TY - JOUR
T1 - Molecular genetic overlap between migraine and major depressive disorder
AU - The International Headache Genetics Consortium
AU - Yang, Yuanhao
AU - Zhao, Huiying
AU - Boomsma, Dorret I.
AU - Ligthart, Lannie
AU - Belin, Andrea C.
AU - Smith, George Davey
AU - Esko, Tonu
AU - Freilinger, Tobias M.
AU - Hansen, Thomas Folkmann
AU - Ikram, M. Arfan
AU - Kallela, Mikko
AU - Kubisch, Christian
AU - Paraskevi, Christofidou
AU - Strachan, David P.
AU - Wessman, Maija
AU - Gormley, Padhraig
AU - Anttila, Verneri
AU - Winsvold, Bendik S.
AU - Palta, Priit
AU - Esko, Tonu
AU - Pers, Tune H.
AU - Farh, Kai How
AU - Cuenca-Leon, Ester
AU - Muona, Mikko
AU - Furlotte, Nicholas A.
AU - Kurth, Tobias
AU - Ingason, Andres
AU - McMahon, George
AU - Ligthart, Lannie
AU - Terwindt, Gisela M.
AU - Kallela, Mikko
AU - Freilinger, Tobias M.
AU - Ran, Caroline
AU - Gordon, Scott G.
AU - Stam, Anine H.
AU - Steinberg, Stacy
AU - Borck, Guntram
AU - Koiranen, Markku
AU - Quaye, Lydia
AU - Adams, Hieab H.H.
AU - Lehtimäki, Terho
AU - Sarin, Antti Pekka
AU - Wedenoja, Juho
AU - Hinds, David A.
AU - Buring, Julie E.
AU - Schürks, Markus
AU - Ridker, Paul M.
AU - Hrafnsdottir, Maria Gudlaug
AU - Stefansson, Hreinn
AU - Penninx, Brenda W.J.H.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85049670236
U2 - 10.1038/s41431-018-0150-2
DO - 10.1038/s41431-018-0150-2
M3 - Article
C2 - 29995844
SN - 1018-4813
VL - 26
SP - 1202
EP - 1216
JO - European journal of human genetics
JF - European journal of human genetics
IS - 8
ER -