Abstract
Previous studies suggested that both maladaptive stress response and circadian dysregulation might have a role in the background of migraine. However, effects of circadian genes on migraine have not been tested yet. In the present study, we investigated the main effect of rs10462028 of the circadian locomotor output cycles kaput (CLOCK) gene and its interaction with different stress factors on migraine. In our cross-sectional study 2,157 subjects recruited from Manchester and Budapest completed the ID-Migraine questionnaire to detect migraine type headaches (migraineID). Additional stress factors were assessed by a shortened version of the Childhood Trauma Questionnaire, the List of Threatening Experiences questionnaire, and a validated questionnaire to identify financial difficulties. Rs10462028 showed no main genetic effect on migraineID. However, chronic stress indexed by financial difficulties showed a significant interaction effect with rs10462028 (p = 0.006 in recessive model) on migraineID. This result remained significant after correction for lifetime bipolar and unipolar depression and was replicated in both subsamples, although only a trend effect was reached after Bonferroni-correction, which is the strictest correction not considering interdependences. Childhood adversity (CHA) and Recent negative life events (RLE) showed no significant gene × stress interaction with rs10462028. In addition, in silico analysis demonstrated that the genetic region tagged by rs10462028 alters the binding of several miRNAs. Our exploratory study suggests that variations in the CLOCK gene, with moderating effect on gene function through miRNA binding, in interaction with financial difficulties might influence the risk of migraine-type headaches. Thus, financial hardship as a chronic stress factor may affect migraine through altering circadian rhythms.
Highlights
Migraine is a debilitating disorder affecting approximately one billion people worldwide (Gormley et al, 2016)
Females represented approximately 70% of our sample, and the average age (±SEM) was 32.9 (±0.22) years. 27.8% of the participants reported two or three symptoms of migraine type headache based on the ID-Migraine questionnaire and were assigned migraineID
We found several potential miRNA binding sites around rs10462028 and rs1801260 with predicted change in binding due to the polymorphisms
Summary
Migraine is a debilitating disorder affecting approximately one billion people worldwide (Gormley et al, 2016). Migraine is heritable with estimated values of 0.34–0.57 (Chasman et al, 2016) reflecting an important role of environmental factors, . A large number of genes of small effects appear to be involved in migraine (Anttila et al, 2013; Gormley et al, 2016), and their interactions with environmental factors have been suggested (Sauro and Becker, 2009; Juhasz et al, 2017) but there is a significant lack of gene × environment interaction studies of migraine. As our knowledge about the pathogenesis of migraine accumulates, we may still overlook important contributing factors. One of these somewhat unacknowledged components might be circadian rhythmicity
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