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Eur J Hum Genet. 2018 Aug;26(8):1202-1216. doi: 10.1038/s41431-018-0150-2. Epub 2018 Jul 11.

Molecular genetic overlap between migraine and major depressive disorder.

Author information

1
Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia. y.yang@imb.uq.edu.au.
2
Institute of Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia. y.yang@imb.uq.edu.au.
3
Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia.
4
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.
5
Department of Biological Psychology, Vrije Universiteit, Amsterdam, The Netherlands.
6
Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
7
Medical Research Council (MRC) Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
8
Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
9
Estonian Genome Center, University of Tartu, Tartu, Estonia.
10
Division of Endocrinology, Boston Children's Hospital, Boston, MA, USA.
11
Department of Neurology and Epileptology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
12
Institute for Stroke and Dementia Research, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
13
Danish Headache Center, Department of Neurology, Rigshospitalet, Glostrup Hospital, University of Copenhagen, Copenhagen, Denmark.
14
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
15
Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
16
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
17
Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.
18
Population Health Research Institute, St George's, University of London, London, UK.
19
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
20
Folkhälsan Institute of Genetics, Helsinki, Finland.
21
Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
22
Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
23
Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia. d.nyholt@qut.edu.au.

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'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.

PMID:
29995844
PMCID:
PMC6057914
DOI:
10.1038/s41431-018-0150-2

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