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     

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.     

Differential twin concordance for multiple sclerosis by latitude of birthplace

OBJECTIVE: To address the inconsistency in the reported concordance of multiple sclerosis (MS) among twins by zygosity, sex, and latitude. METHODS: Four hundred eighteen medically documented monozygotic (MZ) and 380 same-sex dizygotic (DZ) pairs were ascertained from 1980 to 1992 and followed. The study population was representative of twins with multiple sclerosis. Twins from Canada and adjacent US states (at or above 41-42 degrees N) were considered "northern," and ancestry was dichotomized from descent from high-risk populations. Diagnosis before median age 29.3 years was considered "early." RESULTS: The MZ/DZ concordance ratio was 2.9 (95% confidence interval [CI], 1.0-8.9) among men and 2.6 (95% CI, 1.5-4.5) among women. The average age at northern diagnosis was independent of ancestry and 2 years earlier for both MZ (p < 0.02) and DZ (p < 0.01) patients. Among DZ twins, concordance was independent of all characteristics. Among MZ twins, concordance was 1.9 times (95% CI, 1.2-3.2) greater among northern twins, 1.9 (95% CI, 1.1-3.6) times greater among twins with high-risk ancestry, and 2.1 (95% CI, 1.2-3.6) times greater if diagnosis was early. Ancestry and early diagnosis made independent significant contributions to the differential concordance by latitude. INTERPRETATION: Multiple sclerosis is similarly heritable by sex, and the apparent variation in MZ concordance by latitude is influenced by environmental and genetic factors.     

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.     

Genetic and environmental factors in febrile seizures: a Danish population-based twin study

The relative importance of genetic and environmental factors in the etiology of febrile seizures was estimated using a large, unselected population-based twin sample. A total of 34,076 twins (aged 12-41 years), recruited from the Danish Twin Registry, were screened for febrile seizures by questionnaire. Information was obtained from 11,872 complete pairs. Concordance rates, odds ratios and correlations were used to assess the degree of similarity in monozygotic (MZ) and dizygotic (DZ) twins. Model fitting and estimation of heritability (proportion of the population variance attributable to genetic variation) were performed using standard biometrical methods. Significantly higher probandwise concordance rates were found for MZ compared with DZ twins (0.36 and 0.12, P < 0.01). Odds ratios and correlations showed a similar pattern. An etiological model including additive genetic effects and individual-specific environmental factors provided the best fit to the data with a heritability for febrile seizures of 70% (95% CI: 61-77%). The remaining 30% of the variation could be attributed to individual-specific environmental factors. In conclusion, this study has confirmed a major impact of genetic factors in the etiology of febrile seizures. Future studies aimed at identifying the specific genetic factors and environmental exposures involved in determining febrile seizure risk are clearly warranted.     

Genetic and environmental influences on depressive symptoms by age and gender in African American twins

Depression is typically considered relative to individuals and thought to originate from both biological and environmental factors. However, the environmental constraints and insults that African Americans experience likely influence the concordance by age and gender for depression scores among adult African American twins. Monozygotic (MZ) (n = 102) and Dizygotic (DZ) (n = 110) twins, age 25-88 years in the Carolina African American Twin Study of Aging were examined using an 11-item version of the CES-D measure of depressive symptomatology. Those participants with scores above nine were considered depressed. Overall, the MZ pairs had a higher concordance than the DZ pairs implying genetic influence. Both MZ and DZ males had higher concordances than either female zygosity groups. The difference between the concordance rates for MZ and DZ twin pairs was greater in males than females. By age group, the difference between the concordance rates for younger MZ and DZ twin pairs was much larger than for older pairs. The results suggest that, even though African Americans may be at risk for depression due to contextual/environmental factors, genetic influences remain important.     

Hippocampal volumes in schizophrenic twins

CONTEXT: The effects of genes and environment on brain abnormalities in schizophrenia remain unclear. OBJECTIVE: To examine the contributions of genes and environment to hippocampal volume reduction in schizophrenia. DESIGN: Population-based twin cohort study. SETTING: Finland. PARTICIPANTS: Seven monozygotic (MZ) twin pairs concordant for schizophrenia and 16 MZ and 32 dizygotic (DZ) twin pairs discordant for schizophrenia, ascertained so as to be representative of all such probands in a Finnish birth cohort, along with 28 MZ and 26 DZ healthy comparison twin pairs without a family history of psychosis. MAIN OUTCOME MEASURES: Hippocampal volume measurements taken from high-resolution magnetic resonance images. RESULTS: Hippocampal volumes of probands were smaller than those of their nonschizophrenic MZ and DZ co-twins and healthy twins. Hippocampal volumes of probands' non-ill co-twins were smaller than those of healthy twins, but those of non-ill MZ and DZ co-twins of schizophrenic patients were similar. The intraclass correlations for hippocampal volumes among healthy and discordant MZ pairs were larger than those among the respective DZ pairs. The intraclass correlation for healthy MZ pairs was larger than that for discordant MZ pairs, and the variance component estimate for additive genetic effects was lower in discordant twins than in healthy twins. CONCLUSIONS: Although hippocampal volume in healthy individuals is largely affected by genetic factors, it is subject to substantially greater modulation by environmental factors in schizophrenic patients and their relatives. The results are discussed in view of assumptions underlying classic twin methods.     

