REVIEW

Twin Studies in Diabetes MellitusC.H. Hawkes*

Department of Clinical Neurology, Leeds General Infirmary, LeedsLS1 3EX

Twin studies are a valuable way of determining the relative significance of genetic andenvironmental factors in the aetiology of disease. In diabetes mellitus, they are ofimportance, since the aetiologies of Type 1 (insulin-dependent) and Type 2 (non-insulin-dependent) diabetes mellitus are probably different. However the results of twin studieshave not always been reliable. Strict adherence to methodological guidelines is necessaryto ensure the validity of the results that are obtained. These guidelines relate toascertainment of a twin sample, confirmation of zygosity, and effects of sampling. Criticalreview of twin studies in diabetes performed to date imply provisionally a very stronggenetic input to the aetiology of Type 1 diabetes. In Type 2 diabetes genetic andenvironmental factors are probably of equal importance. 1997 by John Wiley & Sons, Ltd.

No of Figures: 0. No of Tables: 2. No of Refs: 30

KEY WORDS Diabetes mellitus Twin studies Twin study methodology

Accepted 6 November 1996

3. Biometrical genetic methods. These involve ascer-Introductiontainment of risk factors, metabolites, normal aspectsof behaviour/functioning, physical or psychologicalTwin studies have a compelling interest for many

clinicians and although the basic principles are relatively characteristics which may be indices of underlyingliability to disease. Genetic models may then besimple the concepts are rarely understood. A previously

held view that Type 2 (non-insulin-dependent) diabetes fitted to the data analysing the covariance in MZand DZ pairs.2mellitus is mainly inherited and Type 1 (insulin-

dependent) diabetes less firmly so1 is, as I hope toThe fundamental aim of classical twin study is to

demonstrate, derived from faulty data and probably thecompare concordance rates in monozygotic (MZ) and

reverse is true. Before this can be appreciated somedizygotic (DZ) twins. When the MZ rate is significantly

knowledge of twin study principles is essential. Thishigher than DZ this indicates that genetic factors are

survey will therefore cover basic twin methodology andimportant in aetiology; approximately equal MZ:DZ

results of twin studies relating to diabetes. Review of theconcordance infers environmental cause, particularly if

evidence for various gene defects in diabetes is beyondthe concordance rates are no higher than the population

the scope of this article and will not be discussed.rate would allow by chance. This point may be under-

It will be recalled that if twin pairs are geneticallystood in principle by reference to Table 1. Taking the

identical they are monozygous (MZ), otherwise they arefirst row of data3 it will be seen that the concordance

dizygous (DZ) and have no more genetic similarity thansiblings. If both twins in a pair have the same disease Table 1. Volunteer twin studies in diabetesor trait they are said to be concordant.

The classical twin study is a well documented and MZ pairs DZ pairspowerful means of assessing the role of genetic andenvironmental factors in disease. Its value depends First author N C P N C Pcrucially on careful methodology, especially how twin

Then-Berg3 Type 1 37 18 0.49 55 9 0.16pairs are sampled and investigated.Type 2 19 13 0.69 46 11 0.24There are three main approaches:

Gottleib4 Type 1 30 9 0.3 60 2 0.31. Classical twin method. The percentage of concordant Type 2 14 2 0.14 26 9 0.35pairs (concordance rate) for disease in MZ and DZ

Pyke1 a Type 1 178 86 0.48twins is compared so that the relative contributions ofType 2 95 75 0.79genetic and environmental factors may be estimated.

Japan Diabetes Type 1 11 5 0.45 10 0 0.002. Co-twin control method. This requires examinationSociety13 a? Type 2 46 37 0.83 10 4 0.4of MZ twin pairs discordant for a disease (or other

particular risk factor). The healthy (or unexposed)aLike sex study [? = presumed].

co-twin provides a genetically matched pair control. Type 1, insulin-dependent diabetes; Type 2, non-insulin-dependent dia-betes.N, sample size; C, number of concordant pairs; P, pairwise concord-ance rate.* Correspondence to: C.H. Hawkes, 22 Henley Rd, Ipswich IP1 3SL, UK

