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Objective: 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. [ABSTRACT FROM AUTHOR]

Migraine and tension-type headache (TTH) are often viewed as distinct entities and defined as such in the International Classification of Headache Disorders, 2nd edition (ICHD-II) criteria, although there is also empirical evidence to suggest they may be etiologically similar. This study aims to investigate whether migraine and TTH are etiologically related conditions. First, we explored whether migraine and TTH were associated with the same environmental and lifestyle risk factors at the population level. Second, we examined comorbidity of migraine and TTH in a twin design. By comparing the associations in monozygotic (MZ) and dizygotic (DZ) twin pairs, we investigated whether the comorbidity can be explained by genetic factors that influence both conditions. Results indicated that migraine and TTH were largely associated with the same environmental and lifestyle factors, including younger age, female sex, higher body mass index, more depression, stress at home, and less participation in regular exercise, with consistently stronger effects for migraine than for TTH. Migraine in one twin was significantly associated with TTH in the other twin. A stronger cross-trait, cross-twin association in MZ than DZ twins suggested that this comorbidity may also be partly due to shared genetic factors, although the difference in associations was not significant. In conclusion, our findings are consistent with the hypothesis that migraine and TTH have partly shared etiologies. For both treatment and research, it may be advisable not to make a rigid distinction, but to treat migraine and TTH as related conditions. [ABSTRACT FROM PUBLISHER]

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. [ABSTRACT FROM AUTHOR]

Migraine and major depressive disorder (MDD) are comorbid, moderately heritable and to some extent influenced by the same genes. In a previous paper, we suggested the possibility of causality (one trait causing the other) underlying this comorbidity. We present a new application of polygenic (genetic risk) score analysis to investigate the mechanisms underlying the genetic overlap of migraine and MDD. Genetic risk scores were constructed based on data from two discovery samples in which genome-wide association analyses (GWA) were performed for migraine and MDD, respectively. The Australian Twin Migraine GWA study ( N = 6,350) included 2,825 migraine cases and 3,525 controls, 805 of whom met the diagnostic criteria for MDD. The RADIANT GWA study ( N = 3,230) included 1,636 MDD cases and 1,594 controls. Genetic risk scores for migraine and for MDD were used to predict pure and comorbid forms of migraine and MDD in an independent Dutch target sample (NTR-NESDA, N = 2,966), which included 1,476 MDD cases and 1,058 migraine cases (723 of these individuals had both disorders concurrently). The observed patterns of prediction suggest that the 'pure' forms of migraine and MDD are genetically distinct disorders. The subgroup of individuals with comorbid MDD and migraine were genetically most similar to MDD patients. These results indicate that in at least a subset of migraine patients with MDD, migraine may be a symptom or consequence of MDD. [ABSTRACT FROM AUTHOR]

Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P < 5 × 10−8). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B. [ABSTRACT FROM AUTHOR]

Abstract: There is a well-established comorbidity between migraine and anxiety and depression (A/D). Here, we investigate whether this relationship is specific for migraine and A/D or whether other types of pain are also consistently associated with A/D. In addition, we test whether there is a consistent association between migraine and other types of pain when comorbidity with A/D is controlled for. Data on A/D, migraine, and 6 nonheadache pain locations (back, neck, orofacial area, abdomen, joints, and chest) were analyzed in 2,981 participants from the Netherlands Study of Depression and Anxiety (NESDA). It was tested whether the prevalence of pain in each individual location, as well as the total number of pain locations, depended on A/D and migraine status. A/D was consistently associated with pain in all measured locations. Migraine was also associated with pain in all anatomical sites, but these associations weakened substantially after correction for A/D severity, suggesting that a considerable part of the comorbidity of migraine and other types of pain may be explained by A/D. These findings emphasize the importance of accounting for A/D in studies of pain comorbidity. This will contribute to a better understanding of the mechanisms underlying A/D and pain. Perspective: Anxiety and depression are consistently associated with pain, regardless of anatomical site. These disorders may be important factors in the co-occurrence of different pain disorders. Awareness of this comorbidity and a better understanding of the underlying mechanisms may facilitate adequate treatment of both types of conditions. [Copyright &y& Elsevier]

