Table 4 Mendelian randomization studies for causal associations of genetic variants predisposing for migraine and its comorbid disorders and traits
Comorbidity/Trait | Number of patients included | Direction of causality examined | Main finding(s) | Reference | |
|---|---|---|---|---|---|
Migraine | Comorbidity/Trait | ||||
Cardio−/vascular comorbidities | |||||
Ischemic Stroke | GERA cohort, UK Biobank and International Headache Genetics Consortium: 85,726 migraine cases and 803,292 controls | MEGASTROKE consortium: 40,585 cases and 406,111 controls | One-directional | No causal associations of migraine and ischemic stroke | Shu et al. [152] |
Stroke (ischemic and hemorrhagic) | International Headache Genetics Consortium: Any migraine: 59,674 cases and 316,078 controls MwA: 6332 cases and 144,883 controls MO: 8348 cases and 139,622 controls | MEGASTROKE consortium: All stroke: 40,585 cases and 406,111 controls Ischemic stroke: 34,217 cases and 406,111 controls Hemorrhagic stroke: 3223 cases and 3725 controls | One-directional | No causal association of migraine and stroke, ischemic stroke, and hemorrhagic stroke Migraine liability possibly associated with decreased large-artery atherosclerosis risk | Lee et al. [153] |
Stroke and Cervical Artery Dissection | International Headache Genetics Consortium: Any migraine: 59,674 cases and 316,078 controls MwA: 6332 cases and 144,883 controls MO: 8348 cases and 139,622 controls | MEGASTROKE consortium: CeAD: 1393 cases and 14,416 controls All stroke: 40,585 cases and 406,111 controls Ischemic stroke: 34,217 cases and 406,111 controls Large artery stroke: 4373 cases and 297,290 controls Cardioembolic stroke: 7193 cases and 355,68 controls Small vessel stroke: 5386 cases and 343,560 controls | One-directional | Migraine liability associated with increased risk for CeAD Migraine liability associated with decreased risk of large artery stroke | Daghlas et al. [154] |
Coronary artery disease and atrial fibrillation | International Headache Genetics Consortium: 59,674 migraine cases and 316,078 controls | Coronary artery disease: 76,014 cases and 264,785 controls Myocardial infarction: 43,676 cases and 128,199 controls Angina: 10,618 cases and 326,065 controls Atrial fibrillation: 60,620 and 970,216 | One-directional | Migraine liability associated with decreased risk of coronary artery disease, myocardial infarction, and angina, but not on atrial fibrillation | Daghlas et al. [143] |
Blood pressure | International Headache Genetics Consortium: 59,674 cases and 316,078 controls | 757,601 | Bidirectional | Genetically predicted elevated DBP and SBP, and decreased PP associated with increased migraine risk Migraine liability associated with increased SBP and PP, but not DBP | Guo et al. [145] |
Forty-seven traits from the UK Biobank | International Headache Genetics Consortium: 59,674 cases and 316,078 controls | UK Biobank and a combined meta-analysis: for DBP n > 1 million individuals | One-directional | Genetically predicted elevated DBP associated with increased migraine risk | Siewert et al. [144] |
Cardiovascular risk factors and lifestyle | |||||
Alcohol, coffee consumption, smoking | 7759 cases and 504,902 controls FinnGen study: 6687 cases and 144,780 controls UK Biobank: 1072 cases and 360,122 controls | Bidirectional | Genetically predicted alcohol and coffee consumption inversely associated with migraine risk, smoking initiation associated with increased migraine risk Migraine liability inversely associated with alcohol consumption, not associated with coffee consumption or smoking initiation | Yuan et al. [155] | |
Coffee consumption | MwA: 6332 cases and 144,883 controls MO: 8348 cases and 139,622 controls | UK Biobank: 375,833 participants | One-directional | Genetically predicted increase of coffee consumption not associated with the risk of any migraine, MwA or MO | Chen et al. [156] |
Smoking | HUNT study: 7522 cases and 35,342 controls | One-directional | No causal relationship between smoking intensity and migraine | Johnsen et al. [157] | |
Brain morphometry and cognition | |||||
Cognition and brain volume | International Headache Genetics Consortium: 59,674 migraine cases and 316,078 controls | Alzheimer’s disease: 71,880 cases and 383,378 controls Measure of general intelligence: 269,867 subjects Measure of intracranial volume: 11,373 subjects Seven subcortical brain volumes ∼ 13,000 subjects | One-directional | Migraine liability not associated with Alzheimer’s disease, intelligence, or any brain volume measures | Daghlas et al. [151] |