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.     

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.     

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.     

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 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.     

Multiple sclerosis in a nationwide series of twins

A nation wide Finnish Twin Cohort was linked with sickness insurance and hospital discharge registers on the basis of the unique identification number assigned to each Finnish citizen. The study series consisted of 4,063 monozygotic (MZ) and 9,001 dizygotic (DZ) same-sexed twin pairs born before 1958 and alive in 1981. Altogether, 22 subjects representing 11 MZ pairs and 10 DZ pairs showed clinically definite multiple sclerosis (MS). In one MZ pair both members had the disease. The frequency of MS among DZ twins corresponded to the figure in the Finnish population, but the prevalence was higher in MZ twins than in DZ twins.     

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.     

Heterogeneity in the inheritance of alcoholism. A study of male and female twins

Genetic influence on risk for alcoholism was examined in a US treatment sample of 50 monozygotic (MZ) and 64 dizygotic (DZ) male and 31 MZ and 24 DZ female same-sex twin pairs. For the DSM-III composite diagnosis of Alcohol Abuse and/or Dependence, statistically significant MZ/DZ differences in concordance were found with male, but not female, twins. For specific diagnoses, MZ/DZ differences were found in male subjects for both Alcohol Abuse and Alcohol Dependence, while MZ/DZ differences in female subjects were found only for Alcohol Dependence. The male MZ/DZ concordance difference for composite diagnosis but not for Alcohol Dependence could be accounted for statistically by differences in age of onset between MZ and DZ probands. As with alcohol, differences in MZ/DZ concordance were found for DSM-III composite diagnoses of Other Substance Abuse and/or Dependence with male, but not female, twins. Using Epidemiological Catchment Area data to estimate the population base rates of both alcohol and other substance use disorders allowed for heritability analyses that showed genetic factors to have only a modest influence on overall risk in both sexes (heritability estimates of approximately 0.35 for male subjects and 0.24 for female subjects). However, evidence for heterogeneity in the pattern of inheritance was also found, suggesting forms of alcoholism that may be moderately to highly heritable.     

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.     

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.     

Twin studies of affective illness.

In a summary of the major twin studies of affective illness, there are significant differences between monozygotic (MZ) and dizygotic (DZ) concordance rates for both unipolar and bipolar illness, indicating the importance of genetic factors in the etiology of affective illness. However, since 28% of MZ twins are discordant for bipolar illness and 60% of MZ twins are discordant for unipolar illness, environmental factors are important as well. In addition, there is a significant difference between unipolar and bipolar concordance for MZ twins (although not for DZ twins). This supports other evidence that unipolar and bipolar illness are separate entities, and it suggests the possibility that genetic factors are more important in the occurrence of bipolar illness than in unipolar illness.     

High concordance of bipolar I disorder in a nationwide sample of twins

OBJECTIVE: The few studies of bipolar I disorder in twins have consistently emphasized the genetic contribution to disease liability. The authors report what appears to be the first twin study of bipolar I disorder involving a population-based twin sample, in which the diagnoses were made by using structured, personal interviews. METHOD: All Finnish same-sex twins (N=19,124) born from 1940 to 1957 were screened for a diagnosis of bipolar I disorder as recorded in the National Hospital Discharge Register between 1969 and 1991 or self-reported in surveys of the Finnish Twin Cohort in 1975, 1981, and 1990. Thirty-eight pairs were thereby identified and invited to participate in the study; the participation rate was 68%. Lifetime diagnoses were made by using the Structured Clinical Interview for DSM-IV. The authors calculated probandwise and pairwise concordances and correlations in liability and applied biometrical model fitting. RESULTS: The probandwise concordance rates were 0.43 (95% CI=0.10 to 0.82) for monozygotic twins and 0.06 (95% CI=0.00 to 0.27) for dizygotic twins. The correlations in liability were 0.85 and 0.41, respectively. The model with no familial transmission was rejected. The best-fitting model was the one in which genetic and specific environmental factors explained the variance in liability, with a heritability estimate of 0.93 (95% CI=0.69 to 1.00). CONCLUSIONS: The high heritability of bipolar disorder was demonstrated in a nationwide population-based twin sample assessed with structured personal interviews.     

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.