is also a symptom of the Polycystic Ovary Syndrome
(PCOS). The Netherlands Twin Register study including 1332 MZ
and 1873 DZ twins showed that this syndrome is also influenced
by genetic factors with a concordance for PCOS of 71% in MZ
twins compared with 38% in the DZ twins.32 The UK Twin Registry has conducted a GWAS in twins with acne, but so far, no obvious hits have been reliably identified. The power of the study was
an issue, as only several hundred cases were available compared
with several thousand controls. A larger acne case-control–GWAS
study based in the UK is underway, and the results are awaited.
Psoriasis
Many anecdotal case reports on the higher concordance for psoriasis and psoriatic arthritis in MZ twins were published in the literature since the 1950s. In 1978, a study based on MZ twins in
Denmark not only showed that 18 of 32 MZ pairs were concordant for psoriasis which supports a genetic influence but also
highlighted the issue of discordance of psoriasis in MZ pairs.33
The Queensland Twin Registry reported a concordance of 35% for
psoriasis in MZ twins compared with 12% in DZ pairs.34 A study
of psoriatic arthritis in 228 affected twins showed a higher concordance for the disease in MZ twins compared with DZ twins.35
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Grjibovski et al.36 found that the heritability for psoriasis was 66%
in more than 8000 twins in Norway. Data from this study showed
that zygosity and gender did not affect the disease prevalence
reported at 4.2%. Zhang et al.37 conducted the first large GWAS
study to identify susceptibility variants for psoriasis. Using a twostage case-control design 1139 cases and 1132 controls were
included with a replication set of 5721 cases and 7340 controls.
They reported strong replication for two known susceptibility loci,
MHC and IL12B, and identified a new susceptibility locus within
the LCE gene cluster on 1q21. The most significant finding of
another GWAS, carried out in the USA, with 1359 cases and 1400
controls, was SNP rs12191877, which is in tight linkage disequilibrium with HLA-Cw*0602, the consensus risk allele for psoriasis.38
Other skin diseases
Many skin diseases including very rare ones have been reported to
be more correlated within MZ twins compared with DZ twins,
and these include sarcoidosis, lupus, lichen sclerosus and atrophicus, albinism, vitiligo, Netherton syndrome amongst many.39–42
Polymorphic light eruption has also been shown to be under significant genetic influence with heritability of 84%.43 The UK Twin
registry in collaboration with other groups identified new genes
for male pattern baldness and female hair thinning.44 The same
research group also found that the development of varicose veins
is highly genetic with heritability of 86%.45
The future of the twin model
Missing heritability
Genetic studies of many common diseases have benefited from the
twin model with heritability studies and pathways analyses. More
recently, GWAS of well phenotyped twin cohorts have uncovered
new genes and new pathways. Whilst it is clear that GWAS do not
need to rely on the twin model, the collection of large twin datasets with varied and detailed phenotypes has led to very valuable
twin cohorts with genotypes. The hundreds of novel variants published over the last few years prove that GWAS do deliver. However, the GWAS studies published so far do not provide clues to
the source of the vast majority of the genetic variance for these
common disorders.46 The question in the last 2 years in genetics
has therefore been ‘where is the missing heritability?’.47 More than
500 GWAS have been carried out to date reporting on hundreds
of SNPs associations, but cannot explain more than a small
percentage of the genetic effect. For example, genes for naevi and
melanoma have been discovered with the recent GWAS, but they
only explain a small proportion of the variance in naevi and melanoma susceptibility. With a few exceptions such as macular degeneration, few diseases have explained more than 10% of the
variance despite large studies including thousands of patients.
There is still a large part of the heritability missing. This may be
explained in part by common variants that are not detected by the
current GWAS, as these may be in even greater number with even
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lower effects, therefore needing higher number of cases and
controls to produce some hits. More recent GWAS for height
and weight have exceeded 150 000 patients, and these studies
still explain less than 14% of variance for these two traits with
hundreds of genes. Alternatively, there may be many rarer variants
with moderate effects that will not be picked up by the current
GWAS. Sequencing is a likely next step, which can accurately
detect variants in the range of 0.1–10%, which, although currently
expensive (over $ 2000 per person), is reducing in price rapidly.
Several twin cohorts, including the TwinsUK, will have whole genome sequence within the next year.
