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Genome-Wide Association Study Reveals Three Susceptibility Loci For LETTERS Genome-­wide association study reveals three susceptibility loci for common migraine in the general population Daniel I Chasman1,2,23, Markus Schürks1,3,23, Verneri Anttila4,5,22, Boukje de Vries6, Ulf Schminke7, Lenore J Launer8, Gisela M Terwindt9, Arn M J M van den Maagdenberg6,9, Konstanze Fendrich10, Henry Völzke11, Florian Ernst12, Lyn R Griffiths13, Julie E Buring1, Mikko Kallela14,22, Tobias Freilinger15,22, Christian Kubisch16,22, Paul M Ridker1,2, Aarno Palotie4,5,17–19,22, Michel D Ferrari9, Wolfgang Hoffmann10, Robert Y L Zee1,24 & Tobias Kurth1,20,21,24 Migraine is a common, heterogeneous and heritable attacks of headache associated with gastrointestinal and autonomic neurological disorder. Its pathophysiology is incompletely nervous system symptoms2. Up to one third of affected individuals understood, and its genetic influences at the population level may also experience transient focal neurological symptoms known as are unknown. In a population-based genome-wide analysis aura. Current concepts view migraine primarily as a multi-­factorial including 5,122 migraineurs and 18,108 non-migraineurs, brain disorder with heritability estimates as high as 50% (ref. 3). rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) Yet, progress in genetic analysis has been largely restricted to rare and rs11172113 (12q13.3, LRP1) were among the top monogenic subtypes of migraine, and very little is known about the seven associations (P < 5 × 10−6) with migraine. These SNPs underlying genetic variants for common forms of migraine, including were significant in a meta-analysis among three replication migraine with and without aura4. A recent genome-­wide association cohorts and met genome-wide significance in a meta-analysis study (GWAS) identified a genetic variant on chromosome 8q22.1 combining the discovery and replication cohorts (rs2651899, associated with migraine in a large clinic-­based sample of European odds ratio (OR) = 1.11, P = 3.8 × 10−9; rs10166942, OR = 0.85, individuals with migraine5. P = 5.5 × 10−12; and rs11172113, OR = 0.90, P = 4.3 × 10−9). In order to identify common genetic variants for migraine at the The associations at rs2651899 and rs10166942 were specific population level, we performed a GWAS among 23,230 women with Nature America, Inc. All rights reserved. All rights Inc. America, Nature 1 for migraine compared with non-migraine headache. None complete genotype and migraine information and verified European 1 of the three SNP associations was preferential for migraine ancestry from the Women’s Genome Health Study (WGHS)6, a large © 20 with aura or without aura, nor were any associations population-­based cohort (Supplementary Note). Migraine was reported specific for migraine features. TRPM8 has been the focus by 5,122 women compared to 18,108 women not reporting migraine. of neuropathic pain models, whereas LRP1 modulates The clinical profile between migraineurs and non-­migraineurs differed neuronal glutamate signaling, plausibly linking both genes most strongly for age, postmenopausal hormone use, physical activity to migraine pathophysiology. and alcohol consumption (Supplementary Table 1). In the discovery stage genome-­wide scan among genotyped SNPs, Migraine is a common and often debilitating disorder affecting up to no SNPs reached the conventional threshold association of P < 5 × 10−8 20% of the population, with women being affected three to four times in age-­adjusted logistic models assuming an additive relationship more often than men1. Clinically, migraine manifests with recurrent between the minor allele dose and the log-­odds of migraine. 1Division of Preventive Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 2Donald W. Reynolds Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. 3Department of Neurology, University Hospital Essen, Essen, Germany. 4Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. 5Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland. 6Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands. 7Department of Neurology, Ernst-Moritz- Arndt University, Greifswald, Germany. 8National Institute of Aging, Laboratory for Epidemiology, Demography, and Biometry, Bethesda, Maryland, USA. 9Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands. 10Institute for Community Medicine, Section Epidemiology of Health Care and Community Health, Ernst-Moritz-Arndt University, Greifswald, Germany. 11Institute for Community Medicine, Section Clinical Epidemiological Research, Ernst-Moritz-Arndt University, Greifswald, Germany. 12Interfaculty Institute for Genetics and Functional Genomics, Ernst-Moritz-Arndt University, Greifswald, Germany. 13Genomics Research Centre, Griffith Health Institute, Griffith University, Gold Coast, Queensland, Australia. 14Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland. 15Department of Neurology, Klinikum Großhadern, Ludwig-Maximilians-Universität and Institute for Stroke and Dementia Research, Klinikum der Universität München, Munich, Germany. 