Molecular genetic overlap between migraine and major depressive disorder

The International Headache Genetics Consortium

doi:10.1038/s41431-018-0150-2

Molecular genetic overlap between migraine and major depressive disorder

The International Headache Genetics Consortium

Statistical and Genomic Epidemiology Laboratory
Queensland University of Technology
University of Queensland
Sun Yat-Sen University
Department of Biological Psychology
Vrije Universiteit Amsterdam
Karolinska Institutet
University of Bristol
Program in Medical and Population Genetics
Broad Institute
University of Tartu
Division of Endocrinology
Boston Children's Hospital
Department of Neurology and Epileptology
University of Tübingen
Ludwig Maximilian University of Munich
Danish Headache Center
University of Copenhagen
Institute of Biological Psychiatry
Department of Epidemiology
Erasmus University Rotterdam
Department of Radiology
Department of Neurology
Department of Neurology
Helsinki University Hospital
Institute of Human Genetics
University of Hamburg
Department of Twin Research and Genetic Epidemiology
King's College London
Population Health Research Institute
St. George's University of London
University of Helsinki
Folkhalsan
Psychiatric and Neurodevelopmental Genetics Unit
Massachusetts General Hospital
Wellcome Trust Sanger Institute
University of Oslo
Department of Neurology
Institute of Clinical Medicine
Department of Epidemiology Research
Statens Serum Institut
Analytic and Translational Genetics Unit
Illumina, Inc.
Pediatric Neurology
Vall d'Hebron Research Institute
Neuroscience Center
Molecular Neurology Research Program
23andMe Inc.
Institute of Public Health
Charité – Universitätsmedizin Berlin
Division of Preventive Medicine
Brigham and Women’s Hospital
deCODE Genetics
Department of Neurology
Leiden University
Department of Genetics and Computational Biology
Queensland Institute of Medical Research
Institute of Human Genetics
Ulm University
Center for Life Course Epidemiology and Systems Medicine
University of Oulu
Department of Clinical Chemistry
Fimlab Laboratories
Department of Public Health
Harvard University
University of Duisburg-Essen
Landspitali University Hospital

Research output: Contribution to journal › Article › peer-review

72 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
Pages (from-to)	1202-1216
Number of pages	15
Journal	European Journal of Human Genetics
Volume	26
Issue number	8
DOIs	https://doi.org/10.1038/s41431-018-0150-2
Publication status	Published - 1 Aug 2018
Externally published	Yes

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10.1038/s41431-018-0150-2

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@article{a94cf254f2e348d686f4570dbad2cbce,

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 {\texttimes} 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 {\texttimes} 10−6). Pathway analysis of genes with PFisher{\textquoteright}s-combined≤ 1 {\texttimes} 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 = "\{The International Headache Genetics Consortium\} and 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 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 Ridker, \{Paul M.\} and Hrafnsdottir, \{Maria Gudlaug\} and Hreinn Stefansson and Ring, \{Susan M.\} and Hottenga, \{Jouke Jan\}",

note = "Publisher Copyright: {\textcopyright} 2018, European Society of Human Genetics.",

year = "2018",

month = aug,

day = "1",

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

language = "English",

volume = "26",

pages = "1202--1216",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Springer Nature",

number = "8",

}

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 - 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 - Ring, Susan M.

AU - Hottenga, Jouke Jan

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

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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