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Molecular genetic overlap between migraine and major depressive disorder

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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, Padhraig Gormley, Verneri Anttila, Bendik S. Winsvold, Priit Palta, Tonu Esko & 30 others Tune H. Pers, Kai How Farh, Ester Cuenca-Leon, Mikko Muona, Nicholas A. Furlotte, Tobias Kurth, Andres Ingason, George McMahon, Lannie Ligthart, Gisela M. Terwindt, Mikko Kallela, Tobias M. Freilinger, Caroline Ran, Scott G. Gordon, Anine H. Stam, Stacy Steinberg, Guntram Borck, Markku Koiranen, Lydia Quaye, Hieab H.H. Adams, Terho Lehtimäki, Antti Pekka Sarin, Juho Wedenoja, David A. Hinds, Julie E. Buring, Markus Schürks, Anne Francke Christensen, Thomas Folkmann Hansen, Thomas Werge, Jes Olesen

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 × 10−3suggested 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.

Original languageEnglish
JournalEuropean Journal of Human Genetics
Issue number8
Pages (from-to)1202-1216
Number of pages15
Publication statusPublished - 2018

ID: 209805004