Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

Anttila, Vesa; Stefánsson, Hreinn; Kallela, Mikko; Todt, Unda; Terwindt, G.M.; Ms, Calafato; Nyholt, Dale R.; As, Dimas; Freilinger, Tobias; Müller‐Myhsok, Bertram; Artto,; Inouye, Michael; Alakurtti, Kirsi; Kaunisto, Mari A.; Hämäläinen, Eija; B, de Vries; Stam, AH; Weller, CM; Heinze, Axel; Heinze‐Kuhn, Katja; Goebel, Ingrid; Borck, Guntram; Göbel, Hartmut; Steinberg, Stacy; Wolf, Christiane; Björnsson, Ásgeir; Guðmundsson, Guðmundur A.; Kirchmann, Malene; Hauge, Anne Werner; Werge, Thomas; Schoenen, Jean; Eriksson, Johan G.; Hagen, Katie R.; Stovner, Lars Jacob; He, Wenwu; Meitinger, Thomas; Alexander, Michael P.; Moebus, Susanne; Schreiber, Stefan; Aulchenko, Yurii S.; Breteler, Monique M.B.; Ag, Uitterlinden; Hofman, Albert; Duijn, Cornelia M. van; Tikka-Kleemola, P.; Vepsäläinen, Salli; Lucae, Susanne; Tozzi, Federica; Muglia, Pierandrea; Barrett, Jeff; Kaprio, Jaakko; Färkkilä, Markus; Peltonen, Leena; Stefánsson, Kāri; Ja, Zwart; Ferrari, Michel D.; Olesen, Jes; Daly, Mark J.; Wessman, Maija; Maagdenberg, van den; Dichgans, Martin; Kubisch, Christian; Dermitzakis, Emmanouil T.; Frants, R.R.; Palotie, Aarno

doi:10.1038/ng.652

Cited by 327 publications

(177 citation statements)

References 39 publications

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“…Another GWAS study reported that the C allele of rs2952768 in the Chr2q33.3 was associated with more analgesic requirements in human (Nishizawa et al., 2014). Multiple GWAS studies have proposed genes ( PRDM16 , TRPM8 or LRP1 ) and locus (Chr8q22.1) to be involved in the migraine (Anttila et al, 2010; Chasman et al., 2011). Therefore, there is growing evidence of the involvement of SNPs in pain pathways, although much more research is required, including particularly replication studies, and consensus on feasible and relevant phenotype ascertainment.…”

Section: Discussionmentioning

confidence: 99%

A genome‐wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain

Wang

Deshmukh

Zuydam

et al. 2015

European Journal of Pain

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BackgroundNeuropathic pain, caused by a lesion or a disease affecting the somatosensory system, is one of the most common complications in diabetic patients. The purpose of this study is to identify genetic factors contributing to this type of pain in a general diabetic population.MethodWe accessed the Genetics of Diabetes Audit and Research Tayside (GoDARTS) datasets that contain prescription information and monofilament test results for 9439 diabetic patients, among which 6927 diabetic individuals were genotyped by Affymetrix SNP6.0 or Illumina OmniExpress chips. Cases of neuropathic pain were defined as diabetic patients with a prescription history of at least one of five drugs specifically indicated for the treatment of neuropathic pain and in whom monofilament test result was positive for sensory neuropathy in at least one foot. Controls were individuals who did not have a record of receiving any opioid analgesics. Imputation of non‐genotyped SNPs was performed by IMPUTE2, with reference files from 1000 Genomes Phase I datasets.ResultsAfter data cleaning and relevant exclusions, imputed genotypes of 572 diabetic neuropathic pain cases and 2491 diabetic controls were used in the Fisher's exact test. We identified a cluster in the Chr8p21.3, next to GFRA2 with a lowest p‐value of 1.77 × 10−7 at rs17428041. The narrow‐sense heritability of this phenotype was 11.00%.ConclusionThis genome‐wide association study on diabetic neuropathic pain suggests new evidence for the involvement of variants near GFRA2 with the disorder, which needs to be verified in an independent cohort and at the molecular level.

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Section: Discussionmentioning

confidence: 99%

A genome‐wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain

Wang

Deshmukh

Zuydam

et al. 2015

European Journal of Pain

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“…Recently susceptibility loci for migraine, both MwA and MwoA, have been described in genome-wide association studies, and some refer to Glu homeostasis (42)(43)(44). Although no significant metabolite differences were observed in a study using two-dimensional 1 H-MRS, linear discriminant analysis revealed a separation between migraine patients and controls based on Gln and Nacetylaspartylglutamate in the anterior cingulate cortex (ACC) and insula, suggesting glutamatergic abnormalities in the brain of migraine patients compared to controls (45).…”

Section: Glu/glnmentioning

confidence: 99%

Magnetic resonance spectroscopy in migraine: What have we learned so far?

2012

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Objective: To summarize and evaluate proton (1H) and phosphorus (31P) magnetic resonance spectroscopy (MRS) findings in migraine. Methods: A thorough review of 1H and/or 31P-MRS studies in any form of migraine published up to September 2011. Results: Some findings were consistent in all studies, such as a lack of ictal/interictal brain pH change and a disturbed energy metabolism, the latter of which is reflected in a drop in phosphocreatine content, both in the resting brain and in muscle following exercise. In a recent interictal study ATP was found to be significantly decreased in the occipital lobe of migraine with aura patients, reinforcing the concept of a mitochondrial component to the migraine threshold, at least in a subgroup of patients. In several studies a correlation between the extent of the energy disturbance and the clinical phenotype severity was apparent. Less consistent but still congruent with a disturbed energy metabolism is an observed lactate increase in the occipital cortex of several migraine subtypes (MwA, migraine with prolonged aura). No increases in brain glutamate levels were found. Conclusion: The combined abnormalities found in MRS studies imply a mitochondrial component in migraine neurobiology. This could be due to a primary mitochondrial dysfunction or be secondary to, for example, alterations in brain excitability. The extent of variation in the data can be attributed to both the variable clinical inclusion criteria used and the variation in applied methodology. Therefore it is necessary to continue to optimize MRS methodology to gain further insights, especially concerning lactate and glutamate.

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“…Three previously reported loci that were associated to subtypes of migraine (rs1835740 near MTDH, rs10915437 near AJAP1, and rs10504861 near MMP16) 13,16 show only nominal significance (P < 5 × 10 -3 ) in the current meta-analysis (Supplementary Table 3), however, these loci have since been shown to be associated to specific phenotypic features of peer-reviewed) is the author/funder. All rights reserved.…”

Section: Significant Associations At 38 Independent Genomic Locimentioning

confidence: 71%

“…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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Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1

Cited by 327 publications

References 39 publications

A genome‐wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain

A genome‐wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain

Magnetic resonance spectroscopy in migraine: What have we learned so far?

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

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