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

Abstract

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) compared to population cases from the FINRISK cohort (n = 1,101, OR = 1.32, 95% CI = 1.25-1.38, p = 7.2 × 10). 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.

Advance in genetics of migraine

“…In this polygenic risk score study, the genetic load was higher in migraine with aura and hemiplegic migraine cases compared with migraine without aura (Fig. 1) [27 ▪ ]. This could partially explain the lower prevalence of migraine with aura and hemiplegic migraine, as conceivably a higher genetic burden is required for developing these subtypes.…”

“…This is in line with the observation that migraine aggregates in families. A recent study, using a novel approach, used results of the most recent migraine GWAS [14] to create polygenic risk scores to see if the genetic load of these common variants contribute to the aggregation of migraine in families (1589 Finnish families were included) [27 ▪ ]. Indeed, the aggregation of migraine in families can at least partly be explained by the contribution of common polygenic variations.…”

“…This could partially explain the lower prevalence of migraine with aura and hemiplegic migraine, as conceivably a higher genetic burden is required for developing these subtypes. There were no differences found between genetic common variant burden in migraine with aura and hemiplegic migraine (sporadic or familial) [27 ▪ ]. This may be because of a lack of power as there were fewer hemiplegic migraine patients included.…”

Pleiotropy of polygenic factors associated with focal and generalized epilepsy in the general population

“…The use and generation of PRS is a rapidly developing field, with no established best-practice method. We selected the LD-clumping and P-value thresholding method to generate PRS based on a known excellent performance in neurological and psychiatric disorders [35][36][37]. A commonly used alternative is LDpred, a method that accounts for LD between SNPs and thus allows joint modeling with the potential of improvements in the prediction power [38].…”

Psychiatric and sleep abnormalities in school-age children with migraine

“…The study also declared that the most common migraine subtype was episodic migraine without aura with a high percent of included patients had positive family history of migraine. These observations are passing with the works of Le et al [5] as well as Gormley et al [20] who specified that pediatric migraine tends to run in families with high concordance among monozygotic twins pointing to the inherited nature of the disease.…”