Whole Genome Association Study of Migraine in Women

描述(由首席研究人员提供)：这是重新提交的拨款申请1 R01 NS061836-01，现在标题为“全基因组协会对女性偏头痛的研究”，这是对计划公告PA-07-305的回应。在这项申请中，我们申请资金，对27,000多名女性进行一项关于偏头痛和偏头痛特征的全基因组关联研究，其中超过5,000名女性报告患有偏头痛。所有参与者的血液样本中的DNA目前正在使用Illumina平台进行全基因组扫描。此外，还进行了广泛的基于血浆的表型鉴定。大约20%的人口患有偏头痛；然而，在任何年龄，女性受到影响的频率都是男性的3到4倍。偏头痛是大多数与疼痛相关的急诊室就诊的原因，而且可能会作为一种慢性疾病持续终生。尽管偏头痛的发病率很高，相关研究也有很长的历史，但关于偏头痛的病理生理学和影响这种复杂疾病的多种内源性和外源性因素仍然存在许多问题。最近发现了罕见形式的偏头痛的基因突变。虽然连锁分析已经在常见形式的偏头痛中确定了染色体位置，但潜在的基因尚不清楚。此外，常见形式偏头痛的候选基因方法一直令人失望，主要是因为缺乏复制和样本量小。因此，常见形式偏头痛的遗传原因仍然难以捉摸。我们建议1)使用(I)传统的全基因组关联方法和(Ii)新的加权全基因组关联方法来识别新的偏头痛候选遗传变异/基因，以及2)探索已识别的偏头痛候选遗传变异/基因与生物标记物和环境因素之间的相互作用。我们进一步提出了两个次要目标，在这些目标中，我们将主要目标的评估扩展到偏头痛特征，特别是偏头痛先兆状态。为了实现这些目标，我们建议利用妇女健康研究(WHS)的信息，该研究在1993年对45岁及以上的妇女进行了大量的、特征良好的队列调查。已经从27,939名妇女的血液样本中提取了DNA，目前正在对所有现有的DNA样本进行全基因组扫描，预计将于2008年12月完成。在基线和随访期间，超过5,000名妇女报告患有偏头痛。与其他庞大的美国女性群体相比，WHS是一个非同寻常的资源，它不仅拥有关于许多传统流行病学暴露的广泛数据，而且还拥有关于偏头痛的详细信息。此外，基于血浆的表型分析在数量特别多的样本上也是可用的。因此，WHS特别适合以非常经济高效的方式研究偏头痛的基因组学以及基因-基因、基因-生物标记物和基因-环境的相互作用。与公共健康相关的偏头痛是一种非常常见的头痛疾病，尤其影响女性。尽管有大量的研究，但对影响这种复杂疾病的病理生理学和众多内源性和外源性因素知之甚少。尽管最近发现了罕见类型偏头痛的基因突变和更常见类型偏头痛的候选基因，但遗传模式仅被建立在一种非常罕见的偏头痛类型上。因此，我们要求提供资金，使用全基因组方法研究偏头痛的基因组，并评估基因与环境的相互作用。

DESCRIPTION (provided by principal investigator): This is a resubmission of grant application 1 R01 NS061836-01, now entitled "Whole Genome Association Study of Migraine in Women," which is a response to program announcement PA-07-305. In this application, we request funding to conduct a genome-wide association study of migraine and migraine traits within a large prospective cohort of more than 27,000 women, of whom more than 5,000 reported migraine. DNA from blood samples of all participants is presently undergoing a whole genome scan using the Illumina platform. In addition, extensive plasma-based phenotyping has been performed. Approximately 20 percent of the population suffers from migraine headaches; however, at any age, women are affected 3 to 4 times more often than men. Migraines account for most pain-related emergency room visits, and may persist as a chronic condition throughout the lifespan. Despite the high prevalence of migraine and a long history of relevant research, many questions remain regarding the pathophysiology and the multitude of endogenous and exogenous factors that influence this complex disorder. Gene mutations for rare forms of migraine have been recently identified. While linkage analyses have identified chromosomal loci in common forms of migraine, the underlying genes are unknown. In addition, candidate gene approaches in common forms of migraine have been disappointing, mainly due to lack of replication and small samples sizes. Thus, the genetic causes for common forms of migraine remain elusive. We propose 1) to identify novel candidate genetic variants/genes of migraine using (i) a conventional genome-wide association approach and (ii) a novel weighted genome-wide association approach that utilizes information from previously proposed chromosomal loci and 2) to explore interactions between identified candidate genetic variants/genes of migraine with biomarkers and environmental factors. We further propose two secondary aims in which we extend the evaluation of our primary aims to migraine traits, in particular migraine aura status. To achieve these aims, we propose to utilize information from the Women's Health Study (WHS), a large, well-characterized cohort of women 45 years of age and older in 1993. DNA has been extracted from collected blood samples from 27,939 women, and a whole genome scan of all available DNA samples is underway and expected to be completed by December 2008. At baseline and during follow-up, over 5,000 women reported migraine. In contrast to other large cohorts of US women, the WHS is an extraordinary resource that not only has extensive data on many traditional epidemiologic exposures, but also detailed information about migraine. Furthermore, plasma-based phenotyping is available on an exceptionally large number of samples. Thus, the WHS is particularly suited to study the genomics of migraine as well as gene-gene, gene-biomarker, and gene-environment interactions in a very cost-effective way. PUBLIC HEALTH RELEVANCE Migraine is a very common headache disorder that particularly affects women. Despite a large body of research, little is know about the pathophysiology and the multitude of endogenous and exogenous factors that influence this complex disorder. Although recently gene mutations for rare forms and candidate genes for more common forms of migraine have been identified, the mode of inheritance has only been established a very rare migraine form. Thus, we request funding to study the genomic of migraine using a whole genome approach and to evaluate gene-environment interactions.