Genetic causal relationship between immune diseases and migraine: a Mendelian randomization study

Abstract

Background: Migraine has an increased prevalence in several immune disorders, but genetic cause-effect relationships remain unclear. Mendelian randomization (MR) was used in this study to explore whether immune diseases are causally associated with migraine and its subtypes.

Methods: We conducted a two-sample bidirectional multivariate Mendelian randomization study. Single-nucleotide polymorphisms (SNP) for six immune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), allergic rhinitis (AR), asthma and psoriasis, were used as genetic instrumental variables. Summary statistics for migraine were obtained from 3 databases: the International Headache Genetics Consortium (IHGC), UK Biobank, and FinnGen study. MR analyses were performed per outcome database for each exposure and subsequently meta-analyzed. Reverse MR analysis was performed to determine whether migraine were risk factors for immune diseases. In addition, we conducted a genetic correlation to identify shared genetic variants for these two associations.

Results: No significant causal relationship was found between immune diseases and migraine and its subtypes. These results were robust with a series of sensitivity analyses. Using the linkage disequilibrium score regression method (LDSC), we detected no genetic correlation between migraine and immune diseases.

Conclusion: The evidence from our study does not support a causal relationship between immune diseases and migraine. The mechanisms underlying the frequent comorbidity of migraine and several immune diseases need to be further elucidated.

Keywords: Mendelian randomization; causal association; genetic correlation; immune diseases; migraine.

Figure 1

Schematic overview of the present study design. GWAS, genome-wide association study; MR, Mendelian randomization; IVW, inverse variance weighted; IHGC, International Headache Genetics Consortium.

Figure 2

Causal association between immune diseases with migraine. Estimated ORs for the effect of immune diseases on migraine, obtained from an IVW analysis, per outcome database separately and combined over the 3 databases using fixed-effect meta-analyses when the heterogeneity was less than 50%: otherwise, using random-effects meta-analyses. CI, confidence interval; SNPs, single-nucleotide polymorphisms.

Figure 3

Causal association between immune diseases with migraine with aura. Estimated ORs for the effect of immune diseases on migraine with aura, obtained from an IVW analysis, per outcome database separately and combined over the 2 databases using fixed-effect meta-analyses when the heterogeneity was less than 50%: otherwise, using random-effects meta-analyses. CI, confidence interval; SNPs, single-nucleotide polymorphisms.

Figure 4

Causal association between immune diseases with migraine without aura. Estimated ORs for the effect of immune diseases on migraine without aura, obtained from an IVW analysis, per outcome database separately and combined over the 2 databases using fixed-effect meta-analyses when the heterogeneity was less than 50%: otherwise, using random-effects meta-analyses. CI, confidence interval; SNPs, single-nucleotide polymorphisms.

Figure 5

Causal association between migraine with immune diseases. Estimated ORs for the effect of migraine on immune diseases, obtained from an IVW analysis. CI: confidence interval; SNPs, single-nucleotide polymorphisms; AR, allergic rhinitis; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis; T1D, type 1 diabetes; MA, migraine with aura; MO, migraine without aura.