The most recent genome-wide association study of migraine increased the total number of known migraine risk loci to 38. Still, most of the heritability of migraine remains unexplained, and it has been suggested that rare gene dysregulatory variants play an important role in migraine etiology. Addressing the missing heritability of migraine, we aim to fine-map signals from the known migraine risk loci to regulatory mechanisms and associate these to downstream genic targets. We analyzed a large cohort of whole-genome sequenced patients from extended migraine pedigrees (1040 individuals from 155 families). We test for association between rare variants segregating in regulatory regions with migraine. The findings were replicated in an independent case-control cohort (2027 migraineurs, 1650 controls). We report an increased burden of rare variants in one CpG island and three polycomb group response elements near four migraine risk loci. We found that the association is independent of the common risk variants in the loci. The regulatory regions are suggested to affect different genes than those originally tagged by the index SNPs of the migraine loci. Families with familial clustering of migraine have an increased burden of rare variants in regulatory regions near known migraine risk loci, with effects that are independent of the variants in the loci. The possible regulatory targets suggest different genes than those originally tagged by the index SNPs of the migraine loci.

中文翻译：

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家族分析显示在监管区域偏头痛的罕见风险变异。

偏头痛的最新全基因组关联研究将已知的偏头痛风险基因座总数增加到38个。然而，偏头痛的大多数遗传力仍无法解释，并且已表明罕见的基因失调变异体在偏头痛病因中起着重要作用。 。为了解决偏头痛的遗传力缺失问题，我们旨在将已知偏头痛风险基因座的信号精细定位到调节机制，并将这些信号与下游遗传靶标相关联。我们分析了来自扩展偏头痛谱系的全基因组测序患者的大队列（来自155个家庭的1040个人）。我们测试偏头痛的调节区域中分离的罕见变体之间的关联。这些发现被复制到一个独立的病例对照队列中（2027名偏头痛患者，1650名对照人群）。我们报告了增加的一个CpG岛和四个偏头痛风险基因座附近的三个多梳子组响应元素中的罕见变异的负担。我们发现该关联独立于基因座中的常见风险变异。建议调节区域影响与最初由偏头痛基因座的索引SNP标记的基因不同的基因。具有偏头痛家族簇集的家庭在已知偏头痛风险基因座附近的调节区域中具有罕见变体的负担增加，其作用与该基因座中的变体无关。可能的调控靶标提示与最初由偏头痛基因座的索引SNP标记的基因不同的基因。建议调节区域影响与最初由偏头痛基因座的索引SNP标记的基因不同的基因。具有偏头痛家族簇集的家庭在已知偏头痛风险基因座附近的调节区域中具有罕见变体的负担增加，其作用与该基因座中的变体无关。可能的调控靶标提示与最初由偏头痛基因座的索引SNP标记的基因不同的基因。建议调节区域影响与最初由偏头痛基因座的索引SNP标记的基因不同的基因。具有偏头痛家族簇集的家庭在已知偏头痛风险基因座附近的调节区域中具有罕见变体的负担增加，其作用与该基因座中的变体无关。可能的调控靶标提示与最初由偏头痛基因座的索引SNP标记的基因不同的基因。