Genetics and Comorbidity of Migraine

描述(申请人提供)：偏头痛是美国最常见的神经疾病之一，也是全球前20大致残原因之一。据估计，美国偏头痛的一年患病率总体上在8%到15%之间，受影响的女性大约是男性的三倍。据估计，每年全国偏头痛的直接成本负担为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，但其确切机制尚不清楚。最近的研究表明，偏头痛可能与基因有关，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：这项拟议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(SNP)。我们将应用全基因组联合研究(GWAS)方法，将患有偏头痛的凯撒永久北加州(KPNC)成员与未受影响的对照组成员进行比较。次要目标包括在独立样本中复制、按共病亚组分析、4个可能的SNPs/标记的候选基因分析、两组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名完全分型的参与者中提取。通过使用以前开发的识别偏头痛的方法，并将验证问卷邮寄到随机选择的子集，我们计划准确地捕获偏头痛患者，以及一组可比的对照。然后，我们将对偏头痛患者和非头痛对照患者进行GWA比较，以确定与偏头痛相关的基因变异，无论是总体上还是种族/民族亚组内。在我们确定了一组重要的SNPs后，我们将在共同发病的亚组中测试这些SNPs，并在两个独立的偏头痛队列中重复我们的发现。另外两项建议的分析包括在我们的RPGEH队列中复制先前建立的SNPs，以及两组之间的端粒长度比较。摘要：对偏头痛新的候选基因进行GWA检查，测试以前发现的基因，比较端粒长度，这些都是了解偏头痛的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建议的分析将产生可靠的结果，这些结果将适用于更广泛的美国人口。 与公共卫生相关：偏头痛是一种常见而复杂的疾病，既有遗传原因，也有环境原因，然而，这种疾病的确切机制仍不清楚。最近的研究已经发现了与罕见类型偏头痛相关的基因，但对常见和典型偏头痛的研究结果并不一致，可能是因为共病亚组的差异导致了人群分层和混淆。为了解决这些潜在的问题，我们要求提供资金，在基于人群的大规模队列中研究偏头痛的遗传学基础，使用GWA方法并在共病亚组中测试候选基因。

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.