Genome-wide meta-analysis identifies new susceptibility loci for migraine

Anttila, Vesa; Winsvold, Bendik S.; Gormley, Padhraig; Kurth, Tobias; Bettella, Francesco; McMahon, George; Kallela, Mikko; Malik, Rainer; Vries, Boukje de; Terwindt, Gisela M.; Medland, Sarah E.; Todt, Unda; McArdle, Wendy L.; Quaye, Lydia; Koiranen, Markku; Ikram, M. Arfan; Lehtimäki, Terho; Stam, Anine H.; Ligthart, Lannie; Wedenoja, Juho; Dunham, Ian; Neale, Benjamin M.; Palta, Priit; Hämäläinen, Eija; Schuerks, Markus; Rose, Lynda M.; Buring, Julie E.; Ridker, Paul M.; Steinberg, Stacy; Stefánsson, Hreinn; Jakobsson, Finnbogi; Lawlor, Debbie A.; Evans, David M.; Ring, Susan M.; Färkkilä, Markus; Artto, Ville; Kaunisto, Mari A.; Freilinger, Tobias; Schoenen, Jean; Frants, Rune R.; Pelzer, Nadine; Weller, Claudia M; Zielman, Ronald; Heath, Andrew C.; Madden, Pamela A. F.; Montgomery, Grant W.; Martin, Nicholas G.; Borck, Guntram; Goebel, Hartmut; Heinze, Axel; Heinze‐Kuhn, Katja; Williams, Frances; Hartikainen, Anna-Liisa; Pouta, Anneli; Ende, Joyce van den; Uitterlinden, André G.; Hofman, Albert; Amin, Najaf; Hottenga, Jouke‐Jan; Vink, Jacqueline M.; Heikkilä, Kauko; Alexander, Michael P.; Müller‐Myhsok, Bertram; Schreiber, Stefan; Meitinger, Thomas; Wichmann, Heinz Erich; Aromaa, Arpo; Eriksson, Johan G.; Traynor, Bryan J.; Trabzuni, Daniah; Rossin, Elizabeth J.; Lage, Kasper; Jacobs, Suzanne B.R.; Gibbs, J. Raphael; Birney, Ewan; Kaprio, Jaakko; Penninx, Brenda W. J. H.; Boomsma, Dorret I.; Duijn, Cornelia M. van; Raitakari, Olli T.; Järvelin, Marjo‐Riitta; Zwart, John‐Anker; Cherkas, Lynn; Strachan, David P.; Kubisch, Christian; Ferrari, Michel D.; Maagdenberg, Arn M. J. M. van den; Dichgans, Martin; Wessman, Maija; Smith, George Davey; Stefánsson, Kāri; Daly, Mark J.; Nyholt, Dale R.; Chasman, Daniel I.; Palotie, Aarno

doi:10.1038/ng.2676

Cited by 341 publications

(415 citation statements)

References 54 publications

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“…A recent large meta‐analysis of GWAS studies (Anttila et al 2013) identified several susceptible genetic loci for migraine from which only one ( TRPM8 , encoding the transient receptor potential melastatin 8, which is a cold and menthol‐activated ion channel in sensory neurons) has a direct role in pain sensation. The other genetic variants are predominantly expressed in the brain, mainly exert their effects through synaptic and neuronal regulation (Anttila et al 2013; Eising et al 2013a) and thus may contribute to the neuronal hyperexcitability of the migraine brain.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, we used a short screening questionnaire to determine the probability of migraine headache and to identify migraine related symptoms without proper medical diagnosis. Nevertheless, this is a usual method in large population based studies and previous epidemiologic and GWAS studies suggest that this method provides trustworthy results (Anttila et al 2013). …”

Section: Limitationsmentioning

confidence: 99%

“…Recent genome wide association studies (GWAS) have successfully identified several genetic susceptibility loci for migraine (Anttila et al 2013; Gormley et al 2016) but much less is known of which genetic variants operate in the presence of a given environmental effect (Eising et al 2013b). …”

