The relative role of genetic and environmental factors in migraine without aura.

OBJECTIVE: To clarify the relative role of genetic and environmental factors in the etiology of migraine without aura (MO). METHODS: The study population consisted of 5,360 twins, 1,013 monozygotic (MZ) and 1,667 same-gender dizygotic (DZ) twin pairs, from the population-based Danish Twin Registry. A total of 87% completed a simple validated questionnaire screening for migraine. All twin pairs, in whom at least one twin had self-reported migraine or severe headache with accompanying symptoms, were interviewed via telephone by a physician. Ninety percent of the eligible twins were interviewed. Probandwise concordance rates and correlations in liability were calculated, and structural equation model-fitting analyses were applied to quantitate the relative role of genetic and environmental factors in the etiology of MO. RESULTS: The probandwise concordance rate was higher in MZ than DZ twin pairs (0.43 versus 0.31; 95% CI, 0.36 to 0.49 versus 0.26 to 0.36). The correlation in liability was higher in MZ than in DZ twin pairs (0.62 versus 0.41; 95% CI, 0.50 to 0.74 versus 0.29 to 0.53). Structural equation model fitting indicated a highly significant genetic component, because a model with both genetic and environmental components fitted significantly better than a model with only environmental components. The best fitting model implied that the liability to MO resulted from additive genetic effects (61%; 95% CI, 49 to 71%)) and individual-specific environmental effects (39%; 95% CI, 29 to 51%). CONCLUSION: This study indicates that genetic factors play a role in the etiology of migraine without aura. The genetic variability is additive, with a negligible contribution of nonadditive genetic effects. The genetic contributions were similar in men and women despite a higher prevalence in women. Environmental factors are equally important and these factors are individual to the migraineurs.     

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     

A twin study of febrile convulsions in the general population

Seven monozygotic (MZ) and six dizygotic (DZ) twin pairs with febrile convulsions (FC) in the general population were studied. The pairwise concordance rate for FC in MZ 85.7% (6/7) was higher than that in DZ 16.7% (1/6). In a discordant MZ pair, the unaffected co-twin was attacked by epileptic seizures later. Between the concordant DZ twins, the clinical symptoms and EEGs differed in quality. According to the ratio of concordance rate in MZ to that in DZ 5.1, a multifactorial mode of inheritance for FC was suspected.     

A Twin Study of Febrile Convulsions in the General Population

Seven monozygotic (MZ) and six dizygotic (DZ) twin pairs with febrile convulsions (FC) in the general population were studied. The pairwise concordance rate for FC in MZ 85.7% (6/7) was higher than that in DZ 16.7% (1/6). In a discordant MZ pair, the unaffected co-twin was attacked by epi leptic seizures later. Between the concordant DZ twins, the clinical symptoms and EEGs differed in quality. According to the ratio of concordance rate in MZ to that in DZ 5.1, a multifactorial mode of inheritance for FC was suspected.     

GENETIC FACTORS IN FEBRILE CONVULSIONS An Investigation of 64 Same-Sexed Twin Pairs

The importance of genetic factors in the aetiology of febrile convulsions (FC) has been evaluated from a study of 64 same-sexed twin pairs and their siblings. The twin pairs were selected from a twin population of 1631 normal same-sexed twin pairs. Eight of the 26 monozygotic (MZ) pairs were concordant with respect to FC, while the non-proband of one further MZ pair suffered from petit mal epilepsy. Five of the 37 dizygotic (DZ) pairs were concordant with respect to FC. The pairwise concordance rates for the MZ and DZ series were 0.28 and 0.11 respectively (chi² = 1.82, 0.10 < p < 0.20), while the MZ and DZ proband concordance rates were 0.46 and 0.20 respectively. The MZ pairwise concordance rate of 0.57 was significantly higher than the DZ concordance rate of 0.09 in the 30 female pairs (chi² = 5.77, 0.01 < p < 0.02). The incidence of FC in sibs of the propositi was 14%. The combination of a high risk of FC in the sibs of the propositi and the non-significant difference between the concordance rates in MZ and DZ pairs indicates that FC are caused by factors shared by sibs, but that these factors are to a great extent of a non-genetic nature. However, the separate analysis of the female pairs demonstrates the existence of genetic aetiological factors.     

