Concordance for multiple sclerosis in Danish twins: an update of a nationwide study

The occurrence of multiple sclerosis (MS) in twins has not previously been studied in complete nationwide data sets. The existence of almost complete MS and twin registries in Denmark ensures that essentially unbiased samples of MS cases among twins can be obtained. In this population-based study, virtually all Danish MS cases among twins born before 1983 with onset of MS after 1948 and diagnosis before I January 1997 were identified. Of 13 286 MS cases, 178 were twins and, of these 164 twin pairs were discordant and seven were concordant. We found significantly higher proband-wise concordance among monozygotic twins than dizygotic twins, with estimated proband-wise concordances of 24% (95% confidence interval (CI): 5-39%) for monozygotic and 3% (95% CI: 0-8%) for dizygotic twins. Thus, a monozygotic twin whose co-twin has MS has a 24% risk of developing the disease, while the corresponding risk for a dizygotic twin is only 3%. Our results largely confirm previously published concordance estimates and indicate that genetic factors are of importance in susceptibility to MS.     

Parkinson's disease in monozygotic twins

Recent studies of twins have demonstrated an unexpectedly low concordance of Parkinson's disease in monozygotic twins. Only two monozygotic twin pairs concordant for it have been reported. However, both pairs were atypical because of an early age at onset and other unusual features. We studied a monozygotic twin pair concordant for typical Parkinson's disease. The brothers have lived apart for forty years. The onset of tremor occurred three months apart, at age 71. The progression of the symptoms has been identical. Although one of the twins is more severely affected, both have typical manifestations of Parkinson's disease that respond well to dopaminergic medication. The occurrence of Parkinson's disease in these monozygotic twins suggests that genetic susceptibility is important in the tremor-dominant variety of Parkinson's disease.     

Decline in cognitive performance in aging twins. Heritability and biobehavioral predictors from the National Heart, Lung, and Blood Institute Twin Study.

The present study examined the contribution of genetic factors to Digit Symbol performance and its decline in 23 monozygotic twin pairs (mean age at examination 1, 57.1 years) and 21 dizygotic twin pairs (mean age at examination 1, 56.3 years). These men were assessed twice during a 5-year interval as part of the National Heart, Lung, and Blood Institute Twin Study. The prevalence of decline (a change, greater than 1 SD) during the 5-year interval was 35% and 39% for monozygotic and dizygotic twins, respectively. The pairwise concordance for decline was 45% in monozygotic and 8% in dizygotic twin pairs, suggesting a possible role for genetic factors in the decline in Digit Symbol performance in this sample. A comparison of baseline biologic and behavioral characteristics within monozygotic twin pairs discordant for decline in Digit Symbol performance revealed that decliners had higher initial systolic blood pressures, lower serum cholesterol levels, and lower heart rates than nondecliners.     

Multiple sclerosis in twins from continental Italy and Sardinia: a nationwide study

Knowledge about the balance between heritable and nonheritable risk in multiple sclerosis (MS) is based on twin studies in high-prevalence areas. In a study that avoided ascertainment limitations and directly compared continental Italy (medium-prevalence) and Sardinia (high-prevalence), we ascertained 216 pairs from 34,549 patients. This gives a twinning rate of 0.62% among MS patients, significantly less than that of the general population. In continental Italy, probandwise concordance was 14.5% (95% confidence interval, 5.1-23.8) for monozygotic and 4.0% (95% confidence interval, 0.8-7.1) for dizygotic twins. Results in Sardinia resemble those in northern populations but in limited numbers. Monozygotic concordance was 22.2% (95% confidence interval, 0-49.3) probandwise, but no concordant dizygotic pairs were identified. A questionnaire on 80 items possibly related to disease cause was administered to 70 twin pairs, 135 sporadic patients, and 135 healthy volunteers. Variables positively (7) or negatively (2) associated with predisposition and concordance in twins largely overlapped and were mainly linked to infection. If compared with previous studies, our data demonstrate that penetrance in twins appears to correlate with MS prevalence. They highlight the relevance of nonheritable variables in Mediterranean areas. The apparent underrepresentation of MS among Italian twins draws attention to protective factors, shared by twins, that may influence susceptibility.     

Migraine without aura: a population-based twin study.

