We proposed to test the hypothesis that shared genetic susceptibility accounts for the comorbidity of migraine and epilepsy. As a first test of this hypothesis, we compared risks of migraine in relatives of probands with genetic versus nongenetic forms of epilepsy using two proxy measures of genetic susceptibility—a first-degree family history of epilepsy and idiopathic/cryptogenic (versus postnatal symptomatic) epilepsy. Neither of these two measures of genetic susceptibility to epilepsy in probands was associated with risk of migraine in relatives. These findings are consistent with those of a study by Kraus,21
reported by Andermann and Ander-mann,22
in which probands with epilepsy did not differ from controls in terms of the prevalence of migraine in their relatives. These results are not compatible with the hypothesis that shared genetic susceptibility accounts for the comorbidity of migraine and epilepsy.
In assessing risk for migraine in the relatives of probands with epilepsy, we controlled for three factors known or suspected to be associated with migraine risk—the proband's history of migraine, the relative's history of epilepsy, and the relative's gender. Migraine risk was familial, with a significantly higher risk in relatives of probands with migraine than in relatives of those without migraine. The RR of 1.5 is compatible with the findings of previous population-based studies23,24
in which migraine risks were assessed by direct interview with the relatives. Previous studies that relied on proband reports of migraine in relatives or used clinic-based ascertainment schemes may have overestimated the familial aggregation of migraine. Subjects with migraine report migraine in their relatives with greater sensitivity than do controls,17
leading to bias in estimates of relative risk.25
Persons with migraine who seek medical care for their attacks have unusually high migraine disability.26,27
If disability should be associated with familial risk, then ascertainment from clinical settings would also lead to overestimation of relative risk.
As a second test of the hypothesis of shared genetic susceptibility, we assessed risk of epilepsy in relatives of probands with versus without migraine. Migraine in the proband was not associated with epilepsy in either the parents or siblings. There was no association, either, in analyses restricted to the interviewed mothers of the probands, in whom it was possible to control for comorbid migraine in assessing risk of epilepsy. We found an association with epilepsy in only one subgroup of relatives—male offspring of female probands with epilepsy.
This overall pattern of results is inconsistent with predictions based on a model of shared genetic susceptibility to migraine and epilepsy. The single exception occurs in the analysis of sons of female probands with and without migraine. We considered several genetic models that might explain this finding. For each of these genetic models, we postulated that a hypothetical susceptibility genotype increases the risk of both epilepsy and migraine.
First, we considered mitochondrial inheritance. If a susceptibility gene for migraine and epilepsy were located in the mitochondrial genome, we would expect an increased risk of epilepsy in the offspring of female but not male probands with both epilepsy and migraine, as is observed. However, under this model, female probands would be expected to transmit susceptibility with equal probability to their sons and daughters, and not only to their sons. Also, we would expect an increased risk of epilepsy in the mothers of both male and female probands with migraine, which we did not observe. Thus our data are inconsistent with this model.
We can also reject models involving X-linkage. Under an X-linked dominant model, we would expect that risks of epilepsy would be the same in sons and daughters of female probands with both migraine and epilepsy. Under an X-linked recessive model, we would expect higher risks in sons than in daughters of female probands, but we would also expect an increased risk in siblings of female probands with versus without migraine, which we did not observe.
We also considered nongenetic models that might explain this finding. Intrauterine exposures or pregnancy complications would be expected to affect risk in offspring of women but not men with both migraine and epilepsy. However, the relevant exposures would have to be more common in women with both disorders than in women with epilepsy alone, and their effects would have to be restricted to the sons of affected women.
This unpredicted result may have arisen by chance alone. Though statistically significant, the effect is modest. We made multiple comparisons in analyses of epilepsy risk, stratified by the gender of probands and relatives as well as relationship to the proband. The result is inconsistent with the overall pattern of results and is difficult to explain on the basis of any plausible biological model.
The findings in indicate that risk of epilepsy is higher in offspring of female probands than in offspring of male probands. This maternal effect
has been consistently observed in previous studies and cannot be explained by any conventional genetic model.28,29
Our previous analyses indicate that it cannot be explained, either, by intrauterine exposure to seizures or anticonvulsants in offspring of women with epilepsy or by a higher proportion of affected mothers than affected fathers with clinical features of epilepsy associated with high familial risk.30
Perinatal complications that occur with increased frequency in women with epilepsy could not explain the maternal effect either, because they are not associated with increased risk of epilepsy in offspring without cerebral palsy.31
Given our present observation of an association between migraine in female probands and epilepsy risk in their sons, we considered the possibility that the maternal effect might be attributed to a subset of female probands with both epilepsy and migraine. Our data are inconsistent with this possibility, however, because risk was higher in offspring of females than in those of males both for probands with migraine (7.3% versus 1.9%) and for probands without migraine (4.4% versus 1.7%) ().
This study is limited by a number of factors. First, our definition of migraine differs from that recommended by the IHS. Because we began data collection prior to publication of the IHS criteria, we did not collect data on attack duration or frequency, photophobia, or phonophobia. Our criteria would fail to detect rare subtypes of migraine with sensory or hemiplegic aura. On the other hand, we may have included some individuals who do not meet the IHS criteria pertaining to attack duration and frequency. Rates of misclassification caused by these differences in definition would have been nondifferential between our comparison groups and thus could have slightly biased our estimates of RR toward the null hypothesis. However, the degree of misclassification was probably too low to attenuate a strong association between migraine risk in relatives and the proband's family history or etiology of epilepsy.
Second, probands in our series (adults with epilepsy who contacted voluntary organizations for epilepsy) are unrepresentative of the general population of persons with epilepsy. The proportion with partial onset seizures (84%) is higher than in prevalent cases of all ages in Rochester (59%),2
but is similar to that in other series of adults with epilepsy ascertained from clinical care settings.14,15
Furthermore, because our probands are adult prevalent epilepsy cases, persons with childhood-onset epilepsies that remit before adulthood, many of which are associated with high familial risk, were largely excluded from our sample of probands. This selection limits the generalizability of our findings. Thus the genetic relations between epilepsy and migraine could prove to be different in early-onset, remitting epilepsies that were excluded from our series.
Third, although epilepsy status was ascertained for most individuals in every pedigree, migraine status was ascertained only in persons who were interviewed directly. Consequently, when we evaluated the effect of the proband's history of migraine on epilepsy risk in relatives, we could not control for the confounding effect of migraine in the relatives. This confounding effect would be expected to lead to an increased risk of epilepsy in relatives of probands with migraine because (1) migraine in the proband is associated with migraine in relatives (caused by the familial aggregation of migraine) and (2) epilepsy in the relatives is associated with migraine in the relatives (caused by the comorbidity of epilepsy and migraine). This confounding may have partly explained the increased risk of epilepsy we observed in sons of female probands with migraine, although if so, it is difficult to explain why the association was limited to this subgroup.
Despite these limitations, the study results suggest that the comorbidity of migraine and epilepsy cannot be explained by genetic mechanisms which predispose to both disorders. The pattern of results is compatible with the model that both migraine and epilepsy are caused by a condition of neuronal excitability that results from genetic as well as environmental risk factors.