The Riddle of Migraine's Biogenesis

Much as Jefferson urged us to question authority, the scientific method compels its adherents to test (and, even when entirely certain, test yet again). As such, science can be at once unkind to the fervent believer and warmly receptive to doubters and cynics. Rarely does scientific investigation yield “the answer”; more often are revealed intriguing possibilities or, at best, fragments of “the answer. ” This is true especially for Big Questions. Two such Big Questions: (1) is migraine genetic in origin? (2) if so, what is the molecular basis of that origin? The first question appears simple enough . and is one that most subspecialists in the field would be likely to answer in the affirmative. Migraine certainly seems to be familial. If one defines migraine in clinical (ICHD) terms, then about 10% of the general population actively is afflicted by migraine, and roughly half of those individuals report that a first degree relative similarly is afflicted; go directly to those relatives, and the prevalence of migraine rises to around 90%. What of that minority who apparently lack any family history of migraine? It’s perhaps most convenient to regard them as “new progenitors”; as a consequence of spontaneous mutations occurring during embryogenesis (so the story is told), they are the Abrahams of migraine, each begetting his or her own new family line. Extensive evidence has emerged to suggest that migraine’s familial tendency is indeed genetic in origin. Twin studies consistently have supported a genetic basis for migraine and, interestingly, at least one study indicated a more prominent genetic effect in women. A big step closer to the molecular level, specific genes and susceptibility loci predisposing both to familial hemiplegic migraine and the far more common forms of migraine have been identified. And so over the years I’ve blithely assured patients, their families, and audiences from my position at the lectern that migraine is indeed genetic; that the precise genetics of the disorder are multifactorial but that the inheritance pattern often suggests an autosomal dominant gene with incomplete penetrance; that instead of any single “migraine gene” there exists a myriad of genetic polymorphisms that can sum up to produce the familiar constellation of symptoms we term “migraine”; and that the female preponderance in migraine simply reflects that gender’s tendency regularly to experience frequent and dramatic fluctuations in the levels of sex hormones. I’ve heard this same tetralogy voiced by many of my colleagues in headache medicine, and while there may be a certain comfort and safety in numbers, science is indifferent to majority rule. That’s the problem with such tetralogies; if one accepts the first premise or two to be true, then what follows may fall into line through sheer inertia. In the paper with which this editorial is paired, Wieser et al report that in families not overtly related a susceptibility locus on Xp22 may predispose to a variety of migraine phenotypes. At least as intriguing to me, from their findings one is led to speculate that the gender-related difference in migraine prevalence may have its primary basis not in fluctuations of sex hormones but rather in a high susceptibility X-linked gene. Whatever the implications of this research, it’s refreshing and “scientific” to observe a consortium of ISSN 0017-8748 doi: 10.1111/j.1526-4610.2010. 01686.x Published by Wiley Periodicals, Inc. Headache © 2010 American Headache Society