To investigate the importance of genetic and environmental factors to the etiology of migraine without aura and to compare the symptomatology of migraine without aura in monozygotic and dizygotic twins, 2,680 twin pairs were recruited from the population-based Danish Twin Registry. Monozygotic (MZ) and same-sex dizygotic (DZ) twin pairs, where at least one twin had self-reported migraine or self-reported severe headache with accompanying symptoms, were telephone interviewed by a physician. The participation rate in the telephone interview was 90%. The pairwise concordance rate was significantly higher in MZ than in DZ twin pairs (28% vs 18%). The probandwise concordance rate was 40% (95% CI, 33-48%) in MZ and 28% (95% CI, 23-33%) in DZ twin pairs. The pairwise concordance rates for the different pain characteristics and accompanying symptoms were not significantly different in MZ and DZ twin pairs. However, comparing all of the pairwise concordance rates of pain characteristics and accompanying symptoms together, MZ twin pairs were significantly more concordant than DZ twin pairs. Our data demonstrate a significant genetic factor in migraine without aura. The size of this factor is modest and the demonstration of susceptibility genes is predicted to be laborious and difficult.     

Alzheimer's disease in 22 twin pairs--13-year follow-up: hormonal, infectious and traumatic factors

We obtained follow-up data on 22 sets of twins where at least one twin had Alzheimer's disease (AD). The concordance rate for monozygotic twins (n = 17 pairs) was 59%, whereas that for dizygotic twins was 40%. In our series 8 monozygotic twins had hysterectomies; all had AD. The twins with hysterectomies also had a tendency to develop AD at an earlier age than their co-twin. Five twins with serious systemic infection developed AD, and they tended to have earlier onset than their corresponding twin. We found no strong evidence that head injury predisposed to AD.     

Genetic epidemiology of epilepsy: a twin study

The study explored the genetic susceptibility and prevalence of epilepsy in twins. The data on epilepsy were retrieved from the health records of 199 pairs of twins. Proband concordance rate in monozygotic (MZ) twins was four times more than that in dizygotic (DZ) twins (0.67 vs. 0.17). Three of 15 (20%) affected twin kinships had epileptic first-degree relatives. These findings indicated significant underlying genetic susceptibility to epilepsy with the Holzinger's heritability estimate being 0.45. The prevalence of epilepsy was similar in MZ (45.45), DZ (45.11) twins, and their non-twin siblings (47.60). In the general population from various nationalities, the mean prevalence rate of epilepsy varied from 5 to 17 per 1000. The appreciably higher prevalence rate in twin kinships could be attributed to peculiar development factors associated with the twinning process or the intrauterine environment of mothers having tendencies to bear twins. Of the genetic markers, PTC locus seemed to be associated with the susceptibility to epilepsy. The allele frequency of non-tasters (t) seemed greater in epileptic twin kinships (0.71) than that in the general population (0.53). The frequency of non-tasters was similar in MZ and DZ twins and singletons: 27.3%, 26%, and 27.7% respectively. The PTC data on the general population was based on a sample of 278 individuals.     

The complex genetic aetiology of multiple sclerosis

A large body of immunologic, epidemiologic, and genetic data indicate that tissue injury in multiple sclerosis (MS) results from an abnormal immune response to one or more myelin antigens that develops in genetically susceptible individuals after exposure to an as-yet undefined casual agent. A genetic component in MS is indicated by an increased relative risk to siblings compared to the general population and an increased concordance rate in monozygotic compared to dizygotic twins. The past few years have seen real progress in defining the genetic basis of MS setting the stage for new approaches for the final characterisation of the genes involved in MS susceptibility and pathogenesis. Whole genome screens conducted in different populations identified discrete chromosomal regions potentially harbouring MS susceptibility genes, however, with the exception of the Major Histocompatibility Complex (MHC) on 6p21, no single locus generated overwhelming evidence of linkage. These results suggest a complex genetic aetiology, including multiple genes of small to moderate effect and probable genetic heterogeneity. The identification and characterisation of MS susceptibility genes and their correlation with disease phenotypes is likely to define the basic aetiology of the disease, improve risk assessment and influence therapeutics.     

