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Twin studies estimate the extent of the genetic and nongenetic contribution to a trait by comparing the similarity of monozygotic (MZ) and dizygotic (DZ) twins.

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    Type 1 Diabetes MellitusTwin StudiesAdverse Drug Reactions20.1.3 Predisposition to Adverse Drug ReactionsGenetics of PainDisadvantages of Twin Studies of Pain HeritabilityAdvances in asthma genetics2.1 Twin studiesUrolithiasis
    Twin StudiesGENETICS | Clinical Genetics of EpilepsyTwin StudiesGENETIC ASPECTS OF AFFECTIVE DISORDERS9.3.2 Twin studiesParkinson’s Disease; EpidemiologyTwin StudiesMedical Epigenetics and TwinsConclusionsThe Epigenetics of Autoimmunity: An Overview1.2.2 The Involvement of Nongenetic Factors in AutoimmunityWhy are identical twins often used in research studies?Why do researchers use twins to study heritability?What is the heritability of identical twins?Why are identical twins used when studying epigenetics?

From: Encyclopedia of Sleep, 2013

Type 1 Diabetes Mellitus

Shlomo Melmed MB ChB, MACP, in Williams Textbook of Endocrinology, 2022

Twin Studies

Twin studies of diabetes have made impressive contributions to our understanding of the disease. The study of monozygotic twins of patients with diabetes by Barnett and
coworkers74 contributed to the recognition of distinct forms of diabetes, initially termedjuvenile onset andadult onset, laterinsulin dependent andnon–insulin dependent, and now T1DM and T2DM. The concordance rates for monozygotic and dizygotic twins provide important information regarding genetic factors contributing to a given disease, because monozygotic twins share all germline-inherited polymorphisms or mutations, whereas dizygotic
twins are similar to nontwin siblings of patients with a disease and have only half of their genes in common. For a locus that contributes to disease in a recessive manner, only one quarter of dizygotic twins would be homozygous to a sibling with diabetes that locus, but all monozygotic twins would be homozygous for all recessive loci of their diabetic twin. As overall concordance rates of monozygotic twins for T1DM vary across studies, it is likely that T1DM is heterogeneous and that groups
of monozygotic twins have different genetic causes for their diabetes. With such genetic heterogeneity, one would expect different concordance rates for different genetic causes.

Redondo and coworkers75 analyzed prospective follow-up data from a large series of initially discordant monozygotic twins from the United Kingdom combined with a series from the United States. Progression to diabetes was identical for both series of
twins. There was no length of time of discordance beyond which a monozygotic twin of a patient with T1DM did not have a risk of developing the disease. Nevertheless, the hazard rate for development of diabetes decreased as the period of discordance increased. There was also a marked variation in the risk of diabetes relative to the age which the disorder developed in the index twin. With long-term follow-up, the overall rate of concordance for monozygotic twins exceeds
50%.72 However, if T1DM developed in the index twin after age 25 years, the concordance rate by life table analysis in the study of Redondo and coworkers75 was less than 10%. If diabetes developed in the index twin before age 5 years, the concordance rate was 70% after 40 years of follow-up. Therefore, environmental factors, random factors, and non–germline-inherited variations (e.g., imprinting, T-cell receptor polymorphisms, somatic mutations)
likely contribute to lifetime diabetes risk. Interestingly, studies of dizygotic twins suggest that their risk of diabetes may not differ from that of nontwin siblings or, most, may be increased by a factor of two as compared with the 10-fold increase for monozygotic twins.76

Genetic factors influence not only the development of diabetes but also the expression of anti-islet autoantibodies. For identical twins, the expression
of anti-islet autoantibodies is tightly linked to the eventual progression to overt diabetes, and, true to form, monozygotic twins have a highly concordant prevalence for the presence or absence of anti-islet autoantibodies. Dizygotic twins much less often exhibit concordant positivity for anti-islet autoantibodies, and the prevalence is similar to that of nontwin siblings.77

Adverse Drug Reactions

Lauren Walker, … Munir Pirmohamed, in
Handbook of Pharmacogenomics and Stratified Medicine, 2014

20.1.3 Predisposition to Adverse Drug Reactions

Predisposition, and thereby
susceptibility, to ADRs can be due to many factors, including age, gender, genetic variation, pathology, physiological variation, and environmental factors (Table 20.5). It is therefore important to evaluate ADRs on a case-by-case basis and evaluate the role of both environmental and genetic factors. It is difficult to estimate the quantitative contribution of genetic factors to ADRs, which is likely to vary among drugs.