16Institute of Human Genetics, University of Ulm, Ulm, Germany. 17Department of Medical Genetics, University of Helsinki, Helsinki, Finland. 18Department of Medical Genetics, Helsinki University Central Hospital, Helsinki, Finland. 19The Broad Institute of MIT and Harvard, Boston, Massachusetts, USA. 20INSERM Unit 708—Neuroepidemiology, Paris, France. 21UPMC Univ Paris 06, F-75005, Paris, France. 22On behalf of the International Headache Genetics Consortium (IHGC) (full list of consortium members appears in the Supplementary Note). 23These authors contributed equally to this work. 24These authors jointly directed this work. Correspondence should be addressed to M.S. ([email protected]) or T.K. ([email protected]). Received 7 March; accepted 16 May; published online 12 June 2011; doi:10.1038/ng.856 NATURE GENETICS VOLUME 43 | NUMBER 7 | JULY 2011 695 LETTERS Table 1 Discovery and replication statistics for association of three genome-wide significant SNPs with migraine in meta-analysis Locus position a b b 2 SNP (candidate) A1/A2 Stage: cohort (Nmig/Nnon-mig) MAF OR (95% CI) P I % (Phet) rs2651899 1p36.32 C/T Discovery: WGHS (5,122/18,108) 0.43 1.13 (1.08–1.18) 1.4 × 10−7 3,073,572 Replication: GEM (774/942) 0.41 1.07 (0.93–1.23) 0.37 (PRDM16) Replication: SHIP (306/2,260) 0.47 1.25 (1.04–1.49) 0.02 Replication: IHGC (2,748/10,747) 0.42 1.07 (1.00–1.14) 0.04 All replicationc: (3,828/13,949) 1.08 (1.03–1.14) 4.2 × 10−3 21.8 (0.28) Discovery and replicationc: (8,950/32,057) 1.11 (1.07–1.15) 3.8 × 10−9 18.9 (0.30) rs10166942 2q37.1 C/T Discovery: WGHS 0.19 0.86 (0.81–0.91) 2.3 × 10−7 234,489,832 Replication: GEM 0.22 0.80 (0.67–0.96) 0.01 (TRPM8) Replication: SHIP 0.18 0.86 (0.67–1.09) 0.21 Replication: IHGC 0.18 0.85 (0.78–0.93) 0.0002 All replicationc 0.84 (0.79–0.91) 5.0 × 10−6 0.0 (0.80) Discovery and replicationc 0.85 (0.82–0.89) 5.5 × 10−12 0.0 (0.90) rs11172113 12q13.3 C/T Discovery: WGHS 0.41 0.90 (0.86–0.94) 3.7 × 10−6 55,813,550 Replication: GEM 0.41 0.96 (0.84–1.11) 0.62 (LRP1) Replication: SHIP 0.42 0.81 (0.67–0.98) 0.03 Replication: IHGC 0.41 0.90 (0.85–0.96) 0.0014 All replicationc 0.90 (0.85–0.95) 3.0 × 10−4 0.3 (0.37) Discovery and replicationc 0.90 (0.87–0.93) 4.3 × 10−9 0.0 (0.57) aNumber of migraineurs/non-migraineurs. bSingle cohort analysis association statistics from an age-adjusted (WGHS), age- and sex-adjusted (GEM and SHIP) or sex-adjusted and country-of- origin–adjusted (IHGC) logistic regression model. Meta-analysis association statistics from an inverse-variance weighted fixed effects model.c Meta-analysis combining estimates from individual cohorts. A1, minor allele ‘+’ strand; A2, major allele ‘+’ strand; MAF, minor allele frequency; OR, odds ratio; CI, confidence interval. All genomic information is from human genome build hg18. 2 I , heterogeneity as estimated proportion of total variance; Phet, P value from test of heterogeneity. WGHS, Women’s Genome Health Study; GEM, Genetic Epidemiology of Migraine study; SHIP, Study of Health in Pomerania; IHGC, International Headache Genetics Consortium. Nevertheless, the top SNPs were more significant than expected for the IHGC, the latter of which is the largest replication cohort (P = the 95% confidence interval for the ordered test statistic under the 0.02 (0.57 × 3 replication cohorts)). In IHGC, there were nominally null hypothesis and, except for one SNP, remained more significant significant associations for rs2078371 and the three SNPs that had after controlling for modest inflation of the test statistic (λGC = 1.03; concordant effects in all three replication cohorts. rs10166942 in GEM Supplementary Fig. 1). Seven independent loci had at least one SNP and both rs2651899 and rs11172113 in SHIP were also nominally with P < 5 × 10−6. We selected the most significant SNP from each significant (Table 1 and Supplementary Table 2). locus for further analysis (Table 1 lists three SNPs which ultimately We then performed a meta-­analysis of the results for the primary reached genome-­wide significance; Supplementary Table 2 lists all SNPs using a fixed-­effects model with inverse-­variance weight-­ SNPs). None of the seven SNPs was associated with non-­migraine ing. Combining only the replication cohorts, the meta-­analysis headache in the WGHS (all P > 0.05, N = 3,001 compared with 14,959 supported association (P < 0.008 (0.05/6)) for the three fully con-­ Nature America, Inc. All rights reserved. All rights Inc. America, Nature controls). The significance and magnitude of the associations of the cordant SNPs: rs2651899 (OR = 1.08, 95% CI 1.03–1.14, P = 4.2 × 1 1 seven SNPs with migrane were essentially unchanged in sensitiv-­ 10−3), rs10166942 (OR = 0.84, 95% CI 0.79–0.91, P = 5.0 × 10−6) and ity analyses using (i) an allele frequency test, (ii) logistic regression rs11172113 (OR = 0.90, 95% CI 0.85–0.95, P = 3.0 × 10−4) (see Table 1 © 20 without adjustment or (iii) logistic regression adjusted for clinical and Supplementary Table 4).
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