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confidence: 99%

“…Regarding migraine, we demonstrated that a CNR1 haplotype increased the risk of migraine headaches (Juhasz et al 2009b). However, recent migraine GWAS studies could not identify risk genetic variants within the endocannabinoid system (Anttila et al 2013; Gormley et al 2016). Although accumulating evidence suggests that impaired CB1 signalling is associated with chronic stress‐related hyperalgesia (Jennings et al 2015; Lomazzo et al 2015; Rea et al 2014), the relationship between CNR1 gene and migraine has not been investigated in interaction with life stressors.…”

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confidence: 99%

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Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress

Juhász

Csépány

Magyar

et al. 2016

Genes Brain and Behavior

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One of the main effects of the endocannabinoid system in the brain is stress adaptation with presynaptic endocannabinoid receptor 1 (CB1 receptors) playing a major role. In the present study, we investigated whether the effect of the CB1 receptor coding CNR1 gene on migraine and its symptoms is conditional on life stress. In a cross‐sectional European population (n = 2426), recruited from Manchester and Budapest, we used the ID‐Migraine questionnaire for migraine screening, the Life Threatening Experiences questionnaire to measure recent negative life events (RLE), and covered the CNR1 gene with 11 SNPs. The main genetic effects and the CNR1 × RLE interaction with age and sex as covariates were tested. None of the SNPs showed main genetic effects on possible migraine or its symptoms, but 5 SNPs showed nominally significant interaction with RLE on headache with nausea using logistic regression models. The effect of rs806366 remained significant after correction for multiple testing and replicated in the subpopulations. This effect was independent from depression‐ and anxiety‐related phenotypes. In addition, a Bayesian systems‐based analysis demonstrated that in the development of headache with nausea all SNPs were more relevant with higher a posteriori probability in those who experienced recent life stress. In summary, the CNR1 gene in interaction with life stress increased the risk of headache with nausea suggesting a specific pathological mechanism to develop migraine, and indicating that a subgroup of migraine patients, who suffer from life stress triggered migraine with frequent nausea, may benefit from therapies that increase the endocannabinoid tone.

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Section: Discussionmentioning

confidence: 99%

Section: Limitationsmentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress

Juhász

Csépány

Magyar

et al. 2016

Genes Brain and Behavior

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“…Understanding has been limited partly because, to date, only 13 genome-wide significant risk loci have been identified for the prevalent forms of migraine [13][14][15][16] . In familial hemiplegic migraine (FHM), a rare Mendelian form of the disease, three ion transport-related genes (CACNA1A, ATP1A2 and SCN1A) have been implicated [17][18][19] .…”

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confidence: 99%

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Gormley

Anttila

Winsvold

et al. 2015

Preprint

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Migraine is a debilitating neurological disorder affecting around 1 in 7 people worldwide, but its molecular mechanisms remain poorly understood. Some debate exists over whether migraine is a disease of vascular dysfunction, or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we performed the largest genetic study of migraine to date, comprising 59,674 cases and 316,078 controls from 22 GWA studies. We identified 45 independent single nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 x 10-8) that map to 38 distinct genomic loci, including 28 loci not previously reported and the first locus identified on chromosome X. Furthermore, a subset analysis for migraine without aura (MO) identified seven of the same loci as from the full sample, whereas no loci reached genome-wide significance in the migraine with aura (MA) subset. In subsequent computational analyzes, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

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Identification of Susceptibility Loci for Spontaneous Coronary Artery Dissection

et al. 2020

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IMPORTANCE Spontaneous coronary artery dissection (SCAD), an idiopathic disorder that predominantly affects young to middle-aged women, has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden cardiac death.OBJECTIVE To identify common single-nucleotide variants (SNVs) associated with SCAD susceptibility. DESIGN, SETTING, AND PARTICIPANTSThis single-center genome-wide association study examined approximately 5 million genotyped and imputed SNVs and subsequent SNV-targeted replication analysis results in individuals enrolled in the Mayo Clinic SCAD

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Genome-wide meta-analysis identifies new susceptibility loci for migraine

Cited by 341 publications

References 54 publications

Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress

Variants in the CNR1 gene predispose to headache with nausea in the presence of life stress

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine

Identification of Susceptibility Loci for Spontaneous Coronary Artery Dissection

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