347CCC 0742–3071/97/050347–06$17.50 1997 by John Wiley & Sons, Ltd. DIABETIC MEDICINE, 1997; 14: 347–352

REVIEWrate for Type 1 diabetic MZ twins is 0.49 (49 %). For Simpler still are questions about similarities which can

establish zygosity accurately in 97.6 % cases.8 The singleDZ pairs it is 0.16 (16 %). Because the MZ rate isconsiderably higher than the DZ rate then significant most discriminant question (for Norwegians) was ‘are

you as alike as two drops of water?’ or the Englishgenetic factors may be inferred and subjected to formalanalysis (q.v.). Conversely in the second study (3rd row4) equivalent: ‘as like as two peas in a pod?’. Few DZ pairs

are similar enough to be misdiagnosed MZ, but aboutthe concordance rate is 0.3 for both MZ and DZ Type1 pairs. This points to environmental factors and is 10 % of MZ pairs are not completely identical in

appearance, and may be misclassified as DZ.9diametrically opposed to the first study! Clearly thereare errors in one dataset, but this is how one makes an Dizygotic twins each have a chorion but so do one-

third of MZ pairs. The remaining two-thirds of MZ twinsapproximate interpretation.have a single chorion. The number of placentae is alsonot a reliable guide to zygosity and often the fetalAscertainment of a Twin Samplemembranes are not examined. Inspection of the fetalmembranes is therefore the least dependable method forThere are three main methods:estimation of zygosity.10

1. Population based. This is the least biased and idealmethod and typically employs a National Twin

Effects of SamplingRegister. Twins may then be contacted directly ifethically permissible or they may be identified

Assuming twin zygosity has been ascertained accuratelythrough cross-linking with a disease register. Thethere are further difficulties which relate to sampling.advantages are that the largest possible number of

twins are recruited, and biases associated withMZ:DZ Ratiosampling are low or known. Unfortunately twin

registries are not widely available and are confinedThe adequacy of a twin sample may be checked simplymainly to Scandinavian countries and parts of theby examination of the relative number of MZ and DZUnited States of America.pairs. For same sex pairs this should be roughly equal,2. Volunteer based. This is a popular but less systematicgiving a ratio of 1:1. Where opposite sex pairs are alsomethod in which researchers scrutinize diseasecollected the number of same and opposite sex DZ pairsindexes, hospital records, advertise through twinshould be equal. About one-third of the sample shouldclubs or societies related to the disease. Suchbe MZ pairs giving a MZ:DZ ratio of 0.5:1.0.methods are subject to unpredictable bias and often

this may be identified if MZ twins are over-represented or if there is a particularly high rate of Volunteer BiasMZ concordance.

3. Individual case studies. Aetiological clues may be It was observed by Lykken et al.11 that in same sex twinderived by case studies of discordant twins. This has samples set up through volunteer recruitment there wasbeen used in a study of risk factors for cardiovascular an excess MZ and female twins—two-thirds were MZdisease in Type 1 diabetic MZ twins.5 It was shown and two-thirds female instead of equal proportions. Hethat systolic blood pressure, high density lipoprotein called this the ‘Rule of Two Thirds’. Such bias probablycholesterol, fibrinogen, and factor VII level were relates to the twins’ own interest in their twinship, whichsignificant risk factors for cardiovascular morbidity. may be stronger in MZ and females. In disease studies,Case studies of MZ twins reared apart (MZA) are of often there is over-recruitment of MZ concordant twins,particular value. If a series of MZA twins are found and these are assumed to be more noteworthy forto be concordant for a disorder, then this provides clinicians. If this occurs the genetic contribution to thestrong evidence for genetic factors in its aetiology. aetiology of the disease in question will be overestimated.Such twins are rare, but it was found for example,that 3 of 5 MZA twins were concordant for migraine.6 Sampling Co-twins: The Definition of

Discordance and Censoring of DataZygosity Ascertainment

It may be difficult to define the nature of disease in anindex twin. Internationally agreed criteria are appropriateThis, of course, is only necessary for like-sexed twins.