Table 20.5. Sources of Altered Susceptibility to ADRs

Susceptibility VariableExamplesAge
Increased susceptibility to hepatotoxicity with flucloxacillina
Increased frequency of cutaneous adverse reactions among femalesb
Azathioprine-induced myelosuppression in patients with significantly reduced thiopurine methyltransferase (TPMT) activityc
Increased risk of lithium toxicity in patients with renal failured
Increased antiepileptic clearance among pregnant women with epilepsy associated with increased seizurese
Environmental factors
Consumption of grapefruit juice can affect bioavailability of numerous medications metabolized by CYP3A4 or transported by OATPf
aOlsson R, Wiholm BE, Sand C, et al. Liver damage from flucloxacillin, cloxacillin and dicloxacillin. J Hepatol 1992;15:154–61.bPistone G, Gurreri R, Alaimo R, et al. Gender differences in adverse drug reactions in dermatological patients in west Sicily: an epidemiological study [Epub ahead of print]. J Dermatol Treat 2013. doi:
:// Ref. [54].dMcKnight RF, Adida M, Budge, K, et al. Lithium toxicity profile: a systematic review and meta-analysis. Lancet 2012;379:721–8.eReisinger TL, Newman M, Loring DW, et al.
Antiepileptic drug clearance and seizure frequency during pregnancy in women with epilepsy. Epilepsy Behav 2013;29: 13–8.fPirmohamed M. Drug–grapefruit juice interactions. BMJ 2013;346:f1. Twin Studies

Twin studies are a valuable tool to assess the relative contribution of genetic and environmental
factors to variation in complex phenotypes, including drug response. Twin studies compare the similarity of a trait between monozygotic (MZ) twins who share 100% genetic identity and that of dizygotic (DZ) twins who on average share only 50% of the genome. It can be assumed that twins are raised in identical environments; therefore, any greater similarity of a trait shared between MZ twins compared to DZ twins can be attributed to genetics.

One of the first
twin studies to identify a pharmacogenetic phenotype for ADR involved the antituberculosis (TB) drug isoniazid. In a study comparing metabolism between five pairs of MZ and DZ twins, investigators showed that the metabolism of isoniazid was far less variable in the former than in the latter [13]. This was later confirmed to be due, least in part, to two distinct acetylation phenotypes (slow and rapid) that are determined by polymorphisms in the
N-acetyltransferase gene [14]. We now know that individuals who are “slow acetylators” are greater risk of toxicity with compounds such as sulphonamides and aromatic amine carcinogens, and with isoniazid, which leads to hepatic toxicity and peripheral neuropathy [15–17]. Twin studies with other drugs, including antipyrine, phenytoin, halothane, and phenylbutazone have all shown that genetic factors are the main determinants
of interindividual variation in metabolism [18]. However, in the majority of cases, it is likely that variability is multigenetic in origin and thus poses challenges in developing predictive tests [19].

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Genetics of Pain

Stephen B. McMahon FMedSci, FSB, in Wall & Melzack’s Textbook of Pain, 2013

Disadvantages of Twin Studies of Pain Heritability

Twin studies may provide estimates of heritability but do not in themselves reveal the genes responsible.
In complex disorders involving genes with small effects, one needs association studies, whose optimal design may be different. (However, one may certainly genotype DZ twins and use their data in association studies.)

