This study employed Mendelian Randomization (MR) analysis to investigate the genetic associations between migraines and lung cancer, including its subtypes, using genetic data from migraines obtained from the UK Biobank OpenGWAS project and lung cancer data from the IEU OpenGWAS project. Our findings suggest a causal relationship between migraines and lung cancer subtypes, identifying migraines as a potential risk factor for both the development and progression of lung cancer.
Migraine, a complex chronic headache disorder, is often associated with various comorbidities. A cross-sectional analysis by Mia T. Minen et al., based on the 2013–2015 US National Health Interview Survey data, found migraines or severe headaches to be associated with multiple chronic health conditions, including depression, anxiety, sleep disturbances, hypertension, and diabetes [11]. Notably, some of these conditions have been linked to an increased risk of lung cancer. Furthermore, comorbid depression and anxiety are common among individuals with migraines [12–13]. Mia Tova Minen et al. discovered that between 41% and 47% of individuals with migraines experience depression, while 51–58% encounter anxiety, noting that these patients are more than 2.5 times as likely to develop depression and frequently experience anxiety disorders, compared to those without migraines. Anxiety disorders occur in migraine sufferers at a rate 2 to 5 times higher than in the general population. Furthermore, Yun-He Wang and colleagues reported a significant association between depression, anxiety, and an increased risk of cancer development, cancer-related mortality, and overall mortality among cancer patients, with adjusted relative risks of 1.13 (95% CI: 1.06–1.19), 1.21 (95% CI: 1.16–1.26), and 1.24 (95% CI: 1.13–1.35) respectively [14]. Depression can impair natural killer (NK) cells and DNA repair enzymes, both vital for the immune response to cancer [14]. It may also directly affect the body's endocrine and immune systems, weakening the immune defense against tumors [15]. Furthermore, depression and anxiety can contribute to cancer progression indirectly by influencing lifestyle choices. Individuals with depression and anxiety are more likely to engage in unhealthy behaviors such as sedentary lifestyles, poor dietary habits, obesity, excessive alcohol use, smoking, and ignoring medical advice [16–17]. Claudia Trudel-Fitzgerald et al. reported in their 24-year prospective cohort study that severe depressive symptoms might increase the risk of lung cancer, potentially through effects on smoking behaviors [18]. Migraines are frequently associated with insomnia and sleep disturbances, which are more prevalent in individuals with migraines than in those without [19–20]. Cindy Tiseo et al. established a link between migraines and sleep disturbances, noting that they share underlying anatomical pathways [21]. The bidirectional relationship between migraine and insomnia can be attributed to the dysfunctional activities of the hypothalamus and brainstem, which are implicated in both conditions as shared pathophysiological mechanisms. These structures are integral to the regulation of sleep-wake cycles and pain management, and their dysfunction may explain the link between migraine and insomnia. Research into how insomnia influences lung cancer risk is scarce; however, potential mechanisms include disruption of circadian rhythms contributing to chronic lung disease, sleep deprivation exacerbating lung inflammation, and reduced immune function potentially facilitating lung cancer progression [22–24]. Jie Wang et al. employed Mendelian randomization analysis to control for smoking's effect and determined that insufficient sleep significantly increases the risk of lung cancer (OR 2.53, 95% CI 1.25–5.12) and lung adenocarcinoma (OR 5.75, 95% CI 2.12–15.65), whereas adequate sleep duration appears to reduce lung cancer risk (OR 0.46, 95% CI 0.26–0.83) [25]. Longitudinal studies have shown that migraine sufferers are at a higher risk of developing hypertension [26]. Pamela M. Rist, ScD, and colleagues, in a prospective cohort study of 29,040 women initially without hypertension, found that after 12.2 years, the incidence of hypertension rose by 9% among women experiencing aura without headache (MA), 21% among women with headache but no aura (MO), and 15% among women with a history of migraines [27]. The relationship between hypertension and cancer, particularly lung cancer, remains contentious due to limited focused research. However, Lee Soon Young et al. observed a notable interaction between hypertension and smoking, indicating an increased risk of lung cancer associated with hypertension [28]. Additionally, migraines have been identified as a risk factor for developing diabetes [29]. While research into the link between diabetes and lung cancer is scarce, leading to varied perspectives, there is evidence that diabetic women, especially those independently managing their condition and postmenopausal women on insulin therapy, are at a higher risk of developing lung cancer compared to non-diabetic counterparts [30–31].
Our study has several notable strengths. It is, to our knowledge, the first to investigate the genetic link between migraine and lung cancer—two conditions previously considered unrelated. We also examined potential mediators in their causal relationship. Moreover, instead of relying on randomized controlled trials (RCTs) or traditional observational studies, which have their limitations, our research utilized Mendelian Randomization (MR) methodology. RCTs, while offering robust evidence, pose ethical dilemmas and high costs, limiting their suitability for exploring causal links between exposures and outcomes. Observational studies may retain unaccounted biases even after adjustments. MR, in contrast, offers more reliable results by effectively addressing potential confounders and eliminating reverse causality concerns.
Nevertheless, our study is subject to certain limitations. Primarily, our cohort consisted exclusively of individuals from Europe, raising questions about the applicability of our results to diverse populations. Additionally, our analysis did not distinguish between different types of migraine, which are classified into various categories such as episodic migraine, chronic migraine, menstrual-related migraine, and vestibular migraine [32–35]. Therefore, the specific association between these migraine variants and lung cancer was not explored. Furthermore, the current body of research on the link between migraine and lung cancer is limited, leaving the exact contributory mechanisms of migraine to lung cancer development unclear. Our investigation did not delineate the precise pathogenic pathways from migraine to lung cancer.
In conclusion, our study provides robust evidence suggesting that genetic predisposition to migraines constitutes a risk factor for lung cancer. Further research is crucial to elucidate the underlying pathogenic mechanisms and intermediary variables connecting migraines and lung cancer, with the objective of reducing lung cancer risk.