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. 2018 May 16;98(4):743-753.e4.
doi: 10.1016/j.neuron.2018.04.014. Epub 2018 May 3.

Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families

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Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families

Padhraig Gormley et al. Neuron. .
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  • Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families.
    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. Gormley P, et al. Neuron. 2018 Sep 5;99(5):1098. doi: 10.1016/j.neuron.2018.08.029. Neuron. 2018. PMID: 30189203 No abstract available.


Complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. The aggregation could be explained by rare, penetrant variants that segregate according to Mendelian inheritance or by the sufficient polygenic accumulation of common variants, each with an individually small effect, or a combination of the two hypotheses. In 8,319 individuals across 1,589 migraine families, we calculated migraine polygenic risk scores (PRS) and found a significantly higher common variant burden in familial cases (n = 5,317, OR = 1.76, 95% CI = 1.71-1.81, p = 1.7 × 10-109) compared to population cases from the FINRISK cohort (n = 1,101, OR = 1.32, 95% CI = 1.25-1.38, p = 7.2 × 10-17). The PRS 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 results demonstrate a significant contribution of common polygenic variation to the familial aggregation of migraine.

Keywords: GWAS; PRS; disease aggregation; familial aggregation; families; genome-wide association study; hemiplegic migraine; migraine; migraine with aura; polygenic risk score.

Conflict of interest statement


The study was partially funded by Merck and Co., Kenilworth, NJ, USA. Members of the 23andMe Research Team are current or former employees of 23andMe, Inc., and hold stock or stock options in 23andMe.


Figure 1
Figure 1. Distributions of the migraine polygenic risk scores (PRS) in the FINRISK population and the Finnish migraine families
For FINRISK, population controls and cases (any migraine subtype) are shown. For the families, family members with no migraine and familial cases (any migraine subtype) are shown. The vertical axis is density of individuals. SD is standard deviation. n is number of individuals.
Figure 2
Figure 2. Enrichment of polygenic risk scores (PRS) in familial and population cases
Odds ratios (OR) given are for one standard deviation (SD) increase in PRS compared to 13,369 FINRISK population controls and calculated using a logistic mixed-model adjusted for genetic relatedness, sex, and age. The PRS was calculated using weights from a published migraine genome-wide association study (GWAS, n = 375,000) (Gormley et al., 2016) for an independent set of 38,872 SNPs (GWAS P-value threshold < 0.1). FINRISK population cases include any migraine cases identified from Finnish National Health Registry data. ‘Families’ are individuals from the Finnish Migraine Families collection. n is number of individuals. CIs are confidence intervals.
Figure 3
Figure 3. Polygenic transmission disequilibrium test (pTDT) in migraine subtypes
The Finnish migraine families were subset into trios and grouped by disease status of the offspring, making 734 trios for offspring with no migraine and 1,486 trios for offspring with any migraine. Trios were further divided into migraine subtypes, including 727 trios for migraine without aura, 571 trios for migraine with typical aura, and 188 trios for hemiplegic migraine. The horizontal axis shows the pTDT deviation (and 95% confidence intervals) from the mean PRS that would be expected to be transmitted by the parents under the null. N is the number of trios. Groups with significant over-transmission are marked with ‘*’.
Figure 4
Figure 4. Mean polygenic risk score (PRS) stratified by age of onset of headaches in migraine cases
The data shows that higher PRS corresponds to earlier age of onset of migraine headache. Means and 95% confidence intervals (CIs) were estimated within the Finnish migraine families using bootstrap resampling (10,000 replicates) within each age of onset bin. n is number of individuals.

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