Twin studies are impractical for the study of phenotypes elicited only by an uncommon disease or traumatic sự kiện that is unlikely to occur in both twins, such as
post-surgical pain syndromes, post-herpetic neuralgia, or spinal disc herniation with spinal root pain. Consider, for example, the study listed inTable 10-3 for sciatica (Heikkila et al 1989). More than 9000 twin pairs were studied with a survey and examination of hospital records. The 269 pairs in which both subjects reported a medical diagnosis of sciatica any time in their life was sufficient to compare concordance in MZ and DZ twins and estimate
heritability as 20%. However, if the more severe criterion of hospital admission was used, only eight pairs had both suffered sciatica, which is insufficient for a comparison. Furthermore, patient recall of hospital admission for sciatica after 1 or 2 decades was often inaccurate. Forty-one percent of patients 60 years and older who had a hospital discharge summary of sciatica did not recall this the time of the survey.

In the twin
studies of clinical pain disorders listed inTable 10-3, one cannot distinguish whether the heritability component reflects genetic effects on development of the structural disease causing pain, on processing of pain from a given lesion, or both. This can be sorted out only if one can measure the magnitude of structural injury the time that the pain is occurring, which is particularly difficult if the disorder strikes members of the twin pair different times. It may be possible
to address these issues in twin registries that include access to hospital records and imaging studies of osteoarthritis, spinal degeneration, or other disorders routinely assessed with high-resolution imaging methods.

Critics of the classic MZ–DZ design point out a flaw in the model’s assumption that MZ twins and DZ twins have similar variance in their environment. Because MZ twins look so much like each other, people are likely to
treat them similarly in many ways; for example, parents often dress them identically. Such environmentally driven inflation of the VDZ term will spuriously increase the value ofh2 in the equation presented earlier.

Advances in asthma genetics

Mayank Bansal, … Anurag Agrawal, in Advances in Genetics,

2.1 Twin studies

Twin studies of a disease, help in understanding both the genetic and environmental effects on a disease. The concept of the twin studies originates from the fact that Monozygotic (MZ) twins share not only their genetic makeup but also most of the environment, whereas Dizygotic (DZ) twins share only about half of their segregating genes. Consequently, the phenotypic differences seen in
MZ twins are generally only due to the environment not shared by them, whereas those in DZ twins are both due to the nonshared environment as well as the genome. Results from twin studies could be quantitated by variables, by calculating the coefficient of variance which is a measure of difference in quantitative traits (e.g., Blood eosinophil counts) between twins, or by estimating the probability of twins to be concordantly affected by the disease by calculation of proband concordance rate or
polychoric correlation (Fig. 1).

Fig. 1. Classical twin model of Asthma. A classical model showing the effect of the genome, common
shared environment and the unshared environment on the Asthma phenotype in twins. Monozygotic twins have a complete correlation of the genome, whereas both dizgotic twins have a correlation of 0.5. The shared environment is also completely correlated across both MZ and DZ twins, whereas the non-shared environment remains completely uncorrelated. (A) contribution of the Genome, (C) from the shared environment and (E) from the unshared environment.

Source: Thomsen

Phenotypic variations between individuals can be explained by a combination of both genetic variations and environmental variations. The genome may contribute to phenotypic variations both linearly (additive) or nonlinearly (nonadditive). These factors can be combined to derive equations for the covariance for MZ and DZ twins separately which have been described by Thomsen (2014).

With respect to Asthma, although most of the twin studies were conducted on the Scandanavian population, the earliest study was conducted in 1936 on 2500 German twins, which found concordance rates of 0.4 in MZ twins and 0.13 in DZ twins (Spaich & Ostertag, 1936). In 1956, a study of 1900 Danish twins found similar concordance rates (Harvald & Hauge, 1956). A 1970s study on Swedish population, based on a self-reported questionnaire,
found the concordance of Asthma to be around 19% in MZ twins and 4.8% in DZ twins. Following that, a Finnish study conducted on almost double the number of participants reported a heritability of 36% based on a concordance rate of 0.13 MZ and 0.7 for DZ twins (Los, Koppelman, & Postma, 1999). Studies in the Australian population separated the heritability based on the sex and found that males had an Asthma heritibility of 75% as compared to 60% in females (Duffy, Martin,
Battistutta, Hopper, & Mathews, 1990). Similar heritability was reported by a Finnish-population based twin study, which found that Asthma risk attributed to genetic factors was around 79% and 21% to environmental factors (Laitinen, Räsänen, Kaprio, Koskenvuo, & Laitinen, 1998). The presence of national twin registries has been instrumental in recruiting populations for such studies. The Danish Twin Registry comprising of more than 85,000
records for twin pairs born after 1870, forms one of the oldest national birth registries. This registry has provided data for many twin studies for Asthma, mainly comprising of twins born between 1931 and 2000 (Thomsen, 2014). Overall, twin studies have shown that MZ twins have almost twice the concordance rates for developing asthma than DZ twins, which inturn suggests that genetic factors do play an important role in Asthma pathophysiology (Bijanzadeh, Mahesh, &
Ramachandra, 2011).

