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Eur J Hum Genet DOI:10.1038/s41431-018-0150-2

Molecular genetic overlap between migraine and major depressive disorder.

Publication TypeJournal Article
Year of Publication2018
AuthorsYang, Y, Zhao, H, Boomsma, DI, Ligthart, L, Belin, AC, Smith, GDavey, Esko, T, Freilinger, TM, Hansen, TFolkmann, M Ikram, A, Kallela, M, Kubisch, C, Paraskevi, C, Strachan, DP, Wessman, M, van den Maagdenberg, AMJM, Terwindt, GM, Nyholt, DR
Corporate AuthorsInternational Headache Genetics Consortium
JournalEur J Hum Genet
Date Published2018 08
KeywordsAnkyrin Repeat, Databases, Genetic, Depressive Disorder, Major, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Migraine Disorders, Polymorphism, Single Nucleotide, Potassium Channels, Tandem Pore Domain

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.


Alternate JournalEur J Hum Genet
PubMed ID29995844
PubMed Central IDPMC6057914
Grant ListR01 AA007535 / AA / NIAAA NIH HHS / United States
R01 MH066206 / MH / NIMH NIH HHS / United States
P50 AA011998 / AA / NIAAA NIH HHS / United States
R01 AA013321 / AA / NIAAA NIH HHS / United States
R01 DA012854 / DA / NIDA NIH HHS / United States
R01 AA013320 / AA / NIAAA NIH HHS / United States
R01 AA014041 / AA / NIAAA NIH HHS / United States
K05 AA017688 / AA / NIAAA NIH HHS / United States
R01 AA013326 / AA / NIAAA NIH HHS / United States
MC_UU_00011/1 / MRC_ / Medical Research Council / United Kingdom
R56 DA012854 / DA / NIDA NIH HHS / United States
R01 AA010249 / AA / NIAAA NIH HHS / United States
K08 DA019951 / DA / NIDA NIH HHS / United States