Comorbidity — the clustered occurrence of two traits or disorders — may be studied in genetically informative designs such as the classical twin study, to test whether genetic and/or environmental factors underlying the two disorders are correlated. When a genetic correlation is found, this can be explained by several mechanisms, including pleiotropy (the same genes influencing multiple traits), and causality (one trait causing the other). With a cotwin control design, it can be investigated which scenario is most plausible. In this design, monozygotic twin pairs discordant for the first trait (i.e., one twin is affected, the other is not) are compared in terms of their risk for the second trait: under a causal model, only the twins affected for the first trait will be at increased risk for the second trait. Under genetic pleiotropy, this risk will be increased in both twins because they share the same risk genes. We first discuss the cotwin control design and then illustrate its application with data on migraine and neuroticism that were collected in 5,200 Dutch twins, including 1,648 complete twin pairs (981 monozygotic and 667 dizygotic pairs). There was a significant association between migraine and neuroticism, which could be attributed to genetic and environmental correlations (rG = .27 and rE = .19). In monozygotic and dizygotic twin pairs discordant for neuroticism, the risk of migraine was significantly higher in the twins with a high neuroticism score. This pattern of results is consistent with a causal relationship, suggesting that neuroticism increases the risk of migraine. [ABSTRACT FROM PUBLISHER]

Migraine is a common neurological disorder with a genetically complex background. This paper describes a meta-analysis of genome-wide association (GWA) studies on migraine, performed by the Dutch-Icelandic migraine genetics (DICE) consortium, which brings together six population-based European migraine cohorts with a total sample size of 10 980 individuals (2446 cases and 8534 controls). A total of 32 SNPs showed marginal evidence for association at a P-value<10−5. The best result was obtained for SNP rs9908234, which had a P-value of 8.00 × 10−8. This top SNP is located in the nerve growth factor receptor (NGFR) gene. However, this SNP did not replicate in three cohorts from the Netherlands and Australia. Of the other 31 SNPs, 18 SNPs were tested in two replication cohorts, but none replicated. In addition, we explored previously identified candidate genes in the meta-analysis data set. This revealed a modest gene-based significant association between migraine and the metadherin (MTDH) gene, previously identified in the first clinic-based GWA study (GWAS) for migraine (Bonferroni-corrected gene-based P-value=0.026). This finding is consistent with the involvement of the glutamate pathway in migraine. Additional research is necessary to further confirm the involvement of glutamate. [ABSTRACT FROM AUTHOR]

( Headache 2010;50:1549-1560) To investigate (1) whether shared genetic factors influence migraine and anxious depression; (2) whether the genetic architecture of migraine depends on anxious depression; (3) whether the association between migraine and anxious depression is causal. Migraine and anxious depression frequently occur together, but little is known about the mechanisms causing this association. A twin study was conducted to model the genetic architecture of migraine and anxious depression and the covariance between them. Anxious depression was also added to the model as a moderator variable to examine whether anxious depression affects the genetic architecture of migraine. Causal models were explored with the co-twin control method. Modest but significant phenotypic (rP = 0.28), genetic (rG = 0.30), and nonshared environmental (rE = 0.26) correlations were found between the 2 traits. Interestingly, the heritability of migraine depended on the level of anxious depression: the higher the anxious depression score, the lower the relative contribution of genetic factors to the individual differences in migraine susceptibility. The observed risk patterns in discordant twins are most consistent with a bidirectional causal relationship. These findings confirm the genetic association between migraine and anxious depression and are consistent with a syndromic association between the 2 traits. This highlights the importance of taking comorbidity into account in genetic studies of migraine, especially in the context of selection for large-scale genotyping efforts. Genetic studies may be most effective when migraine with and without comorbid anxious depression are treated as separate phenotypes. [ABSTRACT FROM AUTHOR]

Introduction and objective: Migraine and major depressive disorder (MDD) frequently co-occur, but it is unclear whether depression is associated with a specific subtype of migraine. The objective of this study was to investigate whether migraine is qualitatively different in MDD patients (N = 1816) and non-depressed controls (N = 3428).Methods: Migraine symptom data were analyzed using multi-group Latent Class Analysis, and a qualitative comparison was made between the symptom profiles of MDD patients and controls, while allowing for differences in migraine prevalence and severity between groups.Results: In both groups, three migrainous headache classes were identified, which differed primarily in terms of severity. Both mild and severe migrainous headaches were two to three times more prevalent in MDD patients. Migraine symptom profiles showed only minor qualitative differences in the MDD and non-MDD groups: in the severe migrainous headache class, significant differences were observed only in the prevalence of aggravation by physical activity (83% and 91% for the non-MDD and MDD groups, respectively) and aura (42% vs. 53%, respectively).Conclusion: The similar overall symptom profiles observed in the MDD and non-MDD subjects suggest that a similar disease process may underlie migraine in both groups. [ABSTRACT FROM PUBLISHER]

