Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Bjornsdottir, Gyda; Chalmer, Mona A.; Stefansdottir, Lilja; Skuladottir, Astros Th.; Einarsson, Gudmundur; Andresdottir, Margret; Beyter, Doruk; Ferkingstad, Egil; Gretarsdottir, Solveig; Halldorsson, Bjarni V.; Halldorsson, Gisli H.; Helgadottir, Anna; Helgason, Hannes; Hjorleifsson Eldjarn, Grimur; Jonasdottir, Adalbjorg; Jonasdottir, Aslaug; Jonsdottir, Ingileif; Knowlton, Kirk U.; Nadauld, Lincoln D.; Lund, Sigrun H.; Magnusson, Olafur Th.; Melsted, Pall; Moore, Kristjan H. S.; Oddsson, Asmundur; Olason, Pall I.; Sigurdsson, Asgeir; Stefansson, Olafur A.; Saemundsdottir, Jona; Sveinbjornsson, Gardar; Tragante, Vinicius; Unnsteinsdottir, Unnur; Walters, G. Bragi; Zink, Florian; Rødevand, Linn; Andreassen, Ole A.; Igland, Jannicke; Lie, Rolv T.; Haavik, Jan; Banasik, Karina; Brunak, Søren; Didriksen, Maria; T. Bruun, Mie; Erikstrup, Christian; Kogelman, Lisette J. A.; Nielsen, Kaspar R.; Sørensen, Erik; Pedersen, Ole B.; Ullum, Henrik; ,; Bay, Jakob; Boldsen, Jens K.; Brodersen, Thorsten; Burgdorf, Kristoffer; Dinh, Khoa M.; Dowsett, Joseph; Feenstra, Bjarke; Geller, Frank; Hindhede, Lotte; Hjalgrim, Henrik; Jacobsen, Rikke L.; Jemec, Gregor; Kaspersen, Katrine; Kjerulf, Bertram D.; Larsen, Margit A. H.; Louloudis, Ioannis; Lundgaard, Agnete; Mikkelsen, Susan; Mikkelsen, Christina; Nissen, Ioanna; Nyegaard, Mette; Henriksen, Alexander P.; Rohde, Palle D.; Rostgaard, Klaus; Swinn, Michael; Thørner, Lise W.; Bruun, Mie T.; Werge, Thomas; Westergaard, David; Masson, Gisli; Thorsteinsdottir, Unnur; Olesen, Jes; Ludvigsson, Petur; Thorarensen, Olafur; Bjornsdottir, Anna; Sigurdardottir, Gudrun R.; Sveinsson, Olafur A.; Ostrowski, Sisse R.; Holm, Hilma; Gudbjartsson, Daniel F.; Thorleifsson, Gudmar; Sulem, Patrick; Stefansson, Hreinn; Thorgeirsson, Thorgeir E.; Hansen, Thomas F.; Stefansson, Kari

doi:10.1038/s41588-023-01538-0

Cited by 19 publications

(10 citation statements)

References 94 publications

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“…With the large-scale GWAS, numerous reliable SNPs and genes associated with genetic risk factors for migraine have been identified [ 8 , 50 ]. However, there exist evident challenges in establishing connections between relevant SNPs and genes with potential pathophysiological pathways.…”

Section: Discussionmentioning

confidence: 99%

“…Current hypotheses propose that vascular function, metal ion homeostasis, neuronal function, and ion channel activity may be implicated in the pathophysiology of migraine; nevertheless, these notions still necessitate validation through high-throughput experiments conducted on cellular and animal models [51]. We sought to explore the potential interactions among SREBF2 or REV1 and previously identified genes associated with migraine susceptibility [8,23,32,33,[50][51][52][53]. However, substantial evidence is currently lacking.…”

Section: Discussionmentioning

confidence: 99%

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A cross-tissue transcriptome-wide association study reveals novel susceptibility genes for migraine

Gui,

Yang,

Tan

et al. 2024

J Headache Pain

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Background Migraine is a common neurological disorder with a strong genetic component. Despite the identification of over 100 loci associated with migraine susceptibility through genome-wide association studies (GWAS), the underlying causative genes and biological mechanisms remain predominantly elusive. Methods The FinnGen R10 dataset, consisting of 333,711 subjects (20,908 cases and 312,803 controls), was utilized in conjunction with the Genotype-Tissue Expression Project (GTEx) v8 EQTls files to conduct cross-tissue transcriptome association studies (TWAS). Functional Summary-based Imputation (FUSION) was employed to validate these findings in single tissues. Additionally, candidate susceptibility genes were screened using Gene Analysis combined with Multi-marker Analysis of Genomic Annotation (MAGMA). Subsequent Mendelian randomization (MR) and colocalization analyses were conducted. Furthermore, GeneMANIA analysis was employed to enhance our understanding of the functional implications of these susceptibility genes. Results We identified a total of 19 susceptibility genes associated with migraine in the cross-tissue TWAS analysis. Two novel susceptibility genes, REV1 and SREBF2, were validated through both single tissue TWAS and MAGMA analysis. Mendelian randomization and colocalization analyses further confirmed these findings. REV1 may reduce the migraine risk by regulating DNA damage repair, while SREBF2 may increase the risk of migraine by regulating cholesterol metabolism. Conclusion Our study identified two novel genes whose predicted expression was associated with the risk of migraine, providing new insights into the genetic framework of migraine.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A cross-tissue transcriptome-wide association study reveals novel susceptibility genes for migraine

