Biomedical subjects
Publications and source records attributed to Axel Skytthe.
The Danish Twin Registry was established formally in 1954 and thus celebrates its 50th anniversary in 2004. Here we give an account of its founding and the early years, and a brief summary of more recent progress.
The genetic influence on susceptibility to diseases of the respiratory system and all-cause mortality was studied using data for identical (MZ) and fraternal (DZ) twins. Data from the Danish Twin Register include 1344 MZ and 2411 DZ male twin pairs and 1470 MZ and 2730 DZ female twin pairs born between 1870 and 1930, where both individuals were alive on 1 011943. We used the correlated gamma-frailty model. Proportions of variance in frailty attributable to genetic and environmental factors were assessed using the structural equation model approach. For all-cause mortality the correlation coefficients of frailty for MZ twins tend to be higher than for DZ twins. For mortality with respect to respiratory diseases this effect was only seen in females, whereas males showed the opposite effect. Five 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 biometric model heritability for cause of death was found to be 0.58 (0.07) for all-cause mortality (AE-model) and zero for diseases of the respiratory system for males. Heritability was 0.63 (0.11) for all-cause mortality (DE-model) and 0.18 (0.09) for diseases of the respiratory system (DE-model) for females. The analysis confirms the presence of a strong genetic influence on individual frailty associated with all-cause mortality. For respiratory diseases, no genetic influence was found in males and only weak genetic influence in females. The nature of genetic influences on frailty with respect to all-cause mortality is probably additive in males and dominant in females, whereas for frailty with respect to deaths caused by respiratory diseases in females, there are genetic factors present which are caused by dominance. Environmental influences are non-shared with exception of frailty with respect to respiratory diseases in males, where the shared environment plays an important role.
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Questionnaire-based zygosity assessment in twins has generally been found to be valid. In this report we evaluate sex- and age-differences in the validity of such questionnaire-based classification when using the four questions that have been the basis of zygosity assessment in The Danish Twin Registry for half a century. Three hundred and forty-two male and 531 female twin pairs were zygosity diagnosed using genetic markers and the results compared with the original questionnaire based classification. We found significant differences in the accuracy of questionnaire based zygosity diagnosis when stratifying the data for sex as well as age: males and monozygotic having the highest misclassification. However, even in the group with the highest misclassification rate the frequency was less than 8%. The overall misclassification rate was only 4%, with a clear tendency towards a higher proportion of misclassified monozygotic than dizygotic twins. The results demonstrate that questionnaire based zygosity diagnosis can still be regarded as a valid and valuable classification method for most purposes.
A major component of variation in body height is due to genetic differences, but environmental factors have a substantial contributory effect. In this study we aimed to analyse whether the genetic architecture of body height varies between affluent western societies. We analysed twin data from eight countries comprising 30,111 complete twin pairs by using the univariate genetic model of the Mx statistical package. Body height and zygosity were self-reported in seven populations and measured directly in one population. We found that there was substantial variation in mean body height between countries; body height was least in Italy (177 cm in men and 163 cm in women) and greatest in the Netherlands (184 cm and 171 cm, respectively). In men there was no corresponding variation in heritability of body height, heritability estimates ranging from 0.87 to 0.93 in populations under an additive genes/unique environment (AE) model. Among women the heritability estimates were generally lower than among men with greater variation between countries, ranging from 0.68 to 0.84 when an additive genes/shared environment/unique environment (ACE) model was used. In four populations where an AE model fit equally well or better, heritability ranged from 0.89 to 0.93. This difference between the sexes was mainly due to the effect of the shared environmental component of variance, which appears to be more important among women than among men in our study populations. Our results indicate that, in general, there are only minor differences in the genetic architecture of height between affluent Caucasian populations, especially among men.