Is the genetic liability in multifactorial disorders higher in concordant than discordant monozygotic twin pairs? A population‐based family twin study of migraine without aura

Migraine without aura (MO) is a multifactorial disorder. Expression of a disorder with multifactorial inheritance depends on the genetic liability and on environmental factors. A high liability is reflected by a high frequency of affected relatives. We have previously shown that monozygotic (MZ) twin pairs have a significant higher concordance of MO than dizygotic twin pairs. The incomplete concordance among MZ twin pairs may be due to a lower genetic liability among discordant than concordant MZ twin pairs. The present study analysed the genetic liability in MZ twin pairs concordant and discordant for MO by the population-relative risk of MO among parents and siblings. The twin pairs were from the population-based Danish Twin Register. First-degree relatives of 29 concordant and 34 discordant MZ twin pairs were blindly telephone interviewed by a physician. The participation rate of the eligible first-degree relatives was 96%. The population-relative risk of MO among parents and siblings was 2.73 (2.39-3.06) in concordant and 2.37 (2.03-2.71) in discordant MZ twin pairs. The relative risk of MO was significantly higher in female first-degree relatives of concordant than of discordant MZ male and female twin pairs. An opposite effect was observed in male first-degree relatives, although this was not significant for male first-degree relatives of female MZ twin pairs. The present study found no statistically significant difference in genetic liability to MO among concordant and discordant MZ twin pairs. However, a difference in genetic liability among MZ and DZ twin pairs is anticipated to be small. Thus, it may be possible to show the effect in a larger study population or by investigating a more frequent trait than MO.     

Concordance and heritability of multiple sclerosis in Finland: study on a nationwide series of twins

Objectives: To evaluate the changes in the multiple sclerosis (MS) concordance in twins, and the contribution of genetic and environmental factors to the aetiology of MS in Finland. Background: Both genes and the environment contribute to the development of MS. A well‐conducted twin study is an excellent means to assess the relative contribution of heritability and environmental factors. Methods: Multiple sclerosis concordance was assessed for 10 Monozygotic and 14 dizygotic twin pairs using pairwise and probandwise concordance rates. The tetrachoric correlations in liability to disease for twin pairs were computed and a polygenic multifactorial model was used to estimate heritability. Results: The pairwise concordance for MZ twins was 30% and for the DZ twins 14.3%, compared with 30% for MZ and 0% for DZ 20 years ago. The corresponding probandwise concordance rates were 46.2% and 25%. The genetic variance (heritability) was 15.3% (95% Cl 0.0–77.6), the common environmental variance 73.7% (95% Cl 14.1–93.9) and the unique environmental variance 11.1% (95% Cl 2.3–30.0). Conclusions: As the concordance of MS in DZ twins has increased during the past two decades and the heritability estimate is low, it seems that the reported increase in MS incidence in Finland is mainly caused by environmental factors.     

Dementia of the Alzheimer type: clinical and family study of 22 twin pairs

We studied 22 twin pairs in which one or both twins had dementia of the Alzheimer type (DAT). In four twins, diagnosis was confirmed by autopsy. Seven monozygotic (MZ) pairs were concordant for DAT; 10 MZ pairs were discordant. Two dizygotic (DZ) pairs were concordant for DAT, and 3 DZ pairs were discordant. The current concordance rate was 41% for MZ twins and 40% for DZ twins. The study supports the belief that, etiologically, DAT cannot be entirely accounted for by a single autosomal dominant gene. The data also suggest that in certain genetic circumstances, disease expression may be delayed in females.     

Is benign rolandic epilepsy genetically determined?