Gui,

Yang,

Tan

et al. 2024

J Headache Pain

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“…Bjornsdottir et al. 27 recently published a meta‐analysis by combining large genome wide association study (GWAS) datasets from European populations, which included approximately 1.2 million individuals. The datasets were sourced from Iceland (deCODE Genetics), Denmark (Copenhagen Hospital Biobank (CHB) and Danish Blood Donor Study (DBDS)), the United Kingdom (UK Biobank), the United States (Intermountain Health), Norway (the Hordaland Health Study (HUSK)), and Finland (FinnGen).…”

Section: Methodsmentioning

confidence: 99%

Identifying novel proteins for migraine by integrating proteomes from blood and CSF with genome‐wide association data

Niu,

Zhang,

Zhang

et al. 2024

CNS Neurosci Ther

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BackgroundProteome‐wide Mendelian randomization studies have been increasingly utilized to identify potential drug targets for diseases. We aimed to identify potential therapeutic targets for migraine and its subtypes through the application of Mendelian randomization and co‐localization analysis methods.MethodsWe utilized cis‐protein quantitative trait loci data for 1378 plasma proteins available from two studies with 7213 individuals and 35,559 individuals, respectively. Summary data for migraine and its subtypes were obtained from a genetic study involving up to 1,339,303 individuals. Proteins that passed both the discovery and validation Mendelian randomization analysis, sensitivity analysis, heterogeneity test, and pleiotropy test, were associated with ≥2 outcomes, and received strong support from co‐localization analysis (PP.H4.abf ≥0.80) and were classified as tier 1 proteins.ResultsWe identified three tier 1 proteins (LRP11, ITIH1, and ADGRF5), whose genes have not been previously identified as causal genes for migraine in genetic studies. LRP11 was significantly associated with the risk of any migraine (OR [odds ratio] = 0.968, 95% CI [confidence interval] = 0.955–0.981, p = 1.27 × 10−6) and significantly/suggestively associated with three migraine subtypes. ITIH1 was significantly associated with the risk of any migraine (OR = 1.044, 95% CI = 1.024–1.065, p = 1.08 × 10−5) and migraine with visual disturbances. ADGRF5 was significantly associated with the risk of any migraine (OR = 0.964, 95% CI = 0.946–0.982, p = 8.74 × 10−5) and suggestively associated with migraine with aura. The effects of LRP11 and ADGRF5 were further replicated using cerebrospinal fluid protein data. Apart from ADGRF5, there was no evidence of potential adverse consequences when modulating the plasma levels. We also identified another four proteins (PLCG1, ARHGAP25, CHGA, and MANBA) with no potential adverse consequences when modulating the plasma levels, and their genes were not reported by previous genetic studies.ConclusionsWe found compelling evidence for two proteins and suggestive evidence for four proteins that could be promising targets for migraine treatment without significant adverse consequences. The corresponding genes were not reported in previous genetic studies. Future studies are needed to confirm the causal role of these proteins and explore the underlying mechanisms.

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“…Further specifics about the studies included in the metaanalysis can be explored in the associated publication. 17 We then examined the association between a high migraine PRS-defined as scores within the top decile of the cohort-and the risk of donor lapse, an association analyzed through Cox regression with similar adjustments as described above. For this analysis, participants were followed from the date of inclusion in DBDS (blood sampling), and the end of follow-up was marked by the same events as before; the date of death, emigration, pregnancy, donor lapse, or the end of the study period on July 29, 2022, whichever came first.…”

Section: Polygenic Risk Scoresmentioning

confidence: 99%

Blood donation and migraine relief: A national population cohort study in Denmark

Davidsson,

Rostgaard,

Chalmer

et al. 2024

Transfusion

Self Cite

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IntroductionMigraine is a prevalent neurological headache disorder. Due to challenges associated with finding effective treatment, many individuals with migraine feel compelled to explore alternative treatment strategies, such as blood donation, hypothesized to provide migraine relief.MethodsThrough logistic, Poisson, and Cox regression methods, we examined the links between migraine and blood donation activities in two population cohorts: Danish blood donors in the Scandinavian Donations and Transfusions Database (SCANDAT‐DK, N >1 million) and the Danish Blood Donor Study (N ~ 100,000).ResultsSCANDAT‐DK analyses showed no link between migraine and the propensity to become a blood donor among males (odds ratio [OR]Males = 0.95 [95% Confidence Interval: 0.86–1.04], and a reduced propensity among females ORFemales = 0.88 [0.83–0.93]). The incidence of migraine was not reduced upon blood donation (standardized incidence ratio [SIR]Males = 0.94 [0.83–1.06]; SIRFemales = 1.04 [0.99–1.10]). Donors with migraine demonstrated longer intervals between donations (hazard ratio [HR]Males = 0.87 [0.85–0.91], HRFemales = 0.80 [0.78–0.82]), and an increased risk of donor lapse (ORMales = 1.23 [1.14–1.32]; ORFemales = 1.28 [1.22–1.33]). Results were corroborated in DBDS using self‐reported migraine. Genetic predisposition to migraine associated with longer intervals in females (HRFemales = 0.98 [0.97–0.99]), but not in males.DiscussionOur findings do not support the hypothesis that blood donation serves as a viable treatment strategy among migraine patients. Future prospective investigations may help to elucidate the underlying biological mechanisms by which blood donation may influence migraine pathology.

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Rare variants with large effects provide functional insights into the pathology of migraine subtypes, with and without aura

Cited by 19 publications

References 94 publications

A cross-tissue transcriptome-wide association study reveals novel susceptibility genes for migraine

A cross-tissue transcriptome-wide association study reveals novel susceptibility genes for migraine

Identifying novel proteins for migraine by integrating proteomes from blood and CSF with genome‐wide association data

Blood donation and migraine relief: A national population cohort study in Denmark

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