Previous twin studies have indicated that approximately 25% of the variation in life span can be attributed to genetic factors and recent studies have also suggested a moderate clustering of extreme longevity within families. Here we discuss various definitions of extreme longevity and some analytical approaches with special attention to the challenges due to censored data. Lexis diagrams are provided for the Danish, Dutch, Finnish, Italian, Norwegian, and Swedish Twin registries hereby outlining possibilities for longevity studies within GenomEUtwin. We extend previous analyses of lifespan for the Danish 1870-1900 twin cohorts to include the new 1901-1910 cohorts, which are consistent with the previous findings. The size of the twin cohorts in GenomEUtwin and the existence of population-based, nationwide health and death registers make epidemiological studies of longevity very powerful. The combined GenomEUtwin sample will also allow detailed age-specific heritability analyses of lifespan. Finally, it will provide a resource for identifying unusual sibships (i.e., dizygotic twin pairs) where both survived to extreme ages, as a basis for discovering genetic variants of importance for extreme survival.
BACKGROUND: Although several genetic determinants (mutations or polymorphisms) have been associated with increased risk of venous thromboembolism, the overall influence of genetic factors on this disease is unknown. METHODS: We linked the Danish Twin Registry, which includes twins born 1870-1953, with the Danish National Registry of Patients, comprising all hospitalizations in Denmark since 1977. We then determined the risk of venous thromboembolism as determined from discharge diagnosis. RESULTS: We identified 26,982 twins who were alive on 1 January 1977, and computed measures of familial and genetic association of venous thrombotic disorders. Individuals were classified according to zygosity and hospitalization with venous thromboembolism. Since 1977, 678 twins were hospitalized with an episode of venous thromboembolism. Of these, only 545 pairs (281 male pairs and 264 female pairs) were alive in 1977. For men, the concordance rates for mono- and dizygotic twin pairs, respectively, were 0.22 (95% confidence interval = 0.14 to 0.30) and 0.08 (0.04-0.12). The odds ratio (interpreted as the relative risk of venous thromboembolism for one twin, given venous thromboembolism in the partner twin) was 13.5 (7.3-24.8) among monozygotic twins and 3.8 (1.8-8.3) among dizygotic twins. The respective correlations for venous thromboembolism were 0.55 (0.38-0.70) and 0.26 (0.09-0.42). The proportion of the variance attributable to genetic effects on venous thromboembolism in males was 55% (39%-68%). The remaining variation could be attributed to men's nonfamilial environments. In contrast, for women there was no intra-twin pair similarity for venous thromboembolism. CONCLUSIONS: We found differences in genetic susceptibility to venous thromboembolism between the sexes, with genetic factors playing a substantially stronger role in males than in females.
BACKGROUND: A previous study demonstrated a 40% higher rate of schizophrenia in dizygotic twins than in the general population. The aim of the present study is to evaluate whether genes influencing the rate of dizygotic twinning and genes of importance for developing schizophrenia can be associated. METHOD: Through record linkage between The Danish Twin Register, The Danish Psychiatric Central Register, and The Danish Civil Registration System, the rate of schizophrenia in singleton siblings of dizygotic and monozygotic twins was compared with the rate in siblings of singletons. RESULTS: The rate of first admission to hospital for schizophrenia in siblings of dizygotic twins was 35% greater than the rate in siblings of singletons. The result was statistically significant (p = 0.04). The rate in siblings of monozygotic twins was not increased. CONCLUSION: The results are in accordance with a theory of a linkage between genes influencing the rate of dizygotic twinning and genes influencing the threshold for developing schizophrenia.
BACKGROUND: Long-lived individuals are rare and may be selected in part for the genetic factors that promote successful aging. The children of long-lived parents may therefore age more successfully than the children of short-lived parents. METHODS: We used three major cross-sectional population-based surveys to study the association of parental longevity with successful aging in offspring. The measures of aging were hand-grip strength, cognitive performance (Mini Mental State Examination and a cognitive composite score), self-reported diseases, and self-rated health. RESULTS: For every additional 10 years the parents lived, their children's grip strength increased by 0.32 kg (95% CI = 0.00-0.63), Mini Mental State Examination score by 0.20 points (95% CI = 0.03-0.37), and cognitive composite score by 0.24 points (95% CI = 0.07-0.40). A 10-year increment of parental life was associated with a reduction by approximately 0.20 in the adjusted odds ratio for their children having each of the following conditions: diabetes; hypertension; ischemic heart disease; heart failure; stroke; or fair, poor, or very poor self-rated health. Almost all the effects were seen solely in the cohort of 70+-year-olds, but not among middle-aged or nonagenarian subjects. CONCLUSIONS: Parental life span is positively associated with the children's physical and cognitive functioning and avoidance of some of the common chronic diseases. However, the effects are small and are seen among offspring who are elderly, but not among the middle-aged or the oldest old.