Benign rolandic epilepsy (BRE) is considered to be a genetically determined idiopathic partial epilepsy. We studied twins with BRE and compared the concordance with a twin sample of idiopathic generalized epilepsy (IGE). All eight BRE pairs (six monozygous [MZ], two dizygous [DZ]) were discordant. MZ pairwise concordance was 0 (95% confidence interval [CI], 0-0.4) for BRE compared with 0.7 (95% CI, 0.5-0.9) for 26 IGE MZ pairs. Our data suggest that conventional genetic influences in BRE are considerably less than for IGE, and other mechanisms need to be explored.     

Laterality of hand, foot, eye, and ear in twins

Information on handedness, footedness, eyedness, and earedness was collected from 33 monozygotic (MZ) twin pairs and 67 dizygotic (DZ) twin pairs. The incidence of nonright-sidedness in the twins is not higher than that reported in the literature for singletons. Similar results are found for the other lateralities. The results of assessing handedness with preference tests do not differ from those carried out with performance tests. There are no differences in incidence of nonright-sidedness between MZ and DZ twins. The concordance of lateralities is similar in MZ and DZ twins. The proportions of Right-Right, Right-Nonright, and Nonright-Nonright pairs in both groups of twins show a binomial distribution. The present results do not confirm a genetic hypothesis of determination of sidedness in humans and are comparable with the results obtained by other twin studies.     

Migraine in twins

A questionnaire study of migraine was carried out using the Institute of Psychiatry voluntary twin register. 1,800 headache questionnaires together with a personality questionnaire were sent and 1,300 replied, a 73% response rate. Concordance rates for migraine in Monozygotic (MZ) twins was 26% and in Dizygotic (DZ) twins 13%, a significant difference(p < 0.05). The concordance rates for migraine in male and female twins was not significantly different. Concordance rates for individual symptoms (e.g. unilaterality, vomiting) did not reveal any particular feature with a markedly higher genetic loading. In 9 MZ and 5 DZ pairs where both twins had common migraine, there was no shared pattern within a twin pair for precipitants or characteristics of attacks. With regard to family history of migraine, there was a common trend to the scores. Thus in MZ twins, if neither twin had migraine, there was a family history in 31%, rising to 45% where one twin had migraine and reaching 60% where both twins were affected. Overall these findings suggest a much lower genetic factor in migraine than previously thought. Results from inter-twin comparisons, taken with family history data, suggested that in some cases migraine may be significantly associated with recurrent childhood vomiting, eczema and travel sickness, but not with epilepsy or asthma. The personality questionnaire findings in twins discordant for migraine showed no significant difference in P, E, N and L scores between the twin with migraine and the partner without it. This finding refutes previous reports of increased neuroticism scores in patients with migraine.     

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.     

Epileptic seizures and syndromes in twins: the importance of genetic factors

The role of genetic factors in the occurrence of epilepsy syndromes was studied in twins recruited from the population-based Danish Twin Registry. A total of 34,076 twins were screened for epilepsy. Cases were confirmed and classified by two neurologists according to the classification systems of the International League Against Epilepsy (ILAE). A total of 214 twin pairs with epileptic seizures and 190 pairs with epilepsy were ascertained. Significantly higher concordance rates were found for monozygotic (MZ) compared to dizygotic (DZ) twins for both epileptic seizures (0.56 for MZ and 0.21 for DZ pairs, P<0.001) and for epilepsy (0.49 for MZ and 0.16 for DZ pairs, P<0.001). Concordance rates were also higher for MZ twins compared to DZ twins for both generalized epilepsy (0.65 for MZ and 0.12 for DZ) and for localization-related epilepsy (0.30 for MZ and 0.10 for DZ). In twin pairs where both members had seizures, 83% of MZ and 65% of DZ pairs had the same major epilepsy syndrome. Genetic factors were found to account for 80% of the liability to both epileptic seizures and epilepsy. In conclusion, analysis of this neurologist-verified epilepsy twin data set has confirmed that genetic factors have a substantial impact on the etiology of epileptic seizures as well as on the occurrence of both generalized and partial epilepsies.     

