A dopamine D4 receptor exon 3 VNTR allele protecting against migraine without aura

Objective As dopamine plays an important role in the pathophysiology of migraine and antimigraine drugs have an effect on the dopamine system, the objective of this study was to examine the dopamine D4 receptor gene for involvement in the cause of migraine. Methods We tested a VNTR‐polymorphism in the dopamine D4 receptor gene, the exon 3 VNTR, in a sample of 190 family trios each with a proband with childhood migraine by using transmission disequilibrium test tests. Results We found a trend for transmission distortion of this marker in migraine, with the common seven‐repeat allele of the VNTR transmitted 58 times and not transmitted 82 times (global likelihood ratio score (LRS) = 12.27, degress of freedom (DF) = 6, p = 0.06; for the 7‐repeat allele: χ2 = 5.1, p = 0.02). This effect came only from migraine without aura (145 trios), with the common 7‐repeat allele transmitted 45 times and not transmitted 69 times (global LRS = 15.18; DF = 6, p = 0.019; for the 7‐repeat allele: χ2 = 6.4, p = 0.01; odds ratio, 0.47), whereas in migraine with aura (45 trios) there was no transmission distortion of the 7‐repeat allele. Interpretation We conclude that seven‐repeat allele of the dopamine D4 receptor VNTR is a protective factor for migraine without aura. Because migraine is a common disorder, this protective effect may have contributed to the positive selection acting on the dopamine D4 receptor exon 3 VNTR seven‐repeat allele in recent human history. We speculate that dopamine function in the lateral parabrachial nucleus is involved in migraine without aura. Ann Neurol 2007