BACKGROUND AND PURPOSE: Few studies have assessed the overall importance of genetic factors on stroke risk, and the results have been contradictory. We used a large, population-based twin register and nationwide registries of death and hospitalization with long-term follow-up to estimate the effect of genetic factors on the risk of stroke. METHODS: Through the population-based Danish Twin Register, we identified same-sex twin pairs born in 1870 through 1952 for whom at least 1 twin was recorded under a stroke diagnosis in the Register of Causes of Death or the Danish National Discharge Register. From the day of the first stroke event in each twin pair, the live co-twins were followed up for stroke. In survival analyses, we estimated the age- and sex-adjusted effect of zygosity on the risk of stroke death or hospitalization for stroke. Concordance rates, tetrachoric correlations, and heritability were also assessed. RESULTS: Thirty-five of 351 monozygotic pairs (10%) and 34 of 639 dizygotic pairs (5%) were concordant for stroke death. The age- and sex-adjusted relative risk of stroke death in monozygotic compared with dizygotic co-twins was 2.1 (95% CI, 1.3 to 3.3). The probandwise concordance rates were 0.18 (95% CI, 0.14 to 0.22) for monozygotic and 0.10 (95% CI, 0.08 to 0.13) for dizygotic pairs. Thirty-three of 309 monozygotic pairs (11%) and 39 of 560 dizygotic pairs (7%) were concordant for stroke hospitalization or stroke death. The age- and sex-adjusted relative risk of stroke hospitalization or stroke death in monozygotic compared with dizygotic co-twins was 1.5 (95% CI, 0.9 to 2.4). The probandwise concordance rates were 0.19 (95% CI, 0.15 to 0.24) for monozygotic and 0.13 (95% CI, 0.10 to 0.16) for dizygotic pairs. The heritability estimates were 0.32 for the liability to stroke death and 0.17 for the liability to stroke hospitalization or stroke death. CONCLUSIONS: The observed increased risk of stroke death and stroke hospitalization in monozygotic compared with dizygotic co-twins suggests that genetic factors increase the risk of stroke and that the size of this effect is moderate.
Several studies have explored the impact of marital bereavement on mortality, while increasing emphasis has recently been placed on genetic factors influencing longevity - in this paper, we study the impact of losing the spouse and losing the co-twin, for twins aged 50 to 70. We use data from the Danish Twin Registry and the Population Register of Denmark for the period 1968 through 1999. Firstly, we use survival analysis to study mortality after the death of the spouse or the co-twin. We find that the risk of dying is highest in the first year after the death of the spouse, as well as in the second year after the death of the co-twin. We then use event history analysis techniques to show that there is a strong impact of the event 'losing the co-twin' even after controlling for age, sex and zygosity and that this effect is significantly higher in the second year of bereavement. The effect is similar for men and women, and it is higher for monozygotic twins. The latter confirms the influence of genetic factors on survival, while the mortality trajectory with a peak in the second year after the death of the co-twin is consistent with the existence of a twin bereavement effect.
The Danish Twin Registry is the oldest national twin register in the world, initiated in 1954 by ascertainment of twins born from 1870 to 1910. During a number of studies birth cohorts have been added to the register, and by the recent addition of birth cohorts from 1931 to 1952 the Registry now comprizes 127 birth cohorts of twins from 1870 to 1996, with a total of more than 65,000 twin pairs included. In all cohorts the ascertainment has been population-based and independent of the traits studied, although different procedures of ascertainment have been employed. In the oldest cohorts only twin pairs with both twins surviving to age 6 have been included while from 1931 all ascertained twins are included. The completeness of the ascertainment after adjustment for infant mortality is high, with approximately 90% ascertained up to 1968, and complete ascertainment of all liveborn twin pairs since 1968. The Danish Twin Registry is used as a source for large studies on genetic influence on aging and age-related health problems, normal variation in clinical parameters associated with the metabolic syndrome and cardiovascular diseases, and clinical studies of specific diseases. The combination of survey data with data obtained by linkage to national health related registers enables follow-up studies both of the general twin population and of twins from clinical studies.