Astrid J. Rodriguez-Acevedo

Association of oestrogen-receptor gene (ESR1) polymorphisms with migraine in the large Norfolk Island pedigree

Background Oestrogen receptor 1 (ESR1) is located in region 6q25.1 and encodes a ligand-activated transcription factor composed of several domains important for hormone binding and transcription activation. Progesterone receptor (PGR) is located in 11q22-23 and mediates the role of progesterone interacting with different transcriptional co-regulators. ESR1 and PGR have previously been implicated in migraine susceptibility. Here, we report the results of an association study of these genes in a migraine pedigree from the genetic isolate of Norfolk Island, a population descended from a small number of Isle of Man “Bounty Mutineer” and Tahitian founders. Methods A significant number of molecular markers in the ESR1 (143) and PGR (43) genes were evaluated in a sample of 285 related individuals (135 males; 150 females). A pedigree-based analysis in the GenABEL package was used to analyse the results. Results and conclusions A total of 10 markers in the ESR1 gene showed association with migraine (p < 0.05) in the Norfolk Island population. No association was detected with PGR. Three haplotypes in ESR1 were found to be associated with migraine (p = 0.004, 0.03, 0.005). Future genetic studies in larger populations and expression analysis are required to clarify the role of ESR1 in migraine susceptibility.

Investigation of brain-derived neurotrophic factor (BDNF) gene variants in migraine.

A number of observations have suggested that brain‐derived neurotrophic factor (BDNF) plays a role in migraine pathophysiology. This study investigates whether variants in the BDNF gene are associated with migraine in an Australian case‐control population.

Genetic epidemiology of migraine and depression

Background Migraine and major depressive disorder (commonly referred to as depression) are both common disorders with a significant impact on society. Studies in both clinical and community-based settings have demonstrated a strong relationship between migraine and depression. In addition to complicating the diagnosis, depression that is comorbid with migraine may lower treatment adherence, increase risk of medication overuse and is associated with migraine chronification, thus leading to higher direct and indirect costs and poorer health-related outcomes with increased disability. Aim The aim of this review is to summarise the current knowledge on the genetic epidemiology of migraine and depression and the possible biological mechanisms underlying their comorbidity. Methods We present a narrative review reporting on the current literature. Results and conclusions Epidemiological findings indicate that there is a bidirectional relationship between migraine and depression, with one disorder increasing the risk for the other and vice versa, suggesting shared biological mechanisms. Twin and family studies indicate that this bidirectional relationship can be explained, at least partly, by shared underlying genetically determined disease mechanisms. Although no genes have been robustly associated with the aetiology of both migraine and depression, genes from serotonergic, dopaminergic and GABAergic systems together with variants in the MTHFR and BDNF genes remain strong candidates.

Genetic association and gene expression studies suggest that genetic variants in the SYNE1 and TNF genes are related to menstrual migraine

BackgroundMenstrual migraine (MM) encompasses pure menstrual migraine (PMM) and menstrually-related migraine (MRM). This study was aimed at investigating genetic variants that are potentially related to MM, specifically undertaking genotyping and mRNA expression analysis of the ESR1, PGR, SYNE1 and TNF genes in MM cases and non-migraine controls.MethodsA total of 37 variants distributed across 14 genes were genotyped in 437 DNA samples (282 cases and 155 controls). In addition levels of gene expression were determined in 74 cDNA samples (41 cases and 33 controls). Association and correlation analysis were performed using Plink and RStudio.ResultsSNPs rs3093664 and rs9371601 in TNF and SYNE1 genes respectively, were significantly associated with migraine in the MM population (p = 0.008; p = 0.009 respectively). Analysis of qPCR results found no significant difference in levels of gene expression between cases and controls. However, we found a significant correlation between the expression of ESR1 and SYNE1, ESR1 and PGR and TNF and SYNE1 in samples taken during the follicular phase of the menstrual cycle.ConclusionsOur results show that SNPs rs9371601 and rs3093664 in the SYNE1 and TNF genes respectively, are associated with MM. The present study also provides strong evidence to support the correlation of ESR1, PGR, SYNE1 and TNF gene expression in MM.

