Studies of alcoholism etiology often focus on genetic or psy-chosocial approaches, but not both. Greater understanding of the etiology of alcohol, tobacco and other addictions will come from integration of these research traditions. A research approach is outlined to test three models for the etiology of addictions — behavioral undercontrol, pharmacologic vulnerability, negative affect regulation — addressing key questions including (i) mediators of genetic effects, (ii) genotype-environment correlation effects, (iii) genotype x environment interaction effects, (iv) the developmental unfolding of genetic and environmental effects, (v) subtyping including identification of distinct trajectories of substance involvement, (vi) identification of individual genes that contribute to risk, and (vii) the consequences of excessive use. By using coordinated research designs, including prospective assessment of adolescent twins and their siblings and parents; of adult substance dependent and control twins and their MZ and DZ cotwins, the spouses of these pairs, and their adolescent offspring; and of regular families; by selecting for gene-mapping approaches sibships screened for extreme concordance or discordance on quantitative indices of substance use; and by using experimental (drug challenge) as well as survey approaches, a number of key questions concerning addiction etiology can be addressed. We discuss complementary strengths and weaknesses of different sampling strategies, as well as methods to implement such an integrated approach illustrated for the study of alcoholism etiology. A coordinated program of twin and family studies will allow a comprehensive dissection of the interplay of genetic and environmental risk-factors in the etiology of alcoholism and other addictions.

Problem behavior in children shows a high degree of cooccurrence, both within the domains of internalizing and externalizing behaviors and across domains. Maternal ratings of 207 same- and opposite-sex twin pairs on the Child Behavior Checklist (CBCL/4–18; Achenbach, 1991) were used to determine the etiology of these associations. In the current sample of 4- to 11-year-old children (mean age: 7.6 years) phenotypic correlations were .68 between Internalizing and Externalizing, between .41 and .66 within the internalizing scales, and between .58 and .71 within the externalizing scales. Correlations across domains on the scale level were of similar magnitude. Genetic and shared environmental correlations were generally high, with the exception of the somatic complaints scale which showed low genetic correlations with other scales. These findings of uniformly high shared etiology was seen within and across domains. For example, Attention Problems showed genetic correlations of .65 with Delinquent Behavior and .76 with Aggressive Behavior; the genetic correlations of Attention Problems with internalizing scales were .71 for Anxious/Depressed and .79 for Withdrawn; a low genetic correlation was only shown for the Somatic Complaints scale (rg = .16). Although the magnitude of shared environmental contributions was lower, the environmental correlations were close to unity, indicating that the same family environmental factors were involved in aspects of problem behavior when assessed across domains. Results for the Attention Problems scale were similar to other disruptive behavior, justifying its inclusion with the externalizing scales.

Identifying twins for a population-based register can be achieved through birth records or community surveys. We studied the feasibility and effectiveness of different methods of identifying and recruiting twins to establish a population based register. To trace twins a population survey was carried out using an interviewer administered questionnaire. We also inspected the birth registration certificates at a divisional secretariat reported from a specified hospital between the years of 1985–1997 and compared it to the birth register of this same hospital. To recruit twins a random sample of 75 twin pairs (150 twins) identified at the Divisional Secretariat were contacted through the post and 25 twin pairs (50 twins) were personally visited. The prevalence of twins was 6.5 twins per 1000 people in the area surveyed. The twinning rate at the hospital was 18.92 twins per 1000 births. A discrepancy of 38 multiples births between the hospital labour room records and those registered at the DS was noted. The response from the postal invitation for recruitment was 59% and the response from the personal invitation was 68%. (Difference 9.4% 95% CI; 7.06–11.73). Community survey and systematic inspection of birth records either at the hospital or the birth registration office was an effective method to trace twins. Once traced, personal contact was more effective than the postal invitation for recruitment of younger twins. A cost-effective approach would be to use a postal coverage followed by personal contact for non-responders. The alternative method, community coverage, would have financial implications.

Although there is substantial evidence from studies of singletons that small size at birth is linked with long-term adverse health effects, until recently little was known as to whether these associations extend to twins. A review of published studies suggests that at present there is little consistent evidence that birthsize in twins is associated with increased morbidity or morality. While, these findings may reflect methodological limitations, it is also argued that they arise as a consequence of the substantially different biology of fetal growth in twins.

The advances in reproductive technologies have changed the demographics of multifetal pregnancies. In the first trimester, ultrasound allows to diagnose the number of multiples, chorionicity and amnionicity, the presence or absence of nuchal translucency, early growth discordance, severe malformations and the origin of activities and contacts between multiples. In the second and third trimester, the opportunity to examine the cervix by transvaginal ultrasound should not be missed to detect the risk of premature delivery. Ultrasound is essential for the early grading and treatment of twin-to-twin transfusion syndrome (TTTS), the diagnosis of malformations and growth disturbances. Doppler velocimetry has proven to be able to reduce perinatal mortality in twin pregnancies. Finally, ultrasound is used for the detection of the position of multiples and the decision of the optimal route of delivery. This is of main importance in delayed interval delivery and expectant management of multifetal pregnancies and early cervical dilatation.

