Vibeke Ulrich

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

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.

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.

A comparison of tension-type headache in migraineurs and in non-migraineurs: a population-based study

&NA; The prevalence, sex‐ratio and clinical characteristics of tension‐type headache were analyzed in 4000 people from the general population. The one‐year‐period prevalence of tension‐type headache was not significantly different in people with migraine without aura (83%), in people with migraine with aura (75%) and in people who had never had migraine (76%). The male/female ratio varied from 1:1.19 to 1:1.23 and was not significantly different in the three subgroups. Tension‐type headache was significantly more frequent within the last year and lasted longer in migraineurs than in people who had never had migraine. The pain characteristics and accompanying symptoms were very similar in the three subgroups. Tension‐type headache was often precipitated by stress, mental tension and tiredness. Only migraineurs had episodes of tension‐type headache precipitated by alcohol, over‐matured cheese, chocolate and physical activity. We conclude that tension‐type headache and migraine are separate disorders and not part of a continuum of headache disorders. However, migraine may aggravate and precipitate tension‐type headache possibly due to convergence of various noxious peripheral input into the trigeminal nucleus.

SCREENING FOR MIGRAINE IN THE GENERAL POPULATION : VALIDATION OF A SIMPLE QUESTIONNAIRE

We present validation of a simple questionnaire designed to screen the general population for migraine. It comprises four questions: (1) “Have you ever had migraine?” (2) “Have you ever had severe headache accompanied by nausea?” (3) “Have you ever had severe headache accompanied by hypersensitivity to sound and light?” (4) “Have you ever had visual disturbances lasting 5–60 min followed by headache?” A telephone interview carried out by a physician was used as an index of validity. The study population was 5,360 twins from the population-based Danish Twin Registry. All twin pairs where at least one twin had answered “yes” to at least one of our questions were eligible for the telephone interview (n=2,272 twins). The response rate to the questionnaire was 87%; the participation rate in the telephone interview was 90%. The questionnaire ascertained 85% of all migraineurs (sensitivity). A combination of two questions (questions 1 and 4) extracted 93% of the twins with migraine with aura and 74% of the twins with migraine without aura, yet only 26% of the sample needed to be interviewed. We conclude that in the Danish population two simple questions are sufficient to screen for migraine in selecting participants for a diagnostic clinical interview. Our questionnaire clearly merits further study to document its universal applicability.

The inheritance of migraine with aura estimated by means of structural equation modelling

Studies of migraine with aura (MA) have shown familial aggregation of the disorder, which cannot be explained by simple mendelian inheritance. The interest in a genetic basis for the disorder has increased after identification of three genetic loci for familial hemiplegic migraine (FHM), which is a rare subtype of MA with autosomal dominant inheritance. Both genetic and environmental factors seem to be important in the expression of MA. To elucidate the molecular pathogenesis of MA, knowledge of the relative role of genetic and environmental factors is essential. Twin studies are a classic way to analyse this. We applied structural equation modelling on MA with twin data obtained from a population based twin register in order to evaluate the effects of genes and environment. The correlation in liability of MA was 0.68 in monozygotic (MZ) and 0.22 in dizygotic (DZ) twin pairs, indicating a high degree of genetic determination in the total variance of liability. The best fitting model combined additive genetic effects and environmental effects that were not shared by the twins. The estimate of heritability was 0.65 and similar in males and females.

The prevalence and characteristics of migraine in twins from the general population.

We examined whether prevalence, age at onset, and cessation of migraine without aura and migraine with aura are different among twins and singletons.

Possible Risk Factors and Precipitants for Migraine with Aura in Discordant Twin-Pairs: A Population-Based Study

The aim of the present study was to detect possible risk factors in migraine with aura (MA) by analysis of discordant twin-pairs. In a recent population-based twin study we established that environmental factors account for approximately 50% of the variation in liability to MA. A cohort of 5360 same-gender twin-pairs from the general population was screened for migraine. All twin-pairs with possible migraine were interviewed by a physician. A questionnaire provided information about living conditions and lifestyle. Of the 169 discordant twin-pairs 51 were monozygotic and 118 were dizygotic twin-pairs. Several putative risk factors—schooling, education, marital status, smoking status and alcohol consumption—showed no association with MA. The presence of migraine without aura or tension-type headache did not increase the risk of MA. Stress and mental tension, and bright light precipitated attacks of MA in, respectively, 44% and 28% of the twins.

The relative influence of environment and genes in episodic tension-type headache.

Objective: To examine the relative importance of genetic and environmental influence for the development of tension-type headache by analyses of twins. Methods: The authors screened by questionnaire a population of 5,360 twins born during 1953 to 1960 from the general population for migraine and headache symptoms. The response rate of the questionnaire was 87%. All twin pairs with at least one twin of the pair reporting migraine or headache symptoms were interviewed by telephone by a physician. Correlation of liability and structural equation modeling were applied on tension-type headache. Results: A total of 1,417 subjects had tension-type headache equivalent to a 1-year prevalence of 62%. The male: female ratio was 1:1.24. Chronic tension-type headache was found in 49 twins corresponding to a prevalence of 2% with a male:female ratio of 1:1.21. The prevalence, pain characteristics, frequency, and duration of tension-type headache were similar to what has been found in the general Danish population. The correlation of liability of tension-type headache was low and not significantly different in monozygotic and dizygotic twin pairs: 0.21 (0.03 to 0.39), 0.08 (0 to 0.24). The best fitting model of phenotypic variation consisted of 81% non-shared environmental effects and of 19% additive genetic effects. Conclusions: Environmental influence is of major importance for episodic tension-type headache and a genetic factor, if it exits, is minor. In chronic tension-type headache the genetic factor may be more important. These data clearly separate episodic tension-type headache from migraine without aura where the phenotypic variation consists of non-shared environmental effects of 39% and of 61% additive genetic effects.

Analysis of 31 families with an apparently autosomal-dominant transmission of migraine with aura in the nuclear family.

We analyzed 31 families selected for an apparently autosomal-dominant mode of inheritance of migraine with aura (MA) in the nuclear family. The nuclear families were expanded with first- and second-degree relatives. All interviews were made by physicians experienced in headache diagnoses. The criteria of the International Headache Society were used. The population relative risk among children in nuclear families was similar to the estimated population relative risk of MA assuming an autosomal-dominant mode of inheritance. The population relative risk tended to decrease among first-degree relatives outside nuclear families and further among second-degree relatives. Both first- and second-degree relatives outside the nuclear families had a statistically significant lower risk of MA than expected. Thus, autosomal-dominant inheritance with or without reduced penetrance was unlikely. Autosomal-recessive inheritance was unlikely because of the unequal sex distribution. Other modes of inheritance were considered as well. Mitochondrial and X-linked inheritance were excluded because of paternal transmission. The female preponderance was too low to explain sex-influenced inheritance. We conclude that MA most likely has a multifactorial inheritance even in high-risk families with MA.