Brain morphometry | International Headache Genetics Consortium: 59,674 migraine patients vs 316,078 controls | ENIGMA and CHARGE consortia, UK biobank, ABCD cohort: 66,000 participants | Bidirectional | Genetically determined smaller total brain, hippocampal and ventral diencephalon volume possibly associated with increased migraine risk Migraine liability associated with larger volume of the amygdala | Mitchell et al. [158] |
Sleep disorders | |||||
Insomnia | finn-a-G6_MIGRAINE: 3650 migraine cases and 83,167 controls UK Biobank: 13,597 migraine cases and 449,336 controls | UK Biobank: 462,341 participants | Bidirectional | Genetically determined insomnia significantly associated with increased migraine risk Migraine liability not associated with insomnia risk | Chu et al. [159] |
Sleep disturbances | International Headache Genetics Consortium: 59,674 cases and 316,078 controls | UK Biobank: ≥ 237,627 participants | Bidirectional | Difficulty awakening and liability to insomnia symptoms associated with increased risk of migraine Migraine liability slightly associated with increased napping frequency | Daghlas et al. [146] |
Gastroenterological conditions | |||||
Irritable bowel syndrome | UK Biobank: 1072 cases and 360,122 controls | 1121 cases and 360,073 controls | One-directional | Genetically determined irritable bowel syndrome associated with increased migraine risk | Chen et al. [160] |
Gynecological conditions | |||||
Endometriosis | International Headache Genetics Consortium: 59,674 migraine cases and 316,078 controls | 17,054 cases (all stages of endometriosis) and 191,858 controls | One-directional | No causal association | Adewuyi et al. [147] |
Laboratory parameters | |||||
Clinical chemistry tests (HDL-C, LDL-C, TG, iron, diseases of liver) | 29,209 cases and 172,931 controls | Chemistry test values and data on medically relevant disorders from 23,986 to 452,264 participants | One-directional | No causal associations | Tanha et al. [161] |
Seventy-nine metabolic traits | International Headache Genetics Consortium: 59,674 migraine cases and 316,078 controls | From 6263 to 24,925 | Bidirectional | Genetically predicted shorter length of fatty acids and higher level of a lysophosphatidylethanolamine, LPE(20:4) associated with increased migraine risk | Tanha et al. [162] |
Nineteen lipoprotein subfractions | International Headache Genetics Consortium: 54,552 cases and 297,970 controls | 47,713 participants | Bidirectional | Lipoprotein subfractions not causally related with migraine | Guo et al. [163] |
Serum calcium | International Headache Consortium: 23,285 cases and 95,425 controls | 39,400 participants | One-directional | Genetically predicted increase in serum calcium levels associated with increased migraine liability | Yin et al. [164] |
Twelve blood-based measures of hemostasis | International Headache Genetics Consortium: 59,674 cases and 316,078 controls | CHARGE Consortium Hemostasis Working Group: n = 2583 to n = 120,246 | Bidirectional | Increased FVIII, vWF, and phosphorylated fibrinopeptide A and decreased fibrinogen associated with increased migraine risk (especially MA) Migraine liability not associated with measures of hemostasis | Guo et al. [150] |
Vitamine D Levels | GWAS 1 (Hautakangas et al.): 48,975 cases and 540,381 controls GWAS 2 (Choquet et al.): 28,852 cases and 525,717 controls GWAS 3 (FinnGen): 10,536 cases and 208,845 controls | UK Biobank 417,580 participants | Bidirectional | Genetically determined increase in circulating vitamin D levels associated with a decreased migraine risk Migraine not associated with vitamin D levels | Niu et al. [165] |
Circulating Insulin-Like Growth Factor 1 Levels | GWAS 1 (FinnGen): 10,536 cases and 208,845 controls GWAS 2 (Choquet et al.): 28,852 cases and 554,569 controls | UK Biobank 363,228 participants | Bidirectional | Genetically determined increase in IGF1 levels associated with decreased risk of migraine Migraine not associated with IGF1 levels | Abuduxukuer et al. [166] |
DNA methylation | International Headache Genetics Consortium: 59,674 cases and 316,078 controls | DNA methylation quantitative trait loci from whole blood, n = 639 and fetal brain, n = 166 | One-directional | Not provided | Hannon et al. [167] |
Socioeconomic outcomes | |||||
School absence and educational attainment | Avon Longitudinal Study of Parents and Children: 6113 participants | One-directional | Migraine liability not associated with school absence or educational attainment in childhood and adolescence | Hughes et al. [168] | |
Nineteen social and socioeconomic outcomes | UK Biobank: 10,603 cases, 326,394 controls | One-directional | Migraine liability associated with reduced chance of having a weekly leisure or social activity | Harrison et al. [169] | |