39 research outputs found
Epigenetic DNA methylation changes associated with headache chronification : A retrospective case-control study
No full textBackground The biological mechanisms of headache chronification are poorly understood. We aimed to identify changes in DNA methylation associated with the transformation from episodic to chronic headache. Methods Participants were recruited from the population-based Norwegian HUNT Study. Thirty-six female headache patients who transformed from episodic to chronic headache between baseline and follow-up 11 years later were matched against 35 controls with episodic headache. DNA methylation was quantified at 485,000 CpG sites, and changes in methylation level at these sites were compared between cases and controls by linear regression analysis. Data were analyzed in two stages (Stages 1 and 2) and in a combined meta-analysis. Results None of the top 20 CpG sites identified in Stage 1 replicated in Stage 2 after multiple testing correction. In the combined meta-analysis the strongest associated CpG sites were related to SH2D5 and NPTX2, two brain-expressed genes involved in the regulation of synaptic plasticity. Functional enrichment analysis pointed to processes including calcium ion binding and estrogen receptor pathways. Conclusion In this first genome-wide study of DNA methylation in headache chronification several potentially implicated loci and processes were identified. The study exemplifies the use of prospectively collected population cohorts to search for epigenetic mechanisms of disease.Peer reviewe
Epigenetic DNA methylation changes associated with headache chronification: A retrospective case-control study
No full textBackground
The biological mechanisms of headache chronification are poorly understood. We aimed to identify changes in DNA methylation associated with the transformation from episodic to chronic headache.
Methods
Participants were recruited from the population-based Norwegian HUNT Study. Thirty-six female headache patients who transformed from episodic to chronic headache between baseline and follow-up 11 years later were matched against 35 controls with episodic headache. DNA methylation was quantified at 485,000 CpG sites, and changes in methylation level at these sites were compared between cases and controls by linear regression analysis. Data were analyzed in two stages (Stages 1 and 2) and in a combined meta-analysis.
Results
None of the top 20 CpG sites identified in Stage 1 replicated in Stage 2 after multiple testing correction. In the combined meta-analysis the strongest associated CpG sites were related to SH2D5 and NPTX2, two brain-expressed genes involved in the regulation of synaptic plasticity. Functional enrichment analysis pointed to processes including calcium ion binding and estrogen receptor pathways.
Conclusion
In this first genome-wide study of DNA methylation in headache chronification several potentially implicated loci and processes were identified. The study exemplifies the use of prospectively collected population cohorts to search for epigenetic mechanisms of disease
A causal effects of gut microbiota in the development of migraine
No full textAbstract Background The causal association between the gut microbiome and the development of migraine and its subtypes remains unclear. Methods The single nucleotide polymorphisms concerning gut microbiome were retrieved from the gene-wide association study (GWAS) of the MiBioGen consortium. The summary statistics datasets of migraine, migraine with aura (MA), and migraine without aura (MO) were obtained from the GWAS meta-analysis of the International Headache Genetics Consortium (IHGC) and FinnGen consortium. Inverse variance weighting (IVW) was used as the primary method, complemented by sensitivity analyses for pleiotropy and increasing robustness. Results In IHGC datasets, ten, five, and nine bacterial taxa were found to have a causal association with migraine, MA, and MO, respectively, (IVW, all P < 0.05). Genus.Coprococcus3 and genus.Anaerotruncus were validated in FinnGen datasets. Nine, twelve, and seven bacterial entities were identified for migraine, MA, and MO, respectively. The causal association still exists in family.Bifidobacteriaceae and order.Bifidobacteriales for migraine and MO after FDR correction. The heterogeneity and pleiotropy analyses confirmed the robustness of IVW results. Conclusion Our study demonstrates that gut microbiomes may exert causal effects on migraine, MA, and MO. We provide novel evidence for the dysfunction of the gut-brain axis on migraine. Future study is required to verify the relationship between gut microbiome and the risk of migraine and its subtypes and illustrate the underlying mechanism between them
Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles
No full textGenome-wide association analyses identify 123 susceptibility loci for migraine and implicate neurovascular mechanisms in its pathophysiology. Subtype analyses highlight risk loci specific for migraine with or without aura in addition to shared risk variants. Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.Peer reviewe
Genetic causal relationship between immune diseases and migraine: a Mendelian randomization study
No full textBackground: Migraine has an increased prevalence in several immune disorders, but genetic cause-effect relationships remain unclear. Mendelian randomization (MR) was used in this study to explore whether immune diseases are causally associated with migraine and its subtypes.Methods: We conducted a two-sample bidirectional multivariate Mendelian randomization study. Single-nucleotide polymorphisms (SNP) for six immune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), allergic rhinitis (AR), asthma and psoriasis, were used as genetic instrumental variables. Summary statistics for migraine were obtained from 3 databases: the International Headache Genetics Consortium (IHGC), UK Biobank, and FinnGen study. MR analyses were performed per outcome database for each exposure and subsequently meta-analyzed. Reverse MR analysis was performed to determine whether migraine were risk factors for immune diseases. In addition, we conducted a genetic correlation to identify shared genetic variants for these two associations.Results: No significant causal relationship was found between immune diseases and migraine and its subtypes. These results were robust with a series of sensitivity analyses. Using the linkage disequilibrium score regression method (LDSC), we detected no genetic correlation between migraine and immune diseases.Conclusion: The evidence from our study does not support a causal relationship between immune diseases and migraine. The mechanisms underlying the frequent comorbidity of migraine and several immune diseases need to be further elucidated.Paroxysmal Cerebral Disorder
Correction: Uncovering drug targets for cluster headache through proteome-wide Mendelian randomization analysis
No full textCluster headache : focus on sleep, treatment, and genetics
No full textThe main hypothesis of this thesis is that cluster headache (CH) has a genetic component and by investigating this genetic component we can get insights into pathophysiological mechanisms behind CH. Clinical data can help indicate which genes can be contributing to the disease. The genetic variants can in turn help us better understand the biological mechanisms which give rise to CH. In that way we lay a foundation for developing treatment which can alleviate the suffering of millions of people around the world. This thesis focused on three major areas within CH research: sleep, treatment usage/response, and genetic links to CH pathophysiology.Sleep has long been studied in connection to CH due to the strikingly rhythmic nature of CH attacks which regularly disrupt sleep. In Paper I, we studied sleep patterns of CH participants using actigraph units to record sleep and wake times, complemented with sleep diaries. Actigraphy data showed that, although sleep time did not differ between CH participants and controls, sleep latency and time in bed was increased in CH participants. Participants with CH scored worse in almost all subjective sleep scores. Interestingly, in objective sleep measurements, CH participants in an active bout did not significantly differ to participants in remission.In Paper II, a survey investigating sleep quality, dysfunctional beliefs regarding sleep, and insomnia symptoms was sent to >700 CH participants. The survey results further established that sleep is disturbed during an active bout as compared to participants in remission and even more so to the general population. The sleep scores were additionally correlated to years since last active bout, again indicating participants in remission are still disrupted by the disease. Paper III used a similar method to investigate extent of burnout in the CH cohort. As high as 67.6% of participants in an active bout were in the risk zone for burnout. Burnout symptoms were also present in remission, but to a lesser degree