The most reliable method is by use of minisatellite for diabetes but some diseases have a significant diagnos-tic error rate. This question is universal and not uniqueprobes, or ‘DNA fingerprinting’. This has a negligible

error, less than 1 %.7 Next most valuable is a combination to twin study. A more specific problem arises when anaffected twin has been identified and the co-twin isof blood group analysis, secretor status, haptoglobin

types, dermatoglyphics, etc. If any one factor is different apparently discordant. Concordance MZ twins are oftenaffected within a year or two of each other but therethen the pair are DZ. If all factors are the same, the

likelihood of a DZ pair is very small (around 1 %). are wide variations. In the case of Type 1 and Type 2

348 C.H. HAWKES

REVIEWdiabetes the temporal spread is usually not more than 5 becomes manifest. Both genes and environment are

assumed to contribute to liability and they result fromyears12 but there are exceptions. In the Japanese DiabetesSociety Study13 50 % of either type were concordant in the combined effects of many genes with small effects

and many environmental influences. Computer modelling3 years; 75 % within 6 years but there was one Type 1pair who did not become concordant for 9 years and techniques can be used, e.g. MX or LISREL software

packages.2 Threshold models with additive genetic,another pair with Type 2 who became concordant after18 years. It is hard to determine whether such long dominance components to genetic variances, shared

environmental (i.e. family) or unique environmentaltemporal spread points more to an environmental orgenetic process. Furthermore it may be difficult to define sources of variation in the underlying liability to disease

can be fitted to observed patterns of disease in the twins.true discordance if an apparently healthy co-twin hasborderline glucose intolerance and even more vexing if Goodness-of-fit statistics can then assess the degree to

which the specified model corresponds to the data. Aglucose tolerance has not been evaluated biochemicallyat all. disadvantage of model fitting programmes is that they

are not powerful for small samples (as in all diabetictwin studies) and they depend upon specific, largelySampling Methods and Data Analysisuntestable, assumptions about the way genes and environ-ment interact.The primary measurement in a classical twin study is

the concordance rate. Most studies do not ascertain alltwins in the population and two methods are used to Twin Studies in Diabetesestimate the rate of concordance: ‘probandwise’ (theproportion of affected individuals among the twins of Many early studies were volunteer based and failed to

distinguish Type 1 from Type 2 diabetes. Table 1index cases) and ‘pairwise’ (the proportion of twin pairswho are concordant). Debate continues on the relative summarizes four volunteer studies. The first two cited3,4

have an appropriate ratio of MZ:DZ twins but there ismerits of these approaches but the consensus view isthat the probandwise method is preferable to the a striking deficit of Type 2 subjects. As mentioned above

these two studies point in opposite directions for Typepairwise.14 Many neurological studies do not make clearwhich method is used or draw a distinction. 1 disease and these earlier studies would not conform

to current definitions of diabetes. In the next study1 DZThe usual definition of heritability is expressed by2[rMZ-rDZ] where r is the correlation of liability derived twins were deliberately excluded. The concordance rate

in this survey is extremely high in Type 2 (79 %) andfrom the concordance rate.15 The index is known as h2

or G16 and is called the coefficient of genetic variation. less in Type 1 (48 %). This investigation is widely quotedto suggest major genetic factors in Type 2 and mainlyA value around 0.5 indicates a fairly strong genetic

influence and has been found in schizophrenia for environmental factors in Type 1. This is incorrect. Thestudy design is at fault because it lacks a DZ group andexample; conversely a low value of 0.1 implies more

environmental influence. Statistics such as these which would predictably over-recruit concordant pairs becausemost come from diabetes societies. The higher concord-depend on the comparison of relative numbers of affected

MZ and DZ twins, will be heavily affected by sampling ance in Type 2 may be due to over-representation offemales but details are not supplied. The Japanese Study13biases. If the sampling method results in overidentification

of concordant twins—as in most volunteer based and does not make it clear if opposite sex pairs are included;it has under-representation of Type 2 cases and a deficiteven some ‘population’-based studies—the disorder will

appear more heritable than it really is. If heritability of DZ. None of the studies indicate whether concordanceis measured probandwise or pairwise; presumably theestimates are based solely on the comparison of MZ and

DZ pairs there is a tendency to overestimate the genetic latter. All these four volunteer studies are therefore incon-clusive.component because of the shared environment in MZ

pairs. Hence twin studies in general give an upper limit Later investigations have been population based(Table 2). As expected, the overall concordance rate (i.e.of any genetic contribution.