Amultidisciplinary collaborative study examining cognition in a large sample of twins is outlined. A common experimental protocol and design is used in The Netherlands, Australia and Japan to measure cognitive ability using traditional IQ measures (i.e., psychometric IQ), processing speed (e.g., reaction time [RT] and inspection time [IT]), and working memory (e.g., spatial span, delayed response [DR] performance). The main aim is to investigate the genetic covariation among these cognitive phenotypes in order to use the correlated biological markers in future linkage and association analyses to detect quantitativetrait loci (QTLs). We outline the study and methodology, and report results from our preliminary analyses that examines the heritability of processing speed and working memory indices, and their phenotypic correlation with IQ. Heritability of Full Scale IQ was 87% in the Netherlands, 83% in Australia, and 71% in Japan. Heritability estimates for processing speed and working memory indices ranged from 33–64%. Associations of IQ with RT and IT (−0.28 to −0.36) replicated previous findings with those of higher cognitive ability showing faster speed of processing. Similarly, significant correlations were indicated between IQ and the spatial span working memory task (storage [0.31], executive processing [0.37]) and the DR working memory task (0.25), with those of higher cognitive ability showing better memory performance. These analyses establish the heritability of the processing speed and working memory measures to be used in our collaborative twin study of cognition, and support the findings that individual differences in processing speed and working memory may underlie individual differences in psychometric IQ.

We have used Swedish monozygotic twins concordant for breast cancer to study genetic changes associated with the development of breast cancer. Because loss of heterozygosity (LOH) at a specific genomic region may reflect the presence of a tumour suppressor gene, loss of the same allele in both of the twins concordant for breast cancer may pinpoint a tumour suppressor gene that confers a strong predisposition to breast cancer. DNA samples extracted from the matched tumour and normal tissues of nine twin pairs were analysed for allelic imbalance using a set of microsatellite markers on chromosomes 1, 13, 16 and 17, containing loci with known tumour suppressor genes. The two main regions, where more twin pairs than expected had lost the same allele, were located at 16qtel, including markers D16S393, D16S305 and D16S413, and at 17p13, distal to the p53 locus. Our results show that the monozygotic twin model can be used to suggest candidate regions of potential tumour suppressor genes, even with a limited number of twin pairs.

The objective was to investigate the genetic epidemiology of figural stimuli. Standard figural stimuli were available from 5,325 complete twin pairs: 1,751 (32.9%) were monozygotic females, 1,068 (20.1%) were dizygotic females, 752 (14.1%) were monozygotic males, 495 (9.3%) were dizygotic males, and 1,259 (23.6%) were dizygotic male-female pairs. Univariate twin analyses were used to examine the influences on the individual variation in current body size and ideal body size. These data were analysed separately for men and women in each of five age groups. A factorial analysis of variance, with polychoric correlations between twin pairs as the dependent variable, and age, sex, zygosity, and the three interaction terms (age x sex, age x zygosity, sex x zygosity) as independent variables, was used to examine trends across the whole data set. Results showed genetic influences had the largest impact on the individual variation in current body size measures, whereas non-shared environmental influences were associated with the majority of individual variation in ideal body size. There was a significant main effect of zygosity (heritability) in predicting polychoric correlations for current body size and body dissatisfaction. There was a significant main effect of gender and zygosity in predicting ideal body size, with a gender x zygosity interaction. In common with BMI, heritability is important in influencing the estimation of current body size. Selection of desired body size for both men and women is more strongly influenced by environmental factors.

The classic twin study is sometimes described as “the perfect natural experiment” for the investigation of the aetiology of complex disease, but assumptions of the twin design need to be empirically tested if their results are to be considered unbiased and representative of singleton populations. In this study comparisons of disease and prevalence of lifestyle characteristics have been made between twin participants in the St Thomas' Hospital UK adult twin registry, the largest twin volunteer register in the UK for the study of diseases of ageing, and a parallel population-based study of singleton women. The only differences found were for weight, where monozygotic (MZ) twins were lighter and had a smaller variance than dizygotic (DZ) twins and singletons. For the other variables studied, volunteer twins were not found to differ from age-matched singleton women in distribution or prevalence of: bone mineral density, osteoarthritis, blood pressure, hypertensive drug use, height, history of hysterectomy and ovariectomy, menopausal status and current alcohol and overall tobacco consumption. We conclude that the results of twin studies can be generalised to singleton populations for these measures and disease outcomes.