Epigenetics
Epigenetics looking at methylation and histone modification is
now a rapidly moving area of research in the genetics of complex
traits. These epigenetic changes affect transcription and hence disease expression. The twin model has an invaluable role in epigenetic research that is reviewed in details elsewhere.47 Another
DNA variation which is structural so by definition not epigenetics
is the presence of CNVs. CNVs are stretches of DNA, tens or hundreds of base pair long, that are either deleted or duplicated and
vary between individuals. CNVs could possibly explain part of the
missing heritability, as they go undetected in GWAS, because they
do not alter DNA sequences. Techniques such as comparative
genomic hybridization can identify CNVs by hybridizing DNA to
microarrays. The small CNVs from 2 to 50 m base pairs will
always be very difficult to pick up and may also alter disease
expression. However, recent studies suggest that common large
CNVs are, with the exception of neuropsychiatric diseases, less
important in complex traits than previously thought.48,49 CNVs
could be responsible for the discordance observed in MZ twins for
some diseases including cancer, but this is still only supported by
anecdotal case reports only.50,51 A very recent study looking in
detail at three discordant identical twin pairs for multiple sclerosis
has shown that DNA sequence, CNVs, RNA or methylation status
did not differ significantly within the three pairs.52 The only difference was in allelic imbalance that can only be detected with allelic
specific expression. Recent studies show that many different techniques will be needed to fully elucidate the discordance for many
diseases in MZ pairs and help to unravel the complexities of gene
expression variations.
Twins are ideal to look at differences in DNA methylation profiles between MZ and DZ pairs. Kaminsky et al.53 conducted DNA
methylation analysis in white cells, buccal and gut epithelial cells
in 114 MZ and 80 DZ twins. It appears that DNA methylation differences within MZ and DZ pairs are the greatest at regions without clearly defined regulatory function compared with important
regulatory DNA regions, suggesting that there is a functional stratification of the epigenome. It is now thought that the difference
seen in concordance in MZ twins is more due to these epigenetic
differences rather than due to environmental differences per se.
Javierre et al.54 suggested that lupus discordance in MZ twins
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associates with changes in the pattern of DNA methylation. However, these epigenetic factors can themselves be influenced by environmental factors, and so it is difficult to fully dissociate. As
expected, the studies of DZ twins show more difference within
pairs for the rate of DNA methylation compared with MZ, and so,
the amount of methylation is partly heritable. The methylation
profiles are also tissue specific and, for example, were more pronounced in the buccal mucosa than white cells.53 So, it appears
that MZ can be more similar not only because of DNA sequence
but also because they originate from one zygote with similar epigenomic profile, whereas DZ originate from two zygotes with different epigenomic profiles. In the future, methylation studies will
have to be based on tissues rather than blood, as epigenetic events
appear to be tissue specific, and skin would be ideal as it is more
readily accessible. The Illumina 450K Infinium Methylation BeadChip is promising in allowing examination of more than 450 K of
methylation sites, and MZ pairs discordant for skin diseases or
traits would be ideal for these genome-wide methylation studies.
Another possible explanation for some missing heritability in
GWAS studies may be the definition of a trait or disease. By
assuming that all diseases are the same, for example, atopic dermatitis, and analysing them together in a GWAS looking for variants,
there may be some clinical subtypes with many different genetic
pathways, and this will lead to GWAS missing many variants
because of inaccurate definition of the disease or the phenotype.
Transcriptomics
Twins are also very useful to look at differences in expression profiles in different tissues by comparing these differences within MZ
and DZ pairs. Human regulatory variation is a very complex area
of research as gene expression is an important regulatory process
that determines proportion of the phenotypic difference. The twin
model helps to investigate MZ twins with identical DNA sequence
and assess expression profiles in various tissues. This is achieved
using microarrays and second generation RNA sequencing (RNAseq). The TwinsUK registry has already collected genome-wide
RNA data on more than 800 skin biopsies using the Illumina
whole genome expression array Human HT-12 version and the
data are currently being analysed (the MuTHER study, http://
www.muther.ac.uk). The skin expression data will be compared
with data on fat and white cells collected in the same patients.
Around 15 000 expressed genes were detected in the skin samples,
and at first glance, age is an important variable in the expression
profiles in skin samples.55 These studies are particularly helpful to
further investigate the results of GWAS studies. Some phenotypes
may only manifest themselves in one tissue especially in skin diseases, and therefore, studying the effect of genes on various tissues
in terms of significance and effect size is important. RNA
sequencing, as the next step, is now taking this further by identifying new putative coding exons, and allows us to investigate the
variation in transcription, splicing and allele specific expression
between individuals.56 The TwinsUK twin registry as part of the
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EU funded EuroBATS Consortium has just started RNA sequencing in skin fat and white cells, and these data will be correlated to
the extensive genotypic and phenotypic database already available.
Conclusions
Twins have always fascinated scientists, and to this day, with
recent progresses in high throughput genotyping, twin models are
still providing an invaluable resource to discover new genes and
understand how they work. Skin research has advanced with the
help of twins, as this has allowed us to realize the importance of
genetics on all common skin skin diseases, some of which may
have been ignored. Epigenetics is a new and fast moving area of
genetic research, and identical discordant twins may be more
informative than concordant twins, as they will shed more light
on aetiology. Skin being a readily accessible tissue has proven to
be very useful for transcriptomics, RNA sequencing and methylation studies that are currently under way. These studies are not
only likely to provide significant insights into skin diseases but also
will serve as a window to other less accessible diseases and tissues.
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