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，也是全球20大致残原因之一。据估计，美国偏头痛的一年患病率范围为8-15%，女性的患病率约为男性的三倍。偏头痛的估计国家直接成本负担为每年110亿美元，另外还有60亿美元的间接成本。偏头痛是一种复杂的疾病，既有遗传原因，也有环境原因，但其确切的发病机制仍不清楚。最近的研究暗示了潜在的基因与偏头痛的关联，但总体研究结果并不一致。需要更多的研究来阐明这些遗传和环境途径。研究目的：这项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）方法比较Kaiser Permanente北方加州（KPNC）偏头痛患者与未受影响的对照组成员。次要目的包括在独立样本中的复制，共病亚组的分析，4个推定的SNP/标记的候选基因分析，两组之间的端粒长度的比较，以及表型分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，结合邮寄给随机选择的子集的验证问卷，我们计划准确地捕获患有偏头痛的患者，以及一组可比较的对照。然后，我们将进行GWAS比较偏头痛患者与非头痛对照，以确定总体和种族/民族亚组内与偏头痛相关的遗传变异。在我们确定了一组显著的SNPs后，我们将在共病亚组中测试这些SNPs，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队列中复制先前建立的SNP，以及比较两组之间的端粒长度。总结：进行GWAS以识别偏头痛的新候选基因，测试先前识别的基因，并比较端粒长度都是了解偏头痛遗传基础的重要步骤。在我们庞大的多样化研究人群中完成这些拟议的分析将产生稳健的结果，这些结果将推广到更广泛的美国人群。 公共卫生相关性：偏头痛是一种常见而复杂的疾病，有遗传和环境原因，然而，这种疾病的确切机制仍不清楚。最近的研究已经涉及与罕见类型的偏头痛相关的基因，但常见和经典偏头痛的发现是不一致的，可能是由于共病亚组的差异导致人群分层和混淆。为了解决这些潜在的问题，我们申请资金，研究偏头痛的遗传学基础在一个大的人群为基础的队列使用GWA方法和测试候选基因的共病亚组。

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. PUBLIC HEALTH RELEVANCE: Migraine is a common and complex disorder with both genetic and environmental origins, however, the precise mechanisms of the condition remain unclear. Recent studies have implicated genes associated with rare types of migraine, but the findings for common and classic migraine are inconsistent, possibly due to differences by subgroup of co-morbidity resulting in population stratification and confounding. In order to address these potential issues, we request funding to study the genetics underlying migraine in a large population-based cohort using both a GWA approach and testing candidate genes within subgroups of co-morbidity.