The role of digital device use on the risk of migraine: a univariable and multivariable Mendelian randomization study. Frontiers in Neurology.

Migraine is a common and debilitating neurological disorder characterized by recurrent headaches, often accompanied by nausea, vomiting, and sensitivity to light and sound. It affects over 100 million people worldwide, predominantly under the age of 50, and is the second leading cause of years lived with disability across all age groups. The one-year prevalence rates of migraine in Western countries vary, ranging from 4% to 9% in men and from 11% to 25% in women. Given the severe physical and psychological impact on patients, preventing migraine attacks is crucial.

Previous studies have identified several risk factors that contribute to migraines, including sleep patterns, dietary habits, physical activity, and medication use. Digital dependence, which is closely linked to genetic predisposition, significantly affects brain function and structure. Prolonged exposure to blue light and electromagnetic radiation can lead to neurological disorders such as headaches, sleep disturbances, negative emotions, memory loss, and attention deficits. Observational studies have shown that frequent use of electronic devices is associated with an increased risk of migraines, especially among students. However, traditional observational studies are susceptible to confounding factors that limit the reliability of causal inferences, making it difficult to establish a definitive causal link between digital device use and migraine risk.

Mendelian randomization (MR) is a method that uses measured genetic variation to investigate the causal effect of an exposure on an outcome. Data from genome-wide association studies (GWAS) are often used in the analysis of summary data. A GWAS is an observational study of a genome-wide set of genetic variants in different individuals to determine whether a variant is associated with a trait. In this case, the association between genetic variants and the exposure is derived from the summary results of a GWAS for the exposure. The association between the same genetic variants and the outcome is then derived from the summary results of a GWAS for the outcome. These two sets of pooled results are then used to derive the MR estimate.

Genetic variants, such as single nucleotide polymorphisms (SNPs), are used as proxies for the exposure (or outcome) of interest. These genetic variants are assumed to be randomly distributed and unaffected by confounding factors. By using genetic variants as instruments, MR can help infer causal relationships between exposures and outcomes without the need for traditional randomized controlled trials. The present study investigates the causal relationship between digital device use and migraine risk using Mendelian randomization.

GWAS data on four types of digital device use – mobile phone use, television viewing, computer use, and video gaming – were obtained from the UK Biobank, a large-scale database of genetic and health data from half a million UK participants. Digital device use was self-reported. Mobile phone use was defined as the number of calls made or received per week in the previous three months (n = 386,626 participants). Television use was measured by daily viewing time (n = 437,887), computer use by daily use time (n = 360,895), and video game use by gaming practices (n = 462,433).

GWAS data for migraines were obtained from two large datasets. The primary discovery cohort was FinnGen, a public-private partnership project in Finland that combines genetic data with digital health records from national health registries. It includes 20,908 cases of total migraine, 8,970 cases of migraine with aura (MA), and 7,593 cases of migraine without aura (MO). The replication cohort from the International Headache Genetics Consortium (IHGC) includes 48,975 European migraine cases overall, with 6,332 MA cases and 8,348 MO cases.

To select robust instrumental variables, only SNPs with a p-value < 5e-8 and minor allele frequencies > 0.01 were chosen. SNP independence was ensured using the 1000 Genomes Project European reference panel with a linkage disequilibrium threshold of r² < 0.001 within a 10 megabyte window.

Effect alleles were harmonized between the digital device use and migraine GWAS datasets. The univariable Mendelian randomization (UVMR) approach was used to examine potential causality between digital device use and migraine risk using various statistical methods. A meta-analysis was conducted to combine the causal estimates derived from the discovery and replication datasets, subsequently validating the causal relationship between digital device use and migraines. A multivariable MR analysis was then performed, adjusting for relevant confounders (stroke, physical activity, hypertension, insomnia, clinical depression, alcohol consumption, smoking, and body mass index).

Nine SNPs were uniquely associated with mobile phone use (either positively or negatively). Most of these SNPs have currently unknown functions. However, for three SNPs, the genes and their functions are known. PHLPP2 is a phosphatase involved in the regulation of Akt and PKC signaling pathways. ARPP21 regulates the effect of dopamine on the basal ganglia. FOXP2 appears to be involved in a variety of biological signaling pathways and cascades that may ultimately influence language development. Eighty-nine SNPs were associated with television viewing.

UVMR estimates based on the FinnGen cohort showed that genetically predicted mobile phone use was associated with an increased risk of total migraines (OR = 2.39) and MO (OR = 2.25). Similarly, television viewing was positively associated with an increased risk of total migraines (OR = 1.63) and MO (OR = 2.10), but neither activity was significantly associated with MA. Negative associations were observed between computer use (OR = 0.67) and video gaming (OR = 0.41) with MO, although neither was significantly associated with total migraines or MA.

Meta-analysis estimates from two separate datasets (FinnGen and IHGC) confirmed a significant causal relationship between mobile phone use and total migraines (OR = 1.58) and a suggestive association for MO (OR = 1.73). Television viewing was significantly associated with total migraines (OR = 1.63) and MO (OR = 1.92). No causal relationships were found between computer use, video gaming, and any migraine subtype.

The multivariable MR analysis, adjusted for relevant confounders, confirmed that mobile phone use was associated with an increased risk of migraines (OR = 1.40) and MO (OR = 1.88). Similarly, television viewing increased the risk of migraines (OR = 2.01) and MO (OR = 3.56).

Previous observational studies have highlighted the adverse effects of excessive use of electronic devices on migraines. Regarding mobile phone use, a meta-analysis combining data from 30 cohorts of different ethnicities and populations aged 9-63 years found a positive association between weekly mobile phone use and migraine risk, suggesting that mobile phone radiation may be a risk factor for migraine (Farashi 2022).

The association between electronic device use and migraines may be explained by prolonged exposure to blue light (television) and electromagnetic radiation (mobile phones). A clinical study found that migraine patients had significantly and persistently lower pain perception thresholds after exposure to intense light than healthy individuals (Kowacs 2001). This phenomenon can be attributed to the stimulation of retinal ganglion cells by blue light, which subsequently affects the conduction of the trigeminal nociceptive pathway. This suggests that visual stimuli can trigger migraines and also disrupt sleep.

In addition, the nervous system is highly sensitive to electromagnetic radiation (EMR). Prolonged exposure to radiofrequency EMR can lead to disruptions in neurotransmitter metabolism and oxidative stress in brain cells, both of which have been linked to the development of migraines. Overall, the mechanisms underlying the effects of electronic devices on migraines are complex and multifaceted and require further research.

Editor's note: In this study, significantly stronger effects of mobile phone use (OR = 2.39) on migraine occurrence were observed in the Finnish cohort compared to the pan-European dataset (OR = 1.32). This higher sensitivity of northern populations has also been reported in the literature on electromagnetic hypersensitivity and other conditions. Conversely, the association between migraines and television viewing was identical in both datasets (OR = 1.63). (AT)

"Prolonged exposure to radiofrequency EMR can lead to disruptions in neurotransmitter metabolism and oxidative stress in brain cells, both of which have been linked to the development of migraines."