Data_Sheet_1_Association of Genetic Variants With Migraine Subclassified by Clinical Symptoms in Adult Females.PDF

Migraine is heritable and formally diagnosed by structured criteria that require presence of some but not all possible migraine symptoms which include aura, several distinct manifestations of pain, nausea/vomiting, and sensitivity to light or sound. The most recent genome-wide genetic association study (GWAS) for migraine identified 38 loci. We investigated whether 46 single-nucleotide polymorphisms (SNPs), i.e., genetic variants, at these loci may have especially pronounced, i.e., selective, association with migraine presenting with individual symptoms compared to absence of migraine. Selective genetic associations of SNPs were evaluated through a likelihood framework in the Women's Genome Health Study (WGHS), a population-based cohort of middle-aged women including 3,003 experiencing migraine and 18,108 not experiencing migraine, all with genetic information. SNPs at 12 loci displayed significant selective association for migraine subclassified by specific symptoms, among which six selective associations are novel. Symptoms showing selective association include aura, nausea/vomiting, photophobia, and phonophobia. The selective associations were consistent whether the women met all formal criteria for diagnostic for migraine or lacked one of the diagnostic criteria, formally termed probable migraine. Subsequently, we performed latent class analysis of migraine diagnostic symptoms among 69,861 women experiencing migraine from the WGHS recruitment sample to assess whether there were clusters of specific symptoms that might also have a genetic basis. However, no globally robust latent migraine substructures of diagnostic symptoms were observed nor were there selective genetic associations with specific combinations of symptoms revealed among weakly supported latent classes. The findings extend previously reported selective genetic associations with migraine diagnostic symptoms while supporting models for shared genetic susceptibility across all qualifying migraine at many loci.

偏头痛具有遗传倾向，其正式诊断需遵循结构化标准，即需存在部分而非全部典型偏头痛症状，此类症状包括先兆、多种不同类型的疼痛发作、恶心/呕吐，以及畏光或畏声。最新一项针对偏头痛的全基因组关联研究（Genome-Wide Association Study, GWAS）共鉴定出38个基因座。本研究旨在探究上述基因座上的46个单核苷酸多态性（Single-Nucleotide Polymorphism, SNPs，即遗传变异位点），相较于无偏头痛人群，是否与伴发特定症状的偏头痛存在更为显著的选择性关联。我们基于女性基因组健康研究（Women's Genome Health Study, WGHS）的似然分析框架，对单核苷酸多态性的选择性遗传关联进行了评估：该队列属于基于人群的中年女性研究队列，其中3003名受试者患有偏头痛，18108名无偏头痛病史，所有参与者均具备完整遗传信息。经按特定症状分型后，12个基因座上的单核苷酸多态性显示出显著的选择性关联，其中6种选择性关联为全新发现。存在选择性关联的症状包括先兆、恶心/呕吐、畏光及畏声。无论受试者满足偏头痛的全部正式诊断标准，还是仅符合部分诊断标准（即所谓的可能型偏头痛），上述选择性关联均保持一致。随后，我们针对WGHS招募样本中69861名偏头痛女性的诊断症状开展了潜类别分析（Latent Class Analysis），以评估是否存在可能具备遗传基础的特定症状集群。然而，研究未观察到具备全局稳健性的偏头痛诊断症状潜隐亚结构；在支持度较弱的潜类别中，也未发现与特定症状组合相关的选择性遗传关联。本研究结果拓展了此前已报道的偏头痛诊断症状相关选择性遗传关联发现，同时支持了在众多基因座上，所有符合诊断标准的偏头痛均共享遗传易感性的模型。