In this study we examine the hypothesis that monozygotic (MZ) twins in historical databases are less discordant for birth weight due to negative selection of severely discordant MZ twins. Furthermore, we test the hypothesis that MZ twins are less discordant for birth weight when comparing a volunteer based twin registry with a population based twin registry, due to selective registration. Data were available on 3927 twin pairs from the volunteer Australian Twin Registry born before 1964, 3059 volunteer twin pairs from the Netherlands Twin Register born 1987–1989 and 454 Belgian twin pairs from The East Flanders Prospective Twin Survey born 1987–1989. Intrapair relative birth weight differences (RBWD) were computed for MZ and dizygotic (DZ) twins from each twin registry. Comparing birth weight differences between MZ and DZ twins provides support for the hypothesis that MZ twins are subject to a negative selection in historical databases. Furthermore, Australian MZ twins have a lower RBWD compared to Dutch MZ twins when corrected for the RBWD of Australian and Dutch DZ twins, indicating circumstances which only affect MZ twins. Our hypothesis that MZ twins are less discordant for birth weight in a volunteer based twin registry compared to a population based twin registry had to be rejected. We suggest that investigators using historical databases to test the fetal origins hypothesis should be aware of this increased likelihood of selective exclusion of individuals with extreme morphometric parameters at time of birth.

Outcomes of multifetal pregnancy in prenatal life are markedly affected by chorionicity. Several disease processes are found in monochorionic (MC) twins that do not occur in dichorionic (DC) twins. Improvements in prenatal outcomes will depend on reliable first trimester diagnosis of chorionicity, allowing early monitoring for complications of MC placentation. Particular structures and functions of MC twin placentas affect outcomes and can be targeted for specific treatments, especially in twin-twin transfusion. The causes of severe DC twin fetal growth discordance are clarified. In post-natal life, zygosity is a determining effect in genetic predisposition to many chronic diseases, including neoplasia. Few MC twins know that they are monozygotic (MZ). Few twin researchers realize that MZ twins may be genetically discordant. Abandonment of the word “identical” for MZ twins would assist in clarifying these issues of zygosity, concordance and discordance.

Data of the Danish Twin Registry on monozygotic and dizygotic twins are used to analyse genetic and environmental influences on susceptibility to heart diseases for males and females, respectively. The sample includes 7955 like-sexed twin pairs born between 1870 and 1930. Follow-up was from 1 January 1943 to 31 December 1993 which results in truncation (twin pairs were included in the study if both individuals were still alive at the beginning of the follow-up) and censoring (nearly 40% of the study population was still alive at the end of the follow-up). We use the correlated gamma-frailty model for the genetic analysis of frailty to account for this censoring and truncation. During the follow-up 9370 deaths occurred, 3393 deaths were due to heart diseases in general, including 2476 deaths due to coronary heart disease (CHD). Proportions of variance of frailty attributable to genetic and environmental factors were analyzed using the structural equation model approach. Different standard biometric models are fitted to the data to evaluate the magnitude and nature of genetic and environmental factors on mortality. Using the best fitting model heritability of frailty (liability to death) was found to be 0.55 (0.07) and 0.53 (0.11) with respect to heart diseases and CHD, respectively, for males and 0.52 (0.10) and 0.58 (0.14) for females in a parametric analysis. A semi-parametric analysis shows very similar results. These analyses may indicate the existence of a strong genetic influence on individual frailty associated with mortality caused by heart diseases and CHD in both, males and females. The nature of genetic influences on frailty with respect to heart diseases and CHD is probably additive. No evidence for dominance and shared environment was found.

Epidemiological studies have consistently shown a positive association between size at birth (i.e. birth weight or birth length) and height in children, adolescents and adults. To examine whether this association is explained by genetic or nongenetic (intra-uterine) factors, we investigated birth weight, birth length and height in 60 dizygotic and 68 monozygotic adolescent twin pairs still living with their parents. Birth weight of the twins was obtained from their mothers. Height was measured in a standardised way. The mean age was 17±1.7 years for the dizygotic twins and 16±1.8 years for the monozygotic twins. Both dizygotic and monozygotic twins with the lowest birth weight from each pair had a height that was lower compared to their co-twins with the highest birth weight (dizygotic twins: 172.2±7.9 vs. 173.8±9.4 cm [p = 0.05]; monozygotic twins: 171.1±9.4 vs. 171.8±9.5 cm [p = 0.01]). Similarly, both dizygotic and monozygotic twins with the shortest birth length from each pair had a height that was lower compared to their co-twins with the longest birth length (dizygotic twins: 172.3±7.9 vs. 174.9±9.7 cm [p < 0.05]; monozygotic twins: 168.9±10.6 vs. 169.9±10.2 cm [p < 0.01]). In addition, intra-pair differences in birth weight and birth length were significantly associated with differences in height in both dizygotic twins (regression coefficient: 4.3 cm/kg [95% confidence interval: 1.0 to 7.5] and 0.96 cm/cm [0.17 to 1.74], respectively) and monozygotic twins (2.8 cm/kg [1.4 to 4.1] and 0.73 cm/cm [0.40 to 1.06], respectively). These associations were stronger in dizygotic than in monozygotic twins, but this difference was not statistically significant (for birth weight p = 0.4; and for birth length p = 0.6). However, genetic model fitting indicated that models incorporating a genetic source of the covariance gave a better description of the observed association of birth weight and length with height in later life than models not incorporating this genetic source. The results were similar for data on adult height after 12 years of follow-up in a subgroup of these twin pairs. These data suggest that the association between size at birth and height in later life is influenced by non-genetic intra-uterine and by genetic factors.