Common polygenic variation contributes to risk of migraine in the Norfolk Island population

Abstract

Migraine has been defined as a common disabling primary headache disorder. Epidemiology studies have provided with the undeniable evidence of genetic components as active players in the development of the disease under a polygenic model in which multiple risk alleles exert modest individual effects. Our objective was to test the contribution of a polygenic effect to migraine risk in the Norfolk Island population using a panel of SNPs reported to be disease associated in published migraine GWAS. We also investigated whether individual SNPs were associated with gene expression levels measured in whole blood. Polygenic scores were calculated in a total of 285 related individuals (74 cases, 211 controls) from the Norfolk Island using 51 SNPs previously reported to be associated with migraine in published GWAS. The association between polygenic score and migraine case-control status was tested using logistic regression. Results indicate that a migraine polygenic risk score was associated with migraine case-control status in this population (P = 0.016). This supports the hypothesis that multiple SNPs with weak effects collectively contribute to migraine risk in this population. Amongst the SNPs included in the polygenic model, four were associated with the expression of the USMG5 gene, including rs171251 (P = 0.012). Results from this study provide evidence for a polygenic contribution to migraine risk in an isolated population and highlight specific SNPs that regulate the expression of USMG5, a gene critical for mitochondrial function.

Advances in genetics of migraine

“…With the availability of increasingly large GWAS data sets for migraine, GRS may be applied to: investigating migraine subtypes and endophenotypes, understanding migraine pleiotropy and co-morbidites, disease and phenotype prediction, and for assessing pharmocogenetic effects for personalised medicine [247]. Higher GRS have been correlated with migraine diagnosis in specific cohorts [226, 248], as well as migraine severity, and in cases where migraine is aggregated in families suggesting this results from a higher common variant burden [225, 249]. One particular use of GRS may be in understanding drug reactions and efficacy of therapies.…”

A genetic risk score is differentially associated with migraine with and without aura

“…Rodriguez-Acevedo and coworkers found an association between migraine and a GRS (including 51 genetic variants previously nominally associated with migraine) in a small sample including 74 cases and 211 controls (Rodriguez-Acevedo et al 2015). We used a different approach by selecting only genetic variants previously associated with migraine with a genome-wide significant threshold for which an OR had been reported and we further prioritized variables using a random forest algorithm.…”

Methylome-wide association study of whole blood DNA in the Norfolk Island isolate identifies robust loci associated with age

“…The Norfolk Island Health Study (NIHS) was established in 2000 [16], and several collections have since occurred as part of an extended health survey [49,50]. To reduce the possibility of confounders we selected 24 individuals using stringent criteria, and investigated age at time of collection (aged 24-47 years).…”