and correlated to the length of time since the last active bout.To study possible biological links to the observed sleep patterns and circadian rhythm of attacks we studied genetic variants in biological clock genes. PER, CRY, BMAL1, and CLOCK are the core clock genes which drives the 24-hour rhythm. In Paper IV six genetic variants were genotyped in PER1, PER2, and PER3 which had previous links to diurnal preference or sleep. No significant difference between CH participants and controls was found. In Paper V, genetic variants in BMAL1, and NPAS2, a paralog to CLOCK, were investigated. Variants in BMAL1 (rs3789327) and NPAS2 (rs3768984) were associated with CH. Significant or trending genetic variants in the core clock genes from this study and previous studies were combined in a multi allele risk analysis. This analysis showed that CH participants carried more risk alleles than controls further strengthening the possible role of the biological clock in CH.Treatment response can vary greatly between different individuals and treatment options, and is not fully understood. In Paper VI a survey was sent out to investigate treatment response in a Swedish CH cohort. It confirmed the previously reported wide range of treatment responses observed for CH. Surprisingly, a considerable number of CH participants didn’t take any preventative medication. Side effects were common and prevented some participants with continuing their otherwise effective treatment.Since treatment response varied between participants, Paper VII investigated if genetics could partially explain this variation in the first line treatment, triptans. Five genetic variants which had previously been linked to triptan response in other diseases were genotyped and the allelic distribution was compared between triptan users and non-users. One single nucleotide polymorphism (SNP) previously linked to triptan response in migraine was significantly associated with CH triptan usage, meaning the mechanisms of action behind triptan non-response could be similar.Anecdotally, some CH patients have reported taking vitamin D supplements to improve their CH. To investigate if this was reflected in genetics, a SNP in the VDR gene was genotyped in Paper VIII. We pooled the data from the genotyped SNP and two other VDR SNPs from our previous genome-wide association study (GWAS) with data from a Greek CH cohort into a meta-analysis. No significant associations were found to CH for any of the SNPs.In the last few years genetics have increasingly shown to play an important role in CH pathology. In Paper IX, a meta-GWAS was performed on genetic material from 11 cohorts comparing CH participants to controls. When only including the 10 European cohorts, the four significant loci from previous CH GWAS were replicated, in proximity to the genes MERTK, DUSP10, FTCDNL1, and FHL5. Three new loci reached genome wide significance: WNT2, PLCE1, and LRP1.The next step was to translate the genetic findings to possible biological pathways which can contribute to the disease. MERTK is a cell-surface receptor mostly present on immune cells which plays a role in immune suppression, efferocytosis, and a range of other functions. Paper X investigated its potential role in CH. Trigeminal nerves from rats were stained with MERTK antibodies. MERTK was found to be present in Satellite cells and in Schwann cells close to the nodes of Ranvier which would allow MERTK to bind to its ligands if they were released during neuronal activation. Additionally, the protein expression levels of three of MERTK’s ligands were measured in serum. Protein levels of Galectin-3 were significantly higher in CH participants compared to controls.To further investigate a possible immunological mechanism in CH, in Paper XI cerebral spinal fluid (CSF) and serum samples were sent for an immunoassay which allowed us to look at concentrations of dozens of proteins. Eleven immune system related proteins were elevated in the CSF of CH participants compared to controls. Only two cytokines showed differentiated protein expression in the serum. These data indicate increased inflammatory markers in CH participants both in an active bout and in remission, mostly isolated to the central nervous system.List of scientific papersI. Ran C, Jennysdotter Olofsgård F, Steinberg A, Sjöstrand C, Waldenlind E, Dahlgren A, Belin AC. Patients with cluster headache show signs of insomnia and sleep related stress: results from an actigraphy and self-assessed sleep study. J Headache Pain. 2023 Aug 