DZ Co-twins Research Articles

Risk of Islet and Celiac Autoimmunity in Cotwins of Probands with Type 1 Diabetes

Concordance for persistent islet autoimmunity (IA) and type 1 diabetes (T1D) in monozygotic twins (MZ) after one twin is diagnosed has been highly variable (30-70%), while risk for development of IA in dizygotic twins (DZ) is thought to be similar to non-twin siblings. Since 1995, the Twin Family Study at the Barbara Davis Center has followed 336 twins (168 twin probands diagnosed with T1D and 168 cotwins) with a median follow-up of 14 years (ICR:10-18 years). Zygosity testing confirmed a total of 80 MZ pairs and 88 DZ pairs. Cotwins were followed for the development of IA and celiac autoimmunity (CDA). In MZ cotwins, cumulative incidence for IA was 14% by age 20 and 63% by age 45, while development of CDA was 10% by 20 years. Development of IA and CDA by age 20 was 9.2% and 12.3% in DZ cotwins respectively, with development of IA reaching 70% by age 30 (Figure). In Cox proportional hazards models, only the proband’s age at diagnosis, but not sex, HLA-DR3 nor DR4 were associated with time to IA and CDA in cotwins. In MZ twins, younger age of the proband was associated with an increased hazard ratio (HR) for both IA and CDA, while younger age in DZ twins was associated with an increased HR for IA only. In conclusion, CDA risk does not appear to increase after age 15. With long term follow-up, cumulative incidence for IA is high in DZ twins, similar to MZ twins, suggesting a role of possible early environmental factors shared by T1D-discordant cotwins. Disclosure T.M. Triolo: None. A.R. Fouts: None. L. Pyle: None. L. Yu: None. P. Gottlieb: Advisory Panel; Self; Bristol-Myers Squibb Company. Research Support; Self; Caladrius Biosciences, Inc.. Advisory Panel; Self; Eli Lilly and Company. Board Member; Self; ImmunoMolecular Therapeutics. Consultant; Self; Kamada. Research Support; Self; JDRF, National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk Inc., MacroGenics, Inc., Pfizer Inc.. Advisory Panel; Self; Viacyte, Inc.. Research Support; Self; GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc.. A. Steck: None.

Responsibility and cooperativeness are constrained, not determined.

Responsibility and cooperativeness are constrained, not determined.

Urticaria in Monozygotic and Dizygotic Twins

Aim. To identify risk factors for urticaria, to determine the relative proportion of the susceptibility to urticaria that is due to genetic factors in an adult clinical twin sample, and to further determine whether the genetic susceptibility to urticaria overlaps with the genetic susceptibility to atopic diseases. Methods. A total of 256 complete twin pairs and 63 single twins, who were selected from sibships with self-reported asthma via a questionnaire survey of 21,162 adult twins from the Danish Twin Registry, were clinically interviewed about a history of urticaria and examined for atopic diseases. Data were analysed with Cox proportional hazards regression and variance components models. Results. A total of 151 individuals (26%) had a history of urticaria, whereas 24 (4%) had had symptoms within the past year. Female sex, HR = 2.09 (1.46–2.99), P = 0.000; hay fever, HR = 1.92 (1.36–2.72), P = 0.000; and atopic dermatitis, HR = 1.44 (1.02–2.06), P = 0.041 were significant risk factors for urticaria. After adjustment for sex and age at onset of urticaria in the index twin, the risk of urticaria was increased in MZ cotwins relative to DZ cotwins, HR = 1.42 (0.63–3.18), P = 0.394. Genetic factors explained 45% (16–74%), P = 0.005, of the variation in susceptibility to urticaria. The genetic correlation between urticaria and hay fever was 0.45 (0.01–0.89), P = 0.040. Conclusions. Susceptibility to urticaria is partly determined by genetic factors. Urticaria is more common in women, and in subjects with hay fever and atopic dermatitis, and shares genetic variance with hay fever.

A controlled study of dental erosion in 2‐ to 4‐year‐old twins

Dental erosion (DE) in children is a significant oral health issue and has become a focus for research in clinical paediatric dentistry. This study investigated DE in the primary dentition of 2- to 4-year-old twin and singleton children with regard to the genetic, medical and dietary factors associated with the condition. The 128 subjects consisted of 88 twin children (31 monozygous, 50 dizygous, 7 unknown zygosity) and singletons (n = 40) aged 2-4 years. Medical, dental, and dietary histories were obtained. The children were examined for DE using a modified index. The prevalence of DE by subject affected was 77% in monozygotic twins (MZ), 74% in dizygotic twins (DZ), and 75% in singleton controls (P > 0.1). Of the teeth scored, 12% had mild, 10% moderate, and 1% severe lesions, and DE was more severe in the older age group (P < 0.05). Concordance rates for erosion lesions in MZ and DZ co-twins were not statistically significant. The prevalence of DE and the concordance of erosion lesions were similar between MZ and DZ twins and singleton children, suggesting that the contribution of genetic factors to DE is negligible.

An Integrative Approach for Studying the Etiology of Alcoholism and Other Addictions

AbstractStudies 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.

An Integrative Approach for Studying the Etiology of Alcoholism and

Studies of alcoholism etiology often focus on genetic or psychosocial 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.

