Genetics and Comorbidity of Migraine

描述（由申请人提供）：偏头痛是美国最常见的神经系统疾病之一，是全球20大致残原因之一。在美国，偏头痛的一年患病率估计在8-15%之间，总体上影响女性的人数大约是男性的三倍。据估计，全国每年偏头痛的直接费用负担为110亿美元，另外还有60亿美元的间接费用。偏头痛是一种复杂的疾病，具有遗传和环境的双重起源，但其确切机制尚不清楚。最近的研究暗示了偏头痛与基因的潜在关联，但总体结果并不一致。需要更多的研究来阐明这些遗传和环境途径。研究目的：本研究的主要目的是确定偏头痛的常见遗传变异，以确定是否存在与偏头痛相关的单核苷酸多态性（snp）。我们将应用全基因组关联研究（GWAS）方法来比较Kaiser Permanente北加州（KPNC）偏头痛患者和对照组未受影响的患者。次要目的包括在独立样本中复制、共发病亚组分析、4个假定snp /标记的候选基因分析、两组之间端粒长度的比较以及表型策略的敏感性分析。方法：受试者将从KPNC基因、环境和健康研究计划（RPGEH）的110,266名完全基因分型的参与者中抽取。通过使用先前开发的偏头痛识别方法，并将验证问卷邮寄给随机选择的子集，我们计划准确捕获患有偏头痛的患者，以及一组可比对照。然后，我们将对偏头痛患者和非头痛对照组进行GWAS比较，以确定与偏头痛相关的遗传变异，无论是总体上还是种族/民族亚群内。在我们确定了一组重要的snp后，我们将在共发病的亚组中测试这些snp，并在两个独立的偏头痛队列中重复我们的发现。另外两个建议的分析包括在我们的RPGEH队列中先前建立的snp的复制，以及两组之间端粒长度的比较。摘要：使用GWAS来鉴定偏头痛的新候选基因，测试先前鉴定的基因，比较端粒长度都是了解偏头痛遗传基础的重要步骤。在我们大量不同的研究人群中完成这些建议的分析将产生可靠的结果，这将推广到更广泛的美国人群。

DESCRIPTION (provided by applicant): Migraine is one of the most common neurological disorders in the US, and is among the top 20 causes of disability worldwide. The one-year prevalence of migraine headache in the United States is estimated to range from 8-15% overall affecting approximately three times more women than men. The estimated national direct cost burden of migraine is $11 billion per year, with an additional $6 billion of indirect costs. Migraie is a complex disorder with both genetic and environmental origins, however the precise mechanisms of the condition remain unclear. Recent studies have implicated potential gene associations with migraine, but the overall findings are inconsistent. More research is needed to elucidate these genetic and environmental pathways. Study Aims: The primary aim of this proposed study is to identify common genetic variants for migraine to determine whether there are single nucleotide polymorphisms (SNPs) associated with migraine. We will apply genome-wide association study (GWAS) methodology to compare Kaiser Permanente Northern California (KPNC) members with migraine to a control group of unaffected members. Secondary aims include replication in independent samples, analysis by subgroups of co-morbidity, candidate gene analysis of 4 putative SNPs/markers, comparison of telomere length between the two groups, and a sensitivity analysis of phenotyping strategies. Methods: Subjects will be drawn from the 110,266 fully genotyped participants in the KPNC Research Program on Genes, Environment, and Health (RPGEH). By using previously developed methods for identification of migraine in conjunction with a validation questionnaire mailed to a randomly selected subset, we plan to accurately capture patients who suffer from migraine, as well as a set of comparable controls. We will then perform a GWAS comparing migraine patients with non-headache controls to identify genetic variants associated with migraine both overall and within subgroups of race/ethnicity. After we have determined a set of significant SNPs, we will test these SNPs in subgroups of co-morbidity and replicate our findings in two independent migraine cohorts. Two additional proposed analyses include replication of previously established SNPs in our RPGEH cohort, and comparison of telomere length between the two groups. Summary: Performing GWAS to identify new candidate genes for migraine, testing previously-identified genes, and comparing telomere lengths are all important steps towards understanding the genetic underpinnings of migraine. Completing these proposed analyses in our large diverse study population will yield robust results that will be generalizable to the wider U.S. population.