In the largest-ever family study of migraine we observed that an accumulation of many independent genetic risk variants is the reason why migraine tends to run in families.

The study was based on medical history and genetic data of 1 589 Finnish migraine families. Our family sample included 8 319 individuals of whom 2 357 had migraine without aura, 2 420 had migraine with typical aura and 540 had hemiplegic aura symptoms. This family cohort is unique in its size and several neurologists from all over Finland have participated in recruiting the participants.

Migraine is one of the most common brain disorders worldwide, affecting approximately 10-15% of the adults in developed countries. The molecular mechanisms of migraine and the reasons for familial clustering remain poorly understood. We hypothesized that in addition to some rare, highly penetrant variants, accumulation of common variants with small individual effect sizes contribute to the familial forms of migraine. To study this, we first constructed a polygenetic risk score (PRS) from our previous migraine GWAS consisting of approximately 59 000 cases and 316 000 controls (Gormley et al., 2016). We then investigated the contribution of common polygenic and rare variation to migraine in our large Finnish migraine family cohort.

The genetic risk score explained 1.6% of the phenotypic variance in the population cases and 3.5% in the familial cases (including 2.9% for migraine without aura, 5.5% for migraine with typical aura, and 8.2% for hemiplegic migraine). The genetic burden was shown to be greater in patients that experience aura symptoms during attacks or have an early age of onset of migraine. Of special interest was the contribution of common and rare genetic variation to hemiplegic migraine, a disease primarily thought to be caused by rare pathogenic variants in three ion transporter genes.

Original Article

Gormley P, Kurki MI, Hiekkala ME, Veerapen K, Häppölä P, Mitchell AA, Lal D, Palta P, Surakka I, Kaunisto MA, Hämäläinen E, Vepsäläinen S, Havanka H, Harno H, Ilmavirta M, Nissilä M, Säkö E, Sumelahti ML, Liukkonen J, Sillanpää M, Metsähonkala L, Koskinen S, Lehtimäki T, Raitakari O, Männikkö M, Ran C, Belin AC, Jousilahti P, Anttila V, Salomaa V, Artto V, Färkkilä M; 23andMe Research Team; International Headache Genetics Consortium (IHGC), Runz H, Daly MJ, Neale BM, Ripatti S, Kallela M, Wessman M, Palotie A. Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families. Neuron 98(4): 743-753.e4, 2018 (doi: 10.1016/j.neuron.2018.04.014)