Genetic aspects of multiple sclerosis

A large body of immunological, epidemiological, and genetic data indicate that tissue injury in multiple sclerosis (MS) results from an abnormal immune response to one or more myelin antigens that develops in genetically susceptible individuals after exposure to an as-yet undefined causal agent. A genetic component in MS is indicated by an increased relative risk to siblings compared to the general population, and an increased concordance rate in monozygotic compared to dizygotic twins. The past few years have seen real progress in defining the genetic basis of MS setting the stage for new approaches for the final characterization of the genes involved in MS susceptibility and pathogenesis. Whole genome screens conducted in different populations identified discrete chromosomal regions potentially harboring MS susceptibility genes, however, with the exception of the Major Histocompatibility Complex (MHC) on 6p21, no single locus generated overwhelming evidence of linkage. These results suggest a complex genetic etiology, including multiple genes of small to moderate effect and probable genetic heterogeneity. The identification and characterization of MS susceptibility genes and their correlation with disease phenotypes is likely to define the basic etiology of the disease, improve risk assessment, and influence therapeutics.     

Evidence of a genetic factor in migraine with aura: A population-based Danish twin study

We studied the genetic influence on cause of migraine with aura (MA) by analyzing a twin population. The twin sample consisted of 2,026 monozygotic (MZ) twins and 3,334 same-sex dizygotic (DZ) twins, born from 1953 to 1960, from the population-based New Danish Twin Register. A validated questionnaire was used to screen for migraine, the response rate being 87%, and similar among MZ and DZ twins. All twin pairs with at least 1 twin with possible MA were interviewed by a physician experienced in headache diagnoses. The answers from the questionnaire as well as the zygosity of the twins were blinded for the interviewer. A total of 211 twin pairs were identified, of whom 77 pairs were MZ and 134 pairs were DZ. The lifetime prevalence of MA was 7% and with a male-to-female ratio of 1:1.1. The pairwise concordance rates were significantly higher in MZ (34%) than in DZ twin pairs (12%), emphasizing the importance of genetic factors in MA. However, environmental factors are also important, as the pairwise concordance rate was less than 100% in MZ twin pairs. The recurrence risk of MA was 50% in MZ and 21% in DZ twin pairs. In nontwin siblings, the recurrence risk of MA is 27%, which is similar to the recurrence risk in DZ twins. This indicates that MA is not developed due to specific environmental factors shared by the twins. Ann Neurol 1999;45:242–246     

Genetic or epigenetic difference causing discordance between monozygotic twins as a clue to molecular basis of mental disorders

Classical twin research focused on differentiating genetic factors from environmental factors by comparing the concordance rate between monozygotic (MZ) and dizygotic twins. On the other hand, recent twin research tries to identify genetic or epigenetic differences between MZ twins discordant for mental disorders. There are a number of reports of MZ twins discordant for genetic disorders caused by genetic or epigenetic differences of known pathogenic genes. In the case of mental disorder research, for which the causative gene has not been established yet, we are trying to identify the 'pathogenic gene' by comprehensive analysis of genetic or epigenetic difference between discordant MZ twins. To date, no compelling evidence suggesting such difference between MZ twins has been reported. However, if the genetic or epigenetic difference responsible for the discordant phenotype is found, it will have impact on the biology of mental disorder, in which few conclusive molecular genetic evidences have been obtained.     

A monozygotic twin pair discordant for anorexia nervosa

This case study describes a female monozygotic twinship in which one of the twins presented with anorexia nervosa. The case supports the suggestion from the few such discordant pairs previously reported that the affected twin tends to have been relatively disadvantaged from an early age and to be the less dominant of the pair. A review of previously reported cases suggests a concordance rate for anorexia nervosa of about 50% in female MZ twin pairs. Some methodological problems associated with the derivation of such estimates are noted.     

Neuroanatomic variation in monozygotic twin pairs discordant for the narrow phenotype for autism

OBJECTIVE: The broader autism phenotype includes relatives of individuals with autism who display social and language deficits that are qualitatively similar to those of autism but less severe. In previous studies of monozygotic twins discordant for autism, more than 75% of the twins without autism displayed the broader phenotype. Differences in neuroanatomy between discordant monozygotic twins might be associated with the narrow and broader behavioral phenotypes. The authors examined the relationship of twin pair differences in clinical phenotype to differences in neuroanatomic phenotype. METHOD: The subjects were 16 monozygotic twin pairs between the ages of 5 and 14 years and 16 matched singleton comparison subjects. Seven twin pairs were clinically concordant and nine twin pairs were clinically discordant for strictly defined autism. After magnetic resonance imaging, a semiautomated procedure was applied to images in which the brain tissue was subdivided into neurofunctional regions and segmented into gray, white, and ventricular compartments. RESULTS: Both the concordant and discordant twin pairs exhibited concordance in cerebral gray and white matter volumes. However, only the clinically concordant pairs exhibited concordance in cerebellar gray and white matter volumes. Within the discordant twin pairs, both the twins with autism and their co-twins exhibited frontal, temporal, and occipital white matter volumes that were lower than those of the comparison subjects. CONCLUSIONS: These findings support the role and the limits of genetic liability in autism. Continuing to clarify the neuroanatomic pathways in autistic spectrum disorders could illuminate the etiology of autism and, ultimately, contribute to treatments.     