The Inheritance of Neuropsychological Dysfunction in Twins Discordant for Schizophrenia

While genetic influences in schizophrenia are substantial, the disorder's molecular genetic basis remains elusive. Progress has been hindered by lack of means to detect nonpenetrant carriers of the predisposing genes and by uncertainties concerning the extent of locus heterogeneity. One approach to solving this complexity is to examine the inheritance of pathophysiological processes mediating between genotype and disease phenotype. Here we evaluate whether deficits in neurocognitive functioning covary with degree of genetic relationship with a proband in the unaffected MZ and DZ co-twins of patients with schizophrenia. Twin pairs discordant for schizophrenia were recruited from a total population cohort and were compared with a demographically balanced sample of control twin pairs, on a comprehensive neuropsychological test battery. The following four neuropsychological functions contributed uniquely to the discrimination of degree of genetic loading for schizophrenia and, when combined, were more highly correlated within MZ pairs than within DZ pairs, in both discordant and control twins: spatial working memory (i.e., remembering a sequence of spatial locations over a brief delay), divided attention (i.e., simultaneous performance of a counting and visual-search task), intrusions during recall of a word list (i.e., "remembering" nonlist items), and choice reaction time to visual targets. Together with evidence from human and animal studies of mediation of these functions by partially distinct brain systems, our findings suggest that there are multiple independently inherited dimensions of neural deficit in schizophrenia and encourage a search for genes contributing to quantitative variation in discrete aspects of disease liability. On tests of verbal and visual episodic memory, but not on the liability-related measures, patients were more impaired than their own MZ co-twins, suggesting a preferential impact of nongenetic influences on long-term memory systems.

Diabetic twins in Japan

By the cooperation of members of the Japan Diabetes Society, we collected data on 144 twin pairs with diabetes or glucose intolerance. By the diagnosis of reporting physicians, the concordance rate of diabetes in monozygotic twins (MZ) was 47% (9/10) for IDDM and 87% (68/78) for NIDDM. The concordance rate in dizygotic twins (DZ) was 8% (1/13) and 43% (9/21) for IDDM and NIDDM, respectively. The concordance rate was higher in MZ than in DZ and in IDDM than in NIDDM. In MZ, the concordance rate was higher in twin pairs in which probands developed diabetes at an older age. The discordant period for diabetes was not shorter in discordant pairs than in concordant pairs. The period of living together was irrelevant to concordance for diabetes. When co-twins of NIDDM twins were examined by oral glucose tolerance test, 98% of co-twins of MZ and 92% of co-twins of DZ had diabetes or a milder degree of glucose intolerance, while in IDDM pairs 45% of MZ and 50% of DZ co-twins had normal glucose tolerance. The insulinogenic index (the ratio of the increment of insulin to that of blood glucose 30 min after a glucose load) in discordant NIDDM co-twins was similar to subjects with the same degree of glucose intolerance.

Epidemiologic analysis of gene-environment interaction in twins.

Our aim was to develop a simple method for testing gene-environment interaction in twin data ascertained through affected twins (probands), with known exposure status of both cotwins. To this end we derived formulae for two epidemiologic measures, as a function of prevalence of an exposure and genotype, and disease risk conditional on exposure and genotype: (1) relative risk of disease in exposed vs. unexposed cotwins, stratified by zygosity and proband exposure status (RRE), and (2) relative risk of disease in MZ vs. DZ cotwins, stratified by exposure status of proband and cotwin (RRZ). Then we investigated the behavior of these two measures under different assumptions about the relations between exposure and genotype in terms of their effect on disease risk. If an exposure has a different effect in the presence vs. absence of the genotype, RRE differs between MZ and DZ cotwins. Similarly, if a genotype has a different effect in exposed vs. unexposed persons, RRZ differs between exposed and unexposed cotwins. However, large differences in RRE between MZ and DZ cotwins, or large differences in RRZ between exposed and unexposed cotwins, do not occur except under very extreme conditions, such as a genotype that increases disease risk in exposed individuals, and has a protective effect in unexposed individuals. These results suggest that power to detect gene-environment interaction is limited with this approach. Conversely, if large differences in RRE or RRZ are observed, they are likely to reflect strong gene-environment interaction.

Genetic and environmental influences on body measurements of Belgian twins.

A study of 100 MZ and 67 DZ twin pairs aged 18 to 25 years has shown a highly significant genetic contribution to the following measurements: standing and sitting height; height on tragus; arm length; biacromial, biiliac, and bitrochanteric diameter; weight; circumference of thigh and of upper arm relaxed and contracted; and head length and breadth. The twins were brought up together and of the same socioeconomical, geographical, ethnical, and cultural origin. Zygosity diagnosis was based on 22 to 26 blood groups. The means of the measurements were smaller in MZ than in DZ twins, some of them significantly so. The intraclass correlation coefficients of the MZ cotwins were all significant and greater than those of the DZ cotwins. In families of same geographical origin, sib-sib correlations were somewhat smaller than those of the DZ cotwins, but for the three diameters of the body the order was reversed.

GENETIC FACTORS IN ACTIVITY MOTIVATION

A study of 61 pairs of identical (MZ) and fraternal (DZ) grade-school twin girls found moderate genetic contributions to individual differences in several aspects of activity motivation: reaction time, variety of activity, anxiety, and impatience. Activity motivation was defined by empirical clusters of related measures including ratings, experimental tasks, and interviews. Intraclass correlation coeficients for the MZ and DZ groups were compared, and heritability estimates were computed for every measure. Possible biases in twin research were examined with special emphasis on the environmental similarity of MZ and DZ co-twins.