Molecular genetic overlap between migraine and major depressive disorder

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; 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

doi:10.1038/s41431-018-0150-2

Molecular genetic overlap between migraine and major depressive disorder

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 EskoTune 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

^*Corresponding author for this work

20 Citations (Scopus)

Abstract

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 (r_G= 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_SNP≤ 5 × 10⁻⁸) to migraine and MDD. Moreover, gene-based association analyses revealed significant enrichment of genes nominally associated (P_gene-based≤ 0.05) with both migraine and MDD (P_{binomial-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 (P_{Fisher’s-combined}≤ 3.6 × 10⁻⁶). Pathway analysis of genes with P_{Fisher’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 language	English
Journal	European Journal of Human Genetics
Volume	26
Issue number	8
Pages (from-to)	1202-1216
Number of pages	15
ISSN	1018-4813
DOIs	https://doi.org/10.1038/s41431-018-0150-2
Publication status	Published - 2018

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Yang, Y., Zhao, H., Boomsma, D. I., Ligthart, L., Belin, A. C., Smith, G. D., Esko, T., Freilinger, T. M., Hansen, T. F., Ikram, M. A., Kallela, M., Kubisch, C., Paraskevi, C., Strachan, D. P., Wessman, M., Gormley, P., Anttila, V., Winsvold, B. S., Palta, P., ... Olesen, J. (2018). Molecular genetic overlap between migraine and major depressive disorder. European Journal of Human Genetics, 26(8), 1202-1216. https://doi.org/10.1038/s41431-018-0150-2

Yang, Y, Zhao, H, Boomsma, DI, Ligthart, L, Belin, AC, Smith, GD, Esko, T, Freilinger, TM, Hansen, TF, Ikram, MA, Kallela, M, Kubisch, C, Paraskevi, C, Strachan, DP, Wessman, M, Gormley, P, Anttila, V, Winsvold, BS, Palta, P, Esko, T, Pers, TH, Farh, KH, Cuenca-Leon, E, Muona, M, Furlotte, NA, Kurth, T, Ingason, A, McMahon, G, Ligthart, L, Terwindt, GM, Kallela, M, Freilinger, TM, Ran, C, Gordon, SG, Stam, AH, Steinberg, S, Borck, G, Koiranen, M, Quaye, L, Adams, HHH, Lehtimäki, T, Sarin, AP, Wedenoja, J, Hinds, DA, Buring, JE, Schürks, M, Christensen, AF, Hansen, TF , Werge, T & Olesen, J 2018, 'Molecular genetic overlap between migraine and major depressive disorder', European Journal of Human Genetics, vol. 26, no. 8, pp. 1202-1216. https://doi.org/10.1038/s41431-018-0150-2

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title = "Molecular genetic overlap between migraine and major depressive disorder",

abstract = "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{\textquoteright}s combined gene-based P values that surpassed the genome-wide significance threshold (PFisher{\textquoteright}s-combined≤ 3.6 × 10−6). Pathway analysis of genes with PFisher{\textquoteright}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.",

author = "Yuanhao Yang and Huiying Zhao and Boomsma, {Dorret I.} and Lannie Ligthart and Belin, {Andrea C.} and Smith, {George Davey} and Tonu Esko and Freilinger, {Tobias M.} and Hansen, {Thomas Folkmann} and Ikram, {M. Arfan} and Mikko Kallela and Christian Kubisch and Christofidou Paraskevi and Strachan, {David P.} and Maija Wessman and Padhraig Gormley and Verneri Anttila and Winsvold, {Bendik S.} and Priit Palta and Tonu Esko and Pers, {Tune H.} and Farh, {Kai How} and Ester Cuenca-Leon and Mikko Muona and Furlotte, {Nicholas A.} and Tobias Kurth and Andres Ingason and George McMahon and Lannie Ligthart and Terwindt, {Gisela M.} and Mikko Kallela and Freilinger, {Tobias M.} and Caroline Ran and Gordon, {Scott G.} and Stam, {Anine H.} and Stacy Steinberg and Guntram Borck and Markku Koiranen and Lydia Quaye and Adams, {Hieab H.H.} and Terho Lehtim{\"a}ki and Sarin, {Antti Pekka} and Juho Wedenoja and Hinds, {David A.} and Buring, {Julie E.} and Markus Sch{\"u}rks and Christensen, {Anne Francke} and Hansen, {Thomas Folkmann} and Thomas Werge and Jes Olesen",

year = "2018",

doi = "10.1038/s41431-018-0150-2",

language = "English",

volume = "26",

pages = "1202--1216",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "nature publishing group",

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TY - JOUR

T1 - Molecular genetic overlap between migraine and major depressive disorder

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 - Christensen, Anne Francke

AU - Hansen, Thomas Folkmann

AU - Werge, Thomas

AU - Olesen, Jes

PY - 2018

Y1 - 2018

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.

U2 - 10.1038/s41431-018-0150-2

DO - 10.1038/s41431-018-0150-2

M3 - Journal article

C2 - 29995844

AN - SCOPUS:85049670236

SN - 1018-4813

VL - 26

SP - 1202

EP - 1216

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

IS - 8

ER -

Molecular genetic overlap between migraine and major depressive disorder

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