The estimation of heritability is a limited goal17 and both MZ and DZ) is lower than in volunteer studies.Three of the four listed studies12,19,20 analyse concordanceshould be seen as a first step. Twin studies usually

provide a wealth of data apart from categorization of probandwise and pairwise. All are like sex studies andhave reasonable proportion of MZ and DZ pairs. Onesubjects as affected or not. Ratings of risk factors,

symptom scores, and other information of a quantitive investigation21 shows high MZ:DZ concordance ratioimplying significant genetic factors in Type 1 diabetes.nature may be subjected to regression analyses to

estimate genetic effects.18 Models can be used to estimate There is no Type 2 group. This study relied on self-reported diagnosis—a factor which might overestimatethe contribution of genetic factors to disease such

as diabetes. For a complex disease the polygenic concordance. In another survey19 only Type 2 diabetesis examined and shows equal MZ:DZ concordance. Thismultifactorial model is used most often. This assumes

that there is a normally distributed liability to disease implies environmentally based disease but it must berealized that the numbers are small. In the follow-up toand when a certain threshold level is reached the disease

349TWIN STUDIES IN DIABETES MELLITUS

REVIEWTable 2. Population based twin studies in diabetes mental effects and shared (i.e. family) environmental

effects. The conclusion from this study was that there isMZ Pairs DZ Pairs a very strong genetic input for Type 1 diabetes while

both environmental and genetic factors are importantFirst author N C CR N C CR

are for Type 2.The most recent study from Denmark20 also used aHarvald21 a Type 1 53 32 0.6 (P) 76 10 0.13 (P)

national twin registry, and extracted 95 twin pairs bypostal questionnaire where one or both had Type 1Newman19 a Type 2 25 4 0.276 25 4 0.276disease. This study likewise used WHO critera for

Kaprio12 a Type 1 23 3 0.231 81 2 0.048 classification of diabetes. Most co-twins were evaluatedType 2 142 29 0.339 307 27 0.162 by glucose tolerance testing and zygosity was evaluated

by 11 blood and enzyme type systems. There were farKyvic20 Type 1 26 10 0.53 69 4 0.11 more concordant MZ twins than DZ, giving a heritability

index of 0.72 (SE 0.21), which implies a strong geneticIn the Harvald study21 concordance rates are expressed pairwise; in

component to Type 1 diabetes, in agreement with thethe other three studies, probandwise.aLike sex study. Finnish study. The concordance rate in MZ and DZType 1, insulin-dependent diabetes; Type 2, non-insulin-dependent dia- twins was higher than the analysis from Finland possiblybetes.

because most non-diabetic co-twins in the DanishN, sample size; C, number of concordant pairs; CR, concordance rate;P, pairwise concordance rate. investigation were tested for glucose intolerance. They

found that for Type 1 disease a model which includedadditive genetic effects, shared (i.e. family) and unsharedthis study 10 years later, many more MZ than DZ twins

had become concordant, suggesting an important genetic environmental effects fitted the data best. They temperthis conclusion by pointing out that gene-environmentcomponent and contradicting their earlier sample result.

Unfortunately there were several dropouts in both MZ interaction may be important in Type 1 diabetes, andthat this makes difficult the interpretation of hereditaryand DZ groups in the follow-up study and recruitment

bias was probably strongly in favour of more estimation based on genetic modelling techniques. It isunfortunate that subjects with Type 2 diabetes were notunhealthy patients.

The study from Finland12 is more informative. It is included at this stage by way of comparison. Neitherthis investigation nor that from Finland report on birthbased on their national twin registry and free of major

errors in methodology, except that their diabetic subjects weights but the prevalence of diabetes in the Finnishtwins was no higher than the general population rateare derived from hospital discharge records and the

National Drug Register. Great care was taken with the suggesting that twinning per se is not associated with dia-betes.classification of diabetes and WHO guidelines were

used. Ambiguous cases were reviewed independently. With the exception of the studies from Finland12 andDenmark20, the diabetes twin studies are not conclusive.Zygosity was determined by validated questionnaire.