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.     

Smoking and Parkinson's disease in twins

OBJECTIVE: To test the hypothesis that cigarette smoking protects against the development of PD. BACKGROUND: Smoking has been inversely associated with PD in many studies, but whether this reflects a biologic effect on the underlying disease process or merely confounding or selection bias remains uncertain. METHODS: The authors compared smoking histories in male twin pairs identified from the National Academy of Sciences--National Research Council World War II Veteran Twins Cohort. The amount of cigarettes smoked (in pack-years) was collected until the time of PD onset in the affected twin or until the time of death for the unaffected twin, whichever came first. Differences in pack-years smoked until PD onset and until 10 and 20 years before onset were compared using paired t-tests. Comparisons were made overall and stratified by zygosity and concordance for PD. To assess the role of shared environment, correlation for smoking behaviors was compared between pairs concordant and discordant for PD. RESULTS: Detailed smoking histories were available for 113 twin pairs in which at least one twin had PD (discordant pairs: 43 monozygotic [MZ], 50 dizygotic [DZ]; concordant pairs: 10 MZ, 10 DZ). Within-pair correlation for ever smoking was high in MZ pairs (phi = 0.47, p = 0.001) but not in DZ pairs (phi = 0.007, p = 0.96). In 33 discordant MZ pairs and 39 discordant DZ pairs in which at least one twin had smoked, the twins without PD smoked more than their brothers smoked (32.5 vs. 22.7 pack-years, p = 0.026). This was more marked in the MZ pairs (37.1 vs. 25.3 pack-years, p = 0.077) than in the DZ pairs (28.6 vs. 20.5 pack-years, p = 0.17). A similar relationship was seen when smoking dose was calculated only until 10 years before PD onset, suggesting that the lower dose of smoking in the twin with PD was not the result of early, undiagnosed disease. CONCLUSION: Within twin pairs, risk of PD is inversely correlated with the dose (in pack-years) of cigarette smoking. This effect is most pronounced in MZ twins, despite the high correlation for smoking. Because MZ twins are genetically identical and are similar behaviorally, this difference is unlikely to result from either genetic factors or environmental confounders. These results are compatible with a true biologic protective effect of cigarette smoking.     

Parkinson's disease in twins: a follow-up study.

OBJECTIVE: To reevaluate concordance rates in 9 monozygotic (MZ) and 12 dizygotic (DZ) twin pairs with PD 8 years after the initial study. BACKGROUND: Longitudinal investigations increase accuracy in clinical diagnosis of PD. METHODS: Follow-up by personal interview and clinical examination. RESULTS: Concordance rates were not different between MZ (3/9) and DZ (5/12) twin pairs at follow-up, even when PD-associated dementia and isolated postural tremor were considered diagnostic of familial Lewy body parkinsonism. Evaluation of medical history, personality traits, and blink rate did not reveal putative early or premorbid parkinsonism in 9 co-twins who were motor-asymptomatic during the follow-up interval. However, these co-twins had reduced semantic fluency in comparison with a healthy control group of similar age. None of 7 co-twins without motor signs who underwent PET investigation 6 years previously showed signs of extrapyramidal disease at follow-up, but verbal memory continued to be reduced in 5 of these co-twins. CONCLUSION: Based on concordance rates only, the findings in our twin sample do not support a major genetic impact for the motor expression of PD.     

