Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.
Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
Eur J Hum Genet. 2018 Aug;26(8):1202-1216. doi: 10.1038/s41431-018-0150-2. Epub 2018 Jul 11.
Migraine and major depressive disorder (MDD) are common brain disorders that frequently co-occur. Despite epidemiological evidence that migraine and MDD share a genetic basis, their overlap at the molecular genetic level has not been thoroughly investigated. Using single-nucleotide polymorphism (SNP) and gene-based analysis of genome-wide association study (GWAS) genotype data, we found significant genetic overlap across the two disorders. LD Score regression revealed a significant SNP-based heritability for both migraine (h = 12%) and MDD (h = 19%), and a significant cross-disorder genetic correlation (r = 0.25; P = 0.04). Meta-analysis of results for 8,045,569 SNPs from a migraine GWAS (comprising 30,465 migraine cases and 143,147 control samples) and the top 10,000 SNPs from a MDD GWAS (comprising 75,607 MDD cases and 231,747 healthy controls), implicated three SNPs (rs146377178, rs672931, and rs11858956) with novel genome-wide significant association (P ≤ 5 × 10) to migraine and MDD. Moreover, gene-based association analyses revealed significant enrichment of genes nominally associated (P ≤ 0.05) with both migraine and MDD (P = 0.001). Combining results across migraine and MDD, two genes, ANKDD1B and KCNK5, produced Fisher's combined gene-based P values that surpassed the genome-wide significance threshold (P ≤ 3.6 × 10). Pathway analysis of genes with P ≤ 1 × 10 suggested several pathways, foremost neural-related pathways of signalling and ion channel regulation, to be involved in migraine and MDD aetiology. In conclusion, our study provides strong molecular genetic support for shared genetically determined biological mechanisms underlying migraine and MDD.
偏头痛和重度抑郁症（MDD）是常见的脑部疾病，常同时发生。尽管有流行病学证据表明偏头痛和 MDD 具有共同的遗传基础，但它们在分子遗传水平上的重叠尚未得到彻底研究。我们使用单核苷酸多态性（SNP）和基于基因的全基因组关联研究（GWAS）基因型数据分析，发现这两种疾病之间存在显著的遗传重叠。LD 得分回归显示偏头痛（h=12%）和 MDD（h=19%）具有显著的 SNP 遗传率，并且存在显著的跨疾病遗传相关性（r=0.25；P=0.04）。对偏头痛 GWAS（包含 30465 例偏头痛病例和 143147 例对照样本）中 8045569 个 SNP 和 MDD GWAS（包含 75607 例 MDD 病例和 231747 例健康对照）中前 10000 个 SNP 的元分析表明，三个 SNP（rs146377178、rs672931 和 rs11858956）与偏头痛和 MDD 的全基因组显著关联（P≤5×10）。此外，基于基因的关联分析显示，与偏头痛和 MDD 均显著相关的基因（P≤0.05；P=0.001）有显著富集。将偏头痛和 MDD 的结果相结合，ANKDD1B 和 KCNK5 两个基因产生的 Fisher 联合基因 P 值超过了全基因组显著阈值（P≤3.6×10）。P≤1×10 的基因的通路分析表明，几个与神经相关的信号和离子通道调节通路可能与偏头痛和 MDD 的发病机制有关。总之，我们的研究为偏头痛和 MDD 共同的遗传决定的生物学机制提供了强有力的分子遗传支持。
