Genetic and environmental influences on major recurrent headaches

Abstract: The major recurrent headaches are migraine and tension-type headache. The aim of this thesis is to characterize the main genetic and environmental architecture of these idiopathic conditions of episodic cranial pain using the Swedish Twin Registry. Recurrent headaches were examined in a nationwide cohort of 8 to 9-years-old twins through questionnaires sent to their parents (Paper 1). The prevalence of recurrent headaches was 13.7% (N=2,078 twins) and the heritability 70% (95%CI: 54, 82%) with no differences between the sexes. Further analyses disclosed phenotype heterogeneity, a genetic liability to migraine (88%, 95%CI: 67, 97%) and no genetic effects on tension-type headache. In paper II, the prevalence of severe disabling recurrent headache during the latest years among twins aged 15-47 years (N=25,212) was 10.7% with double the risk of women compared to men (OR=2.1, 95%CI: 1.9, 2.2). Among headache sufferers, 48% of women and 32% of men had migraine headache (chi2 =53.89, P<0.0001) and these proportions increased with increasing age. A significant variation in heritability of migraine headache across age groups ranging from 91% (15-20 years) to 37% (41-47 years) was detected in women (chi2 =20.29, P<0.025). This variation was explained by less environmental variance in adolescents than in adults. In a twin-adoption study of 314 pairs reared apart and 364 pairs matched control pairs reared together (Paper III), variance decomposition of lifetime migraine as assessed at ages 42-81 years revealed essentially the same results as those of the classical reared together design; rearing effects have no major importance and genetic variance is not confounded with specific environments of monozygotic twins. The SALT Headache study (Papers IV-VI) encompassed assessment of lifetime recurrent headaches among twins aged 41-64 years (N=31,192) and subsequent diagnosis of migraine and tension-type headache in line with the International Headache Society (If IS) criteria using lay telephone interviews. Among sufferers of recurrent headaches (lifetime prevalence=26.1%), respectively, 59% (strict criteria) and 87% (liberal criteria) were diagnosed with migraine, tension-type headache, or both. The female-to-male ratio was above two for migraine and below two for tension-type headache. The heritability was 44% (95%CI: 35,52%) for strict migraine and 22% (95%CI: 12, 32%) for strict tension-type headache; genetic effects were mainly non-additive, heritability of tension-type headache differed between men and women (0 versus 30%; chi2 =7.08, P<0.05), and no conclusive relationship between migraine and tension-type headache was found. The heritability of varying definitions of migraine ranged from 52% (95%Cl: 46, 57%) for self-report migraine with other recurrent headaches added to the IHS core phenotype to 37% (95%CI: 30, 44%) for self-report migraine without other recurrent headaches added to the IHS core. In conclusion, recurrent headache is a heterogeneous syndrome, where migraine is an intermediate heritable phenotype and tension-type headache a less heritable phenotype. Genetic variance of migraine is largely non-additive and stable across birth cohorts. Environment modulates manifestation of migraine mainly during adulthood whereas environmental influences on tension-type headache prevail in youth as well. Variation in the threshold of migraine affects the heritability.