The occurrence of epilepsy and febrile seizures in Virginian and Norwegian twins

Twin studies provide an efficient method for examining the importance of genetic and environmental factors in the etiology of disorders such as epilepsy. Population-based twin registries are especially valuable for studies of this type since effects of reporting and self-selection biases on the resulting data are minimized. Among 14,352 twin pairs contained in the Virginia and Norwegian twin panels for whom questionnaire information was available, there was a history of epilepsy in one or both members of 286 pairs; febrile seizures were reported in 257 pairs. Analyses of questionnaire data revealed no significant differences in concordance rates between Virginian and Norwegian twins for either epilepsy or febrile seizures. Probandwise concordance rates for epilepsy were 0.19 in monozygotic twins and 0.07 in dizygotic twins. Analogous rates for febrile seizures were 0.33 (monozygotic) and 0.11 (dizygotic). These results provide further evidence that genetic factors do have a role in the expression of epilepsy and febrile seizures.     

Conjugal multiple sclerosis: population-based prevalence and recurrence risks in offspring. Canadian Collaborative Study Group

From a population-based sample of 15,504 patients attending Canadian multiple sclerosis (MS) clinics, we have determined the frequency of conjugal MS and have estimated the recurrence risk in offspring of such matings. Twenty-three MS cases were found among 13,550 spouses of study probands for a crude conjugal rate of 0.17% (95% CI of 0.10%-0.24%). Despite ascertainment bias that expectedly inflates this number, this is a frequency intermediate between the point prevalence (0.1%) and lifetime risk (0.2%) for the general population and close to an order of magnitude less than reported for half siblings reared apart (1.06%) from the same population. Six of the 49 offspring of conjugal pairs also had MS, and age conversion gives a rate similar to the concordance rate for Canadian monozygotic twins. However, this correction may not be appropriate in this special case. Despite an ascertainment bias in favor of recognizing affected spouses and a large population sample, the common environment in adulthood shared by spousal pairs could not be shown to increase the risk of conjugal MS. Although the high recurrence rate in offspring is similarly subject to an upward bias, the low risk for MS spouses and the high risk for offspring support other data indicating that familial risk is genetically determined. Furthermore, these results imply that susceptibility alleles are shared by unrelated individuals with the disease.     

Essential tremor in twins: an assessment of genetic vs environmental determinants of etiology.

OBJECTIVE: To determine the relative contribution of genetics and environment to essential tremor using a twin study method. METHODS: Twins with postural or kinetic tremor were identified by movement disorders specialists during the conduct of a study investigating PD in members of the National Academy of Sciences and National Research Council World War II Veteran Twins Registry. The diagnosis of essential tremor was made by consensus using established diagnostic criteria. RESULTS: A total of 196 twins had postural or kinetic tremor on examination. Of these, 137 had PD or had a twin with PD and were excluded from this study. Thirty-three others were excluded because of incomplete data for their twin. Sixteen twin pairs were identified in which at least one twin had essential tremor. Pairwise concordance in monozygotic twins was approximately two times that in dizygotic twins (0.60 monozygotic, 0.27 dizygotic). CONCLUSION: This pattern is consistent with a genetic cause of essential tremor. Because monozygotic concordance is not 100%, environmental factors may also play a role in the cause of the disease.     