A Danish population-based twin study on autism spectrum disorders

Genetic epidemiological studies of Autism Spectrum Disorders (ASDs) based on twin pairs ascertained from the population and thoroughly assessed to obtain a high degree of diagnostic validity are few. All twin pairs aged 3–14 years in the nationwide Danish Twin Registry were approached. A three-step procedure was used. Five items from the “Child Behaviour Checklist” (CBCL) were used in the first screening phase, while screening in the second phase included the “Social and Communication Questionnaire” and the “Autism Spectrum Screening Questionnaire”. The final clinical assessment was based on “gold standard” diagnostic research procedures including diagnostic interview, observation and cognitive examination. Classification was based on DSM-IV-TR criteria. The initial sample included 7,296 same-sexed twin pairs and, after two phases of screening and clinical assessment, the final calculations were based on 36 pairs. The probandwise concordance rate for ASD was 95.2 % in monozygotic (MZ) twins (n = 13 pairs) and 4.3 % in dizygotic (DZ) twins (n = 23 pairs). The high MZ and low DZ concordance rate support a genetic aetiology to ASDs.     

Parkinson's disease in twins studied with 18F-dopa and positron emission tomography.

We used 18F-dopa PET to examine concordance for dysfunction of the nigrostriatal dopaminergic system in 18 co-twins of patients with Parkinson's disease (PD) and scanned one clinically concordant monozygotic (MZ) twin pair, 17 asymptomatic co-twins (10 MZ, 7 dizygotic [DZ]), and 13 twins with PD (8 MZ, 5 DZ). Mean 18F-dopa uptake of the twins with PD was significantly reduced in putamen to 38% and in caudate to 66% of normal. Mean putamen 18F-dopa uptake for the 17 asymptomatic co-twins was also significantly reduced (86% of normal), as was putamen tracer uptake for the 10 MZ (87% of normal) and seven DZ (83% of normal) asymptomatic co-twin subgroups. Four of 10 MZ and two of seven DZ asymptomatic co-twins had putamen 18F-dopa uptake reduced more than 2 SDs below the normal mean. Three of these four asymptomatic MZ co-twins had tremor on examination at the time of PET and one has now developed PD 2 years later. Our PET findings give concordances for nigral dysfunction of 45% in the MZ pairs and 29% in the DZ pairs at a 2-SD threshold, and 18% in MZ and 0% in DZ pairs at a 3-SD threshold of significance. These data suggest that the concordance for nigral pathology in PD twins may be higher than previously realized and that the presence of an isolated postural or rest tremor may be a phenotypic expression of PD.     

Twin concordance for dishonorable discharge from the military: with a review of the genetics of antisocial behavior

It has been hypothesized that there is a genetic component to antisocial behavior. To test this hypothesis, twin concordance for dishonorable discharge from the US military was examined among 15,924 twin pairs in the National Academy of Sciences-National Research Council (NAS-NRC) Twin Registry, all of whom served in the US military. Of 62 dizygotic (DZ) twin pairs, at least one of whom had received a dishonorable discharge, one pair (1.6%) was concordant for dishonorable discharge; of 47 monozygotic (MZ) twin pairs, seven (14.9%) were concordant for dishonorable discharge. Concordance rates for dishonorable discharge were significantly greater for MZ vDZ twin pairs. Concordances for dishonorable discharge were not confounded by co-diagnoses of alcoholism. The results are discussed in light of research findings suggesting a genetic component to antisocial behavior.     

Is migraine a genetic illness? The various forms of migraine share a common genetic cause

Is migraine a genetic illness? This question was previously controversial, but today the answer yes is generally accepted. The scientific evidence is the significantly increased familial risk of migraine, and the significantly higher concordance rate of migraine in monozygotic than dizygotic twin pairs. Finally, the three identified ion-channel genes that can cause familial hemiplegic migraine provide very strong evidence of genetics. Mutations in these genes can also cause sporadic hemiplegic migraine. The next question is whether the different types of migraine, i.e. migraine without aura, migraine with aura, sporadic hemiplegic migraine and familial hemiplegic migraine share a common genetic cause. This question is at present controversial. However, the fact that all types of migraine are paroxystic in nature suggest that a common genetic cause could be mutations in ion channels, although a common mutation has not yet been identified in the more common types of migraine: migraine without aura and migraine with aura.