The existence of a genetic basis for migraine susceptibility is unequivocal. Both familial incidence studies and twin studies indicate that migraine susceptibility has a significant genetic component. Even so, genetic inheritance patterns are not simple. Only approximately 50% of migraine susceptibility can be attributed to multiple, additive genes, with the remaining component attributable to what appears to be a wide variety of environmental factors. Therefore, with the exception of a few rare migraine subtypes (eg, mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes [MELAS] syndrome and familial hemiplegic migraine), the genetic contribution to clinical susceptibility seems to be relatively minor and certainly multigenic. Thus, despite considerable efforts by clinicians and scientists around the world, the “genetic” cause of the common forms of migraine and other types of headache remain largely unknown. These observations would seem to make the ongoing search for the genetic basis of migraine susceptibility a daunting task, and yet they have not slowed the extensive international search for just such a molecular and genetic basis. After nearly a decade of genetic research involving migraine, it may be an appropriate time to review the lessons learned from more successful molecular genetic analyses of other common human disorders. For example, cardiovascular disease represents another common public health problem for which genetic and environmental determinants coexist. In striking contrast to research on migraine susceptibility, molecular genetic research in cardiovascular disease has been able to focus successfully on very specific biochemical pathways. More than 35 specific genes are known to be involved in the metabolism of lipids alone, and of major clinical significance is the fact that all known molecular targets for the treatment of hyperlipidemia (eg, 3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase) lie within these same biological pathways. Molecular genetic studies have shown that both common and rare variants of almost every one of the lipid metabolism genes exert an effect on serum lipid concentrations and, therefore, an effect on the susceptibility to cardiovascular disease. The contribution of any single genetic variant (eg, apolipoprotein E variants) on overall disease risk, however, is relatively small. Moreover, hyperlipidemia is only one of many known risk factors for heart disease. Reflecting this multiplicity of risk factors, molecular genetic analyses indicate that the complex interaction of more than 100 genes is likely to be involved in determining an individual’s inherent “susceptibility” to cardiovascular disease. And again, with the exception of very rare forms of familial hyperlipidemia, the search for relevant “susceptibility” genes in cardiovascular disease has been significantly facilitated From Burlingame, Calif.
Headache: The Journal of Head and Face Pain