Twin studies form a convenient platform to segregate and study the effect of genetics and the environment on the disease phenotype. However, there are certain factors which compromise the validity of these studies, the major one being the assumption that twins tend to share a majority of their environment. In addition, assumptions like MZ twins are always genetically alike and that there is an equal prevalence of the disease in MZ and
DZ twins, limit the inferences drawn from such studies, and further validation is essential to gain confidence on the results obtained (Thomsen, 2014).

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Alan S.L. Yu MB, BChir, in Brenner and Rector’s The Kidney, 2022

Twin Studies

Comparison of monozygotic to dizygotic twins and/or plain siblings reared in virtually identical environments have been informative.617,618 Goldfarb and coworkers sampled dizygotic and monozygotic twins from the Vietnam Era Twin Registry and found a
concordance rate of 32% in monozygotic twins compared with 17% in dizygotic twins, an effect that cannot be explained by the documentable dietary information.619 Other twin studies obtained urinary chemistries and found the hereditability of urinary calcium excretion rate to be around 50%.617,618

GENETICS | Clinical Genetics of Epilepsy

S.F. Berkovic, I.E. Scheffer, in
Encyclopedia of Basic Epilepsy Research, 2009

Twin Studies

Twin studies, which were first extensively utilized in epilepsy by Lennox, remain a powerful method
for demonstrating a genetic contribution in diseases with complex genetics. A comparison is made between concordances in identical (monozygotic) and nonidentical (dizygotic) twin pairs. Concordance refers to the presence of a disease in both twins. The degree of genetic contribution in a particular syndrome is judged by the completeness of the concordance in monozygous twins and by the extent to which it exceeds that in dizygotic twins.

Twin studies allow
the distinction of the effects of shared genetic factors from those of shared environmental factors. Moreover, significant results can be achieved in relatively small samples in which detailed and consistent phenotyping is feasible. Study of twins can also aid in classification and nosology, addressing the issue of ‘lumping’ versus ‘splitting.’ If two apparently different syndromes (splitter’s view) occur in monozygotic twins, then the syndromes are quite unlikely to be genetically different,
providing evidence that they would be better regarded as a single entity (lumper’s view). Finally, twins can also be used in matched pair designs, where one twin has had an exposure and the other not. Examples include effects of anticonvulsant exposure or postnatal insults.

In assessing twin studies, care must be taken to account for specific ascertainment biases. These biases include an excess of female monozygotic twins in volunteer twin registries, and
the tendency to over-report cases of concordant monozygotic twins.

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Larry Rifkin, Hugh Gurling, in Biological Aspects of Affective Disorders, 1991

9.3.2 Twin studies

Twin studies compare concordance rates for illness in pairs of monozygotic (MZ) and dizygotic twins (DZ). The central assumption of these studies is that monozygotic twins share the same genes, whilst dizygotic twins have on average 50% of their genes in common. Prenatal and postnatal
familial environmental factors are assumed to be a constant in both sets of twins. Twin studies can give information about the effects of shared (family) environment as well as non-shared (unique, specific) environment. One problem for the twin method is that exposure to the same family environment may have differential effects on MZ twins as compared with DZ twins. In addition, MZ twins share the same placental circulation.