While their Type 1 sample is probably complete, there Taken together the Finnish and Danish studies infer avery strong genetic element for Type 1 diabetes and ahas almost certainly been under-representation of people

with Type 2 diabetes because not all would be taking weaker genetic influence in Type 2, at least for thesecountries. A metanalysis of these two studies wouldprescribed drugs and diet-treated subjects may have

been missed. However the concordance rate in DZ twins probably not contribute further as the results for Type 1are virtually identical and only the Finnish study hasresembled that of siblings so any bias is not likely to be

large. Proportions of DZ and MZ twins are acceptable data on Type 2 disease. Unfortunately the prevalence ofType 1 diabetes is particularly high in Finland and asand so is the ratio of Type 1 to Type 2. The investigators

deliberately avoided testing the presumably non-diabetic the authors point out this is unlikely to be due to astrong environmental agent but could be due to theco-twin for glucose intolerance and relied on drug

prescribing records for diagnosis of diabetes. It was effect of higher penetrance. To validate these observationsa large community-based study will be necessary inargued that if formal glucose tolerance testing had been

done on non-diabetic co-twins, concordance rates might other populations.have been overestimated had non-diabetic twins notbeen tested in the same way. The concordance rate was Environment vs Geneticsmuch higher in MZ than DZ twins, giving a correlationof liability for Type 1 diabetes in MZ twin of 0.727, in Writing on twins is often controversial. A recent article

stated ‘the classic twin study must now be regarded asfavour of a genetic aetiology. Model fitting using the MXpackage gave the best fit to a simple model for Type 1 an unreliable method of estimating the genetic component

in most of the common diseases of adult life’.22 It isdiabetes with additive genetic effects and unsharedenvironmental effects. For Type 2 diabetes, the best argued that differences in intrauterine environment are

relevant to disease of adult onset (‘fetal origins hypothesis’)model was more complex and fitted best with acombination of additive genetic effects, unshared environ- such as cardiovascular disease, hypertension, diabetes,

350 C.H. HAWKES

REVIEWlipid abnormality, allergic and autoimmune conditions, Acknowledgementsand that such factors may confound interpretation of

The author would like to acknowledge the help andtwin studies. However, the case is far from proven.23

guidance of A. Macdonald, Twin Research Fellow,Some evidence has been provided to suggest thatInstitute of Psychiatry, De Crespigny Park, London andretardation in intrauterine growth that occurs in multipleT. Bishop, Department of Genetic Epidemiology, St Jamesbirths is not a predictor of adult morbidity and mortality.24

Hospital, Leeds.However twin mortality was examined in a historicalcohort with a low follow-up rate. The intrauterineenvironment of identical twins may be substantiallydifferent, e.g. birth weights may be dissimilar and this Referenceshas been claimed to influence expression of disease inadult life. One group25 suggests that, because MZ twins 1. Pyke DA. Development of diabetes in identical twins. In:

Camerini-Davalos, RA, Cole H, eds. Early Diabetes: Pre-have a lower body weight than DZ twins, an increaseddiabetes. New York: Plenum Press, 1988: 255–258.concordance for Type 2 diabetes in MZ twins could be

2. Neale MC, Cardon LR. Methodology for Genetic Studiesdue to fetal, not genetic, factors. However, differencesof Twins and Families. NATO ASI Series D: Behavioural

of intrauterine environment in twins are more likely to and Social Sciences, vol 67. Dordrecht, Netherlands:produce discordance which will make MZ twins less Kluwer Academic Publishers, 1990.

3. Then-Berg H. Die erbbiologie des diabetes mellitus. Archalike and tend to diminish any measurement of a geneticRass Ges Biol 1983; 32: 289–340.component in twin studies.26,27 Furthermore the rate of

4. Gottlieb MS, Root HF. Diabetes mellitus in twins. DiabetesType 2 disease in MZ twins is not significantly higher1968; 17: 693–704.

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