The effect of nonresponse on health and lifestyle measures has received extensive study, showing at most relatively modest effects. Nonresponse bias with respect to personality has been less thoroughly investigated. The present study uses data from responding individuals as a proxy for the missing data of their nonresponding family members to examine the presence of nonresponse bias for personality traits and disorders as well as health and lifestyle traits. We looked at the Big Five personality traits, borderline personality disorder (BPD) features, attention-deficit/hyperactivity disorder, Anger, and several measures of health (Body Mass Index, migraine) and lifestyle (smoking, alcohol use). In general, outcomes tend to be slightly more favorable for individuals from highly cooperative families compared to individuals from less cooperative families. The only significant difference was found for BPD features (p = .001). However, the absolute difference in mean scores is very small, less than 1 point for a scale ranging from 0 to 72. In conclusion, survey data on personality, health and lifestyle are relatively unbiased with respect to nonresponse. [ABSTRACT FROM AUTHOR]

Introduction: It is unclear whether patients diagnosed according to International Classification of Headache Disorders criteria for migraine with aura (MA) and migraine without aura (MO) experience distinct disorders or whether their migraine subtypes are genetically related.Aim: Using a novel gene-based (statistical) approach, we aimed to identify individual genes and pathways associated both with MA and MO.Methods: Gene-based tests were performed using genome-wide association summary statistic results from the most recent International Headache Genetics Consortium study comparing 4505 MA cases with 34,813 controls and 4038 MO cases with 40,294 controls. After accounting for non-independence of gene-based test results, we examined the significance of the proportion of shared genes associated with MA and MO.Results: We found a significant overlap in genes associated with MA and MO. Of the total 1514 genes with a nominally significant gene-based p value (pgene-based ≤ 0.05) in the MA subgroup, 107 also produced pgene-based ≤ 0.05 in the MO subgroup. The proportion of overlapping genes is almost double the empirically derived null expectation, producing significant evidence of gene-based overlap (pleiotropy) (pbinomial-test = 1.5 × 10(-4)). Combining results across MA and MO, six genes produced genome-wide significant gene-based p values. Four of these genes (TRPM8, UFL1, FHL5 and LRP1) were located in close proximity to previously reported genome-wide significant SNPs for migraine, while two genes, TARBP2 and NPFF separated by just 259 bp on chromosome 12q13.13, represent a novel risk locus. The genes overlapping in both migraine types were enriched for functions related to inflammation, the cardiovascular system and connective tissue.Conclusions: Our results provide novel insight into the likely genes and biological mechanisms that underlie both MA and MO, and when combined with previous data, highlight the neuropeptide FF-amide peptide encoding gene (NPFF) as a novel candidate risk gene for both types of migraine. [ABSTRACT FROM AUTHOR]

Background: There has been intensive debate whether migraine with aura (MA) and migraine without aura (MO) shouldbe considered distinct subtypes or part of the same disease spectrum. There is also discussion to what extent migrainecases collected in specialised headache clinics differ from cases from population cohorts, and how female cases differfrom male cases with respect to their migraine. To assess the genetic overlap between these migraine subgroups, weexamined genome-wide association (GWA) results from analysis of 23,285 migraine cases and 95,425 populationmatchedcontrols.Methods: Detailed heterogeneity analysis of single-nucleotide polymorphism (SNP) effects (odds ratios) between migrainesubgroups was performed for the 12 independent SNP loci significantly associated (p<5x10-8; thus surpassing thethreshold for genome-wide significance) with migraine susceptibility. Overall genetic overlap was assessed using SNPeffect concordance analysis (SECA) at over 23,000 independent SNPs.Results: Significant heterogeneity of SNP effects (phet<1.4x10-3) was observed between the MA and MO subgroups(for SNP rs9349379), and between the clinic- and population-based subgroups (for SNPs rs10915437, rs6790925 andrs6478241). However, for all 12 SNPs the risk-increasing allele was the same, and SECA found the majority of genomewideSNP effects to be in the same direction across the subgroups.Conclusions: Any differences in common genetic risk across these subgroups are outweighed by the similarities. Metaanalysisof additional migraine GWA datasets, regardless of their major subgroup composition, will identify new susceptibilityloci for migraine. [ABSTRACT FROM AUTHOR]