18;24(1):114.https://doi.org/10.1186/s10194-023-01650-wII. Jennysdotter Olofsgård F, Ran C, Steinberg A, Sjöstrand C, Waldenlind E, Lantz M, Sundholm A, Söderström M, Dahlgren A, Belin AC. Characterization of insomnia and sleep quality in a cluster headache population. [Manuscript]III. Jennysdotter Olofsgård F, Ran C, Steinberg A, Sjöstrand C, Waldenlind E, Lantz M, Sundholm A, Söderström M, Dahlgren A, Belin AC. Evidence of High Rates of Burnout in a Cluster Headache Cohort. [Manuscript]IV. Jennysdotter Olofsgård F, Ran C, Fourier C, Wirth C, Sjöstrand C, Waldenlind E, Steinberg A, Belin AC. PER gene family polymorphisms in relation to cluster headache and circadian rhythm in Sweden. Brain Sci. 2021 Aug 23;11(8):1108.https://doi.org/10.3390/brainsci11081108V. Deborgies Sanches C, Jennysdotter Olofsgård F, Fourier C, Sundholm A, Lantz M, Sjöstrand C, Waldenlind E, Steinberg A, Ran C, Belin AC. Genetic variability within molecular core clock genes in cluster headache. [Manuscript]VI. Smedfors G, Jennysdotter Olofsgård F, Steinberg A, Waldenlind E, Ran C, Belin AC. Use of prescribed and non-prescribed treatments for cluster headache in a Swedish cohort. Brain Sci. 2024 Mar 31;14(4):348.https://doi.org/10.3390/brainsci14040348VII. Jennysdotter Olofsgård F, Ran C, Qin Y, Fourier C, Waldenlind E, Steinberg A, Sjöstrand C, Belin AC. Genetic and phenotypic profiling of triptan users in a Swedish cluster headache cohort. J Mol Neurosci. 2024 Apr 18;74(2):45.https://doi.org/10.1007/s12031-024-02219-1VIII. Jennysdotter Olofsgård F, Ran C, Qin Y, Fourier C, Sjöstrand C, Waldenlind E, Steinberg A, Belin AC. Investigating vitamin D receptor genetic markers in a cluster headache meta-analysis. Int J Mol Sci. 2023 Mar 21;24(6):5950.https://doi.org/10.3390/ijms24065950IX. Winsvold BS, Harder AVE, Ran C, Chalmer MA, Dalmasso MC, Ferkingstad E, Tripathi KP, Bacchelli E, Børte S, Fourier C, Petersen AS, Vijfhuizen LS, Magnusson SH, O'Connor E, Bjornsdottir G, Häppölä P, Wang YF, Callesen I, Kelderman T, Gallardo VJ, de Boer I, Jennysdotter Olofsgård F, Heinze K, Lund N, Thomas LF, Hsu CL, Pirinen M, Hautakangas H, Ribasés M, Guerzoni S, Sivakumar P, Yip J, Heinze A, Küçükali F, Ostrowski SR, Pedersen OB, Kristoffersen ES, Martinsen AE, Artigas MS, Lagrata S, Cainazzo MM, Adebimpe J, Quinn O, Göbel C, Cirkel A, Volk AE, Heilmann-Heimbach S, Skogholt AH, Gabrielsen ME, Wilbrink LA, Danno D, Mehta D, Guðbjartsson DF; HUNT All-In Headache, The International Headache Genetics Consortium, DBDS Genomic Consortium; Rosendaal FR, Willems van Dijk K, Fronczek R, Wagner M, Scherer M, Göbel H, Sleegers K, Sveinsson OA, Pani L, Zoli M, Ramos-Quiroga JA, Dardiotis E, Steinberg A, Riedel-Heller S, Sjöstrand C, Thorgeirsson TE, Stefansson H, Southgate L, Trembath RC, Vandrovcova J, Noordam R, Paemeleire K, Stefansson K, Fann CS, Waldenlind E, Tronvik E, Jensen RH, Chen SP, Houlden H, Terwindt GM, Kubisch C, Maestrini E, Vikelis M, Pozo-Rosich P, Belin AC, Matharu M, van den Maagdenberg AMJM, Hansen TF, Ramirez A, Zwart JA; International Consortium for Cluster Headache Genetics. Cluster headache genomewide association study and meta-analysis identifies eight loci and implicates smoking as causal risk factor. Ann Neurol. 2023 Oct;94(4):713-726.https://doi.org/10.1002/ana.26743X. Edvinsson JCA, Ran C, Jennysdotter Olofsgård F, Steinberg A, Edvinsson L, Belin AC. MERTK in the rat trigeminal system: a potential novel target for cluster headache? J Headache Pain. 2024 May 23;25(1):85.https://doi.org/10.1186/s10194-024-01791-6XI. Ran C, Jennysdotter Olofsgård F, Wellfelt K, Steinberg A, Belin AC. Elevated cytokine levels in the central nervous system of cluster headache patients in bout and in remission. J Headache Pain. 2024 Jul 23;25(1):121.https://doi.org/10.1186/s10194-024-01829-9</p
Migraine polygenic risk score associates with efficacy of migraine-specific drugs