The first significant
twin study of affective disorders and neurosis was conducted by Bertelsen (1979). One hundred and ten same sex twin pairs, where least one thành viên of each pair suffered from a BP or UP disorder requiring hospitalization, were identified by the Danish Twin Study Register. The concordance for the 55 MZ twins was 67%, whilst that for the 52 DZ pairs was 20%. In addition, the concordance for MZ over DZ twins was four times higher if the proband had BP disorder. If
the proband had UP disorder then the concordance in MZ twins was only twice the rate found in DZ twins. There was a tendency for the twin pairs to have the same subtype of affective disorder but overlap was noted with seven pairs of concordant MZ twins having one twin with UP and the other with BP disorder. Bertlesen (1987) later reviewed eight other twin studies and the combined strict concordance (UP to UP and BP to BP) was 59% for MZ and 18% for DZ twins. Gershon et
al. (1975a) combined the results of six studies and found 60% of MZ twins concordant, whereas only 13.3% of DZ twins were concordant. Two series of twins selected on the basis of BP disorder probands have been the most thoroughly investigated over a particularly long time. These are the twins investigated by Bertelsen and those the Maudsley hospital. A recent reassessment of the Maudsley twins has now shown that the concordance for all subtypes of affective disorder in the
co-twins is 100% (A. Reveley, 1990, personal communication). Bertelsen (1988, personal communication) has also followed up his series of twins and if a diagnosis of suicide is counted as a case then the concordance amongst MZ twins is also 100%. It seems plausible, therefore, that the genetic predisposition to BP and related UP disorders is highly penetrant once age-related risk is taken into account. Baron (1980) has analysed concordance
data from the published twin studies by testing multiple threshold models. He found that the multifactorial polygenic model could be rejected and that the autosomal single major locus provided an acceptable fit. This evidence therefore tends to tư vấn the hypothesis that the genetic susceptibility to BP and related UP affective disorder is highly penetrant.

Twin studies of neurotic depression by Slater and Shields (1969) and Torgersen
(1986) show similar concordance for MZ and DZ twin pairs, whilst demonstrating concordance rates higher than the rate in the population. This suggests familial rather than genetic influences. Shapiro (1970) found markedly higher concordance rates in MZ than DZ twins for neurotic depression but the affective disorders that were studied in this twin sample were quite severe. McGuffin and Katz (1989a, 1989b) analysed data from three twin studies and
estimated the relative contributions to the variance in liability to develop depression. They divided the variance into that attributed to genes, common family environment and non-shared (unique, specific) environment. Their model assumed a multifactorial liability threshold in which ‘liability’ to develop the disorder is normally distributed in the population. Their results provide tư vấn for the view that BP illness is largely determined by genetic factors, ‘manic depressive’ UP illness
occupies an intermediate position and neurotic depression is predominantly of non-genetic origin.

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Parkinson’s Disease; Epidemiology

R.Y. Lo, C.M. Tanner, in
Encyclopedia of the Neurological Sciences (Second Edition), 2014

Twin Studies

Twin studies can provide information concerning the relative
contribution of genetic and environmental factors to disease through comparisons of disease concordance in monozygotic and dizygotic twins. Monozygotic twins have identical nuclear deoxyribonucleic acid (DNA; although mitochondrial DNA can differ). Dizygotic twins share genes as frequently as other siblings do – on average, approximately 50%. If concordance in monozygotic twins is greater than that in dizygotic twins, a genetic cause of disease is indicated, whereas similar rates suggest shared
environment. Twin studies tư vấn a strong genetic component for early-onset parkinsonism (pairwise concordance: monozygotic=1.0 and dizygotic=0.17), whereas environmental causes have been suggested for typical, late-onset PD (pairwise concordance: monozygotic=0.16 and dizygotic=0.11). Twin pairs discordant for PD provide an excellent setting for studying environmental determinants, as genetic factors are similar or identical in twins, particularly same-sex twins. Discordant twin pair studies
have confirmed the inverse association of cigarette smoking and PD and identified increased risks of PD in association with head injury and solvent exposure.