Blood gene expression studies in migraine: Potential and caveats

Background Global gene expression analysis may be used to obtain insights into the functional processes underlying migraine. However, there is a shortage of high-quality post-mortem brain tissue samples for genetic analysis. One approach is to use a more accessible tissue as a surrogate, such as peripheral blood. Purpose Discuss the benefits and caveats of blood genomic profiling in migraine and its potential application in the development of biomarkers of migraine susceptibility and outcome. Demonstrate the utility of blood-based expression profiles in migraine by analysing pilot Illumina HT-12 expression data from 76 (38 case, 38 control) whole-blood samples. Conclusion Current evidence suggests peripheral blood is a biologically valid substrate for genetic studies of migraine, and may be used to identify biomarkers and therapeutic pathways. Pilot blood gene expression data confirm that expression profiles significantly differ between migraine case and non-migraine control individuals.

Case-control study of ADARB1 and ADARB2 gene variants in migraine.

BackgroundMigraine causes crippling attacks of severe head pain along with associated nausea, vomiting, photophobia and/or phonophobia. The aim of this study was to investigate single nucleotide polymorphisms (SNPs) in the adenosine deaminase, RNA-specific, B1 (ADARB1) and adenosine deaminase, RNA specific, B2 (ADARB2) genes in an Australian case–control Caucasian population for association with migraine. Both candidate genes are highly expressed in the central nervous system and fit criteria for migraine neuropathology. SNPs in the ADARB2 gene were previously found to be positively associated with migraine in a pedigree-based genome wide association study using the genetic isolate of Norfolk Island, Australia. The ADARB1 gene was also chosen for investigation due to its important function in editing neurotransmitter receptor transcripts.MethodsFour SNPs in ADARB1 and nine in ADARB2 were selected by inspecting blocks of linkage disequilibrium in Haploview for genotyping using either TaqMan or Sequenom assays. These SNPs were genotyped in two-hundred and ninety one patients who satisfied the International Classification of Headache Disorders-II 2004 diagnostic criteria for migraine, and three-hundred and fourteen controls, and PLINK was used for association testing.ResultsChi-square analysis found no significant association between any of the SNPs tested in the ADARB1 and ADARB2 genes in this study and the occurrence of migraine.ConclusionsIn contrast to findings that SNPs in the ADARB2 gene were positively associated with migraine in the Norfolk Island population, we find no evidence to support the involvement of RNA editing genes in migraine susceptibility in an Australian Caucasian population.

RE: Six novel rare non-synonymous mutations for migraine without aura identified by exome sequencing

A recent study by Jiang et al. published by the Journal of Neurogenetics claims the identification of six novel rare mutations involved in the aetiology of migraine without aura (MWO) (Jiang et al., 2015). The authors performed wholeexome sequencing (WES) in a Chinese sample of four related cases (father, two sons, and one daughter) and four unrelated controls. The importance of the two variants UBE2NL T266G and EDAR2 G170A, located on the X chromosome is stressed as an endorsement to the observed sexual dimorphism in the presentation of migraine (i.e. females have up to three times higher risk than males) (Bigal & Lipton, 2009). However, upon review of this publication we have some concerns regarding the study’s main conclusions. As a team of researchers working on unveiling the genetic causes of migraine, we feel it is necessary to pinpoint the reasons why the results presented in the Jiang et al. study may be problematic. In doing so, we hope to promote scientific progress and make suggestions to further strengthen the Jiang et al. study.

Variation H452Y in HTR2A Gene Affects Immediate Visual Memory

Serotonin and its receptors, including the 5-Hydroxytryptamine Receptor 2A encoded by the HTR2A gene, are important for learning and memory in animals and humans. Polymorphic variation in the HTR2A gene, which encodes the 5-HT2A serotonin receptor, has previously been shown to associate with some memory traits, in particular affecting delayed verbal memory. In the current study ie we have examined the HTR2A His452Tyr (H452Y) substitution for association in a cohort of healthy individuals whose memory traits were assessed using a comprehensive battery of memory tests including, but not limited to, measures of prospective and retrospective memory.Although we failed to replicate previous findings of an affect of the polymorphism on delayed verbal memory, we found a significant association between the HTR2A H452Y polymorphism and immediate visual memory, showing that the heterozygous genotype is associated with poorer immediate visual memory, with delayed visual memoryunaffected, although, with correction for multiple testing, this no longer passed significance thresholds. No HTR2A Tyr/Tyr individuals were detected in this cohort due to the low minor allele frequency. This study suggests this variant of HTR2A may have implications on memory consolidation and immediate memory of healthy individuals with further examination of this marker warranted in other cohorts.