No full textObjective To assess whether the polygenic risk score (PRS) for migraine is associated with acute and/or prophylactic migraine treatment response. Methods We interviewed 2,219 unrelated patients at the Danish Headache Center using a semistructured interview to diagnose migraine and assess acute and prophylactic drug response. All patients were genotyped. A PRS was calculated with the linkage disequilibrium pred algorithm using summary statistics from the most recent migraine genome-wide association study comprising similar to 375,000 cases and controls. The PRS was scaled to a unit corresponding to a twofold increase in migraine risk, using 929 unrelated Danish controls as reference. The association of the PRS with treatment response was assessed by logistic regression, and the predictive power of the model by area under the curve using a case-control design with treatment response as outcome. Results A twofold increase in migraine risk associates with positive response to migraine-specific acute treatment (odds ratio [OR] = 1.25 [95% confidence interval (CI) = 1.05-1.49]). The association between migraine risk and migraine-specific acute treatment was replicated in an independent cohort consisting of 5,616 triptan users with prescription history (OR = 3.20 [95% CI = 1.26-8.14]). No association was found for acute treatment with non-migraine-specific weak analgesics and prophylactic treatment response. Conclusions The migraine PRS can significantly identify subgroups of patients with a higher-than-average likelihood of a positive response to triptans, which provides a first step toward genetics-based precision medicine in migraine.Peer reviewe
HMG-CoA reductase is a potential therapeutic target for migraine: a mendelian randomization study
No full text Statins are thought to have positive effects on migraine but existing data are inconclusive. We aimed to evaluate the causal effect of such drugs on migraines using Mendelian randomization. We used four types of genetic instruments as proxies for HMG-CoA reductase inhibition. We included the expression quantitative trait loci of the HMG-CoA reductase gene and genetic variation within or near the HMG-CoA reductase gene region. Variants were associated with low-density lipoprotein cholesterol, apolipoprotein B, and total cholesterol. Genome-wide association study summary data for the three lipids were obtained from the UK Biobank. Comparable data for migraine were obtained from the International Headache Genetic Consortium and the FinnGen Consortium. Inverse variance weighting method was used for the primary analysis. Additional analyses included pleiotropic robust methods, colocalization, and meta-analysis. Genetically determined high expression of HMG-CoA reductase was associated with an increased risk of migraines (OR = 1.55, 95% CI 1.30–1.84, P = 6.87 × 10−7). Similarly, three genetically determined HMG-CoA reductase-mediated lipids were associated with an increased risk of migraine. These conclusions were consistent across meta-analyses. We found no evidence of bias caused by pleiotropy or genetic confounding factors. These findings support the hypothesis that statins can be used to treat migraine. Paroxysmal Cerebral Disorder
Habitual sleep disturbances and migraine : a Mendelian randomization study
No full textObjective Sleep disturbances are associated with increased risk of migraine, however the extent of shared underlying biology and the direction of causal relationships between these traits is unclear. Delineating causality between sleep patterns and migraine may offer new pathophysiologic insights and inform subsequent intervention studies. Here, we used genetic approaches to test for shared genetic influences between sleep patterns and migraine, and to test whether habitual sleep patterns may be causal risk factors for migraine and vice versa. Methods To quantify genetic overlap, we performed genome-wide genetic correlation analyses using genome-wide association studies of nine sleep traits in the UK Biobank (n >= 237,627), and migraine from the International Headache Genetics Consortium (59,674 cases and 316,078 controls). We then tested for potential causal effects between sleep traits and migraine using bidirectional, two-sample Mendelian randomization. Results Seven sleep traits demonstrated genetic overlap with migraine, including insomnia symptoms (rg = 0.29, P <10(-31)) and difficulty awakening (rg = 0.11, P <10(-4)). Mendelian randomization analyses provided evidence for potential causal effects of difficulty awakening on risk of migraine (OR [95% CI] = 1.37 [1.12-1.68], P = 0.002), and nominal evidence that liability to insomnia symptoms increased the risk of migraine (1.09 [1.02-1.16], P = 0.02). In contrast, there was minimal evidence for an effect of migraine liability on sleep patterns or disturbances. Interpretation These data support a shared genetic basis between several sleep traits and migraine, and support potential causal effects of difficulty awakening and insomnia symptoms on migraine risk. Treatment of sleep disturbances may therefore be a promising clinical intervention in the management of migraine.Peer reviewe