Role of genes and environments for explaining Alzheimer disease

CONTEXT: Twin studies using selected samples have shown high heritability for Alzheimer disease (AD). OBJECTIVE: To evaluate genetic and environmental influences on AD in a fully ascertained population of older twins, including like- and unlike-sex pairs. DESIGN: Five-group quantitative genetic model: male monozygotic twins, female monozygotic twins, male dizygotic twins, female dizygotic twins, and unlike-sex twins. SETTING AND PARTICIPANTS: All twins in the Swedish Twin Registry aged 65 years and older. The study included 11,884 twin pairs, among whom were 392 pairs in which 1 or both members had AD. MAIN OUTCOME MEASURES: All individuals were screened for cognitive dysfunction. Suspected cases of dementia and their co-twins received complete clinical diagnostic evaluations for AD. Estimates of heritability, shared environmental influences, and nonshared environmental influences, adjusting for age, were derived from the twin data. RESULTS: Heritability for AD was estimated to be 58% in the full model and 79% in the best-fitting model, with the balance of variation explained by nonshared environmental influences. There were no significant differences between men and women in prevalence or heritability after controlling for age. Within pairs concordant for AD, intrapair difference in age at onset was significantly greater in dizygotic than in monozygotic pairs, suggesting genetic influences on timing of the disease. CONCLUSIONS: In the largest twin study to date, we confirmed that heritability for AD is high and that the same genetic factors are influential for both men and women. However, nongenetic risk factors also play an important role and might be the focus for interventions to reduce disease risk or delay disease onset.     

Genetic and environmental factors in epilepsy: a population-based study of 11900 Danish twin pairs

The contribution of genetic and environmental factors to the occurrence of epilepsy was examined in an unselected sample of twins recruited from the population-based Danish Twin Registry. Information on the occurrence of epilepsy in both members of a twin pair was obtained from 11900 pairs whose ages ranged from 12 to 41 years. Concordance rates, odds ratios and tetrachoric correlations were used to quantify the similarity of monozygotic (MZ) and dizygotic (DZ) twins. The sample was stratified by sex and separated into two age cohorts for analysis. Significantly higher probandwise concordance rates were found for MZ compared with DZ twins (0.37 and 0.08, P<0.01). Odds ratios and tetrachoric correlation showed similar pattern. An etiological model including additive genetic and individual specific environmental factors provided the best overall fit to the data, with 70 and 88% of the liability to develop epilepsy being accounted for by genetic factors in the younger and older cohorts, respectively. Individual specific environmental factors explained the remaining 30 and 12%, respectively. In conclusion, this study has confirmed the substantial impact, which genetic factors have in the etiology of epilepsy. The heritability of epilepsy is high and seems to increase with age.     

Concordance for cognitive impairment: a study of 50 community-dwelling elderly female-female twin pairs

The present study sought to determine concordance of cognitive impairment among elderly female twins. Cognitive testing was performed by telephone interview in a sample of 100 female-female twins older than 65 years. The participants were 32 monozygotic (MZ) and 18 dizygotic (DZ) female twin pairs, all between the ages of 65 and 86 years; their mean age was 70.2 +/- 4.6 years. All were recruited from the Institute of Psychiatry Volunteer Twin Register (IPVTR). We used the Telephone Interview for Cognitive Status (TICS) and analyzed the modified total score. Correlation's of age and zygosity were computed in relation to score on cognitive interview, and differences between MZ twin pairs (n = 32) and DZ pairs (n = 18) were analyzed using the general linear model procedure. Five subjects of the 64 MZ females (7.8%) and one DZ female (2.4%) were found to be cognitively impaired. In no case was the second twin affected. No differences in cognitive score were found between MZ and DZ twin pairs. In both groups a highly significant correlation was found between age and lower score: R(2) = -0.32, P =.009. We conclude that aging-related impairment in cognitive testing did not differ between MZ and DZ elderly female twins. Although the overall sample size was relatively small and error variance may have been introduced by imprecise measures of zygosity, the present findings are suggestive of gender differences in cognitive performance that need further evaluation.     

Are we overestimating the genetic contribution to schizophrenia?

That genetic factors contribute to the etiology of schizophrenia is no longer debated; the nature and magnitude of that contribution, however, are still open for discussion. In this article, concordance rates for twin studies of schizophrenia are reviewed as one means of assessing the magnitude of the genetic contribution. Using only those studies in which representative samples were used and zygosity was determined with reasonable certainty, the pairwise concordance rate for schizophrenia was found to be 28 percent for monozygotic (MZ) and 6 percent for dizygotic (DZ) twins. Review of twin studies of other central nervous system diseases reveals that schizophrenia is most similar to multiple sclerosis (MZ concordance rate 27%). Although genetics remains as the single most clearly defined etiological factor in schizophrenia, the question remains whether we are overestimating the magnitude of the genetic contribution.