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]