A1 Refereed original research article in a scientific journal
Molecular genetic overlap between migraine and major depressive disorder
Authors: Yuanhao Yang, Huiying Zhao, Dorret I Boomsma, Lannie Ligthart, Andrea C. Belin, George Davey Smith, Tonu Esko, Tobias M. Freilinger, Thomas Folkmann Hansen, M. Arfan Ikram, Mikko Kallela, Christian Kubisch, Christofidou Paraskevi, David P. Strachan, Maija Wessman; The International Headache Genetics Consortium, Arn M. J. M. van den Maagdenberg, Gisela M. Terwindt, Dale R. Nyholt
Publisher: Nature Publishing Group
Publication year: 2018
Journal: European Journal of Human Genetics
Journal name in source: European Journal of Human Genetics
Volume: 26
Issue: 8
First page : 1202
Last page: 1216
Number of pages: 15
ISSN: 1018-4813
eISSN: 1476-5438
DOI: https://doi.org/10.1038/s41431-018-0150-2
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 (h2 = 12%) and MDD (h2 = 19%), and a significant cross-disorder genetic correlation (rG = 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 (PSNP ≤ 5 × 10−8) to migraine and MDD. Moreover, gene-based association analyses revealed significant enrichment of genes nominally associated (Pgene-based ≤ 0.05) with both migraine and MDD (Pbinomial-test = 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 (PFisher’s-combined ≤ 3.6 × 10−6). Pathway analysis of genes with PFisher’s-combined ≤ 1 × 10−3
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.