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Medical Epigenetics and Twins

J.C. Eissenberg, in Medical Epigenetics, 2022


Twin studies, particularly studies of monozygotic twin pairs, have provided and will continue to provide the benchmark by which the respective contribution of genetics and environment to traits and disease are estimated. To the extent that twin studies have informed our understanding of epigenetics and disease, they are suggestive of a mechanism by which gene–environment interactions might result
in a chemical change in the nucleus that changes gene expression patterns, altering risk for morbidity and/or mortality.

The mechanistic link between cytosine methylation and monozygotic twin pair discordance remains correlative. The reemergence of hydroxymethyl cytosine and N6-methyladenine as additional, albeit minor, DNA modifications in animals suggests that these marks should also be scrutinized as solo epigenetic modifiers or as
combinatorial marks with potential prognostic value [103].

How environmental changes are mechanistically coupled to changes in DNA methylation is unknown. In the cases of monozygotic twin pairs discordant for imprinting disorders, failure of maintenance methylation has been invoked [104]. It is possible that transient environmental insults could similarly impact maintenance methylation
other loci, with the cumulative effect being epigenetic reprograming a variety of loci that contributes to multifactorial disorders. Alternatively, environmental insults may induce changes in cellular transcription patterns that indirectly result in gain or loss of methylation such loci.

Berdasco and Esteller [105] have tabulated a large number of genetic disorders that are associated with defects in DNA methylating enzymes,
methylated-DNA-binding proteins, histone-modifying enzymes, chromatin-remodeling factors, and microRNA-processing enzymes. Although the authors call the genes encoding these factors “epigenetic genes,” it remains unclear whether, in most or all of these cases, the gene mutations tabulated exert their effects on epigenetic mechanisms, or merely act to facilitate the actions of transcription factors.

A major challenge in interpreting discordant DNA methylation
patterns in twin studies is determining which epigenetic changes are causes of disease risk and which are by-products of pathology. However, even in the absence of a mechanistic model to explain such differences, twin studies, together with rapidly advancing and ever-cheaper genome sequencing technologies, promise to yield important new biomarkers with both diagnostic and predictive value for disease progression, prognosis, and therapeutic effectiveness.

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The Epigenetics of Autoimmunity: An Overview

Hai Long, … Qianjin Lu, in The Epigenetics of Autoimmunity, 2022

1.2.2 The Involvement of Nongenetic Factors in Autoimmunity

Twin studies have been successfully used to research many autoimmune diseases, including SLE. The concordance of disease occurrence in monozygotic twins, who have identical genetic information, is considerably below 100% for most autoimmune diseases [34,35].
This highlights an essential role for nongenetic factors (i.e., environmental influences and epigenetic mechanisms) in the pathogenesis of autoimmune diseases. Evidence suggests that epigenetic mechanisms are important intermediate regulators as the immune system responds to various environmental stimuli (i.e., ultraviolet exposure, drugs, and oxidative stress) [7]. Investigations into the roles of these epigenetic mechanisms in the pathogenesis of autoimmune diseases may provide a
better understanding of these complex diseases.

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URL: ://.sciencedirect/science/article/pii/B9780128099124000015

Why are identical twins often used in research studies?

The basic idea behind studying identical twins is that the results can better determine whether a certain trait, illness, or disorder is influenced more heavily by genetics or by the environment. Identical twins help scientists better understand how epigenetics influences our health.

Why do researchers use twins to study heritability?

Advantages of twin studies
Twin studies allow disentanglement of the shared genetic and environmental factors for the trait of interest. Researchers can estimate the proportion of variance in a trait attributable to genetic variation versus the proportion that is due to shared environment or unshared environment.

What is the heritability of identical twins?

Heritability has historically been estimated from studies of twins. Identical twins have almost no differences in their DNA, while fraternal twins share, on average, 50 percent of their DNA.

Why are identical twins used when studying epigenetics?

Because they have identical genomes, identical twins are ideal subjects for studying the effects of epigenetic modifications – changes to the DNA which control the expression of genes but not the DNA sequence itself.
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