Genetic overlap and causality between blood metabolites and migraine

The availability of genome-wide association studies (GWASs) for human blood metabolome provides an excellent opportunity for study -ing metabolism in a heritable disease such as migraine. Utilizing GWAS summary statistics, we conduct comprehensive pairwise genetic analyses to estimate polygenic genetic overlap and causality between 316 unique blood metabolite levels and migraine risk. We find sig-nificant genome-wide genetic overlap between migraine and 44 metabolites, mostly lipid and organic acid metabolic traits (FDR 0.05). We also identify 36 metabolites, mostly related to lipoproteins, that have shared genetic influences with migraine at eight independent genomic loci (posterior probability 0.9) across chromosomes 3, 5, 6, 9, and 16. The observed relationships between genetic factors influencing blood metabolite levels and genetic risk for migraine suggest an alteration of metabolite levels in individuals with migraine. Our analyses suggest higher levels of fatty acids, except docosahexaenoic acid (DHA), a very long-chain omega-3, in individuals with migraine. Consistently, we found a causally protective role for a longer length of fatty acids against migraine. We also identified a causal effect for a higher level of a lysophosphatidylethanolamine, LPE(20:4), on migraine, thus introducing LPE(20:4) as a potential therapeu-tic target for migraine.

Automated summary

The study utilized genome-wide association studies (GWASs) to investigate the genetic overlap and causality between blood metabolite levels and migraine risk. Significant genetic overlap was found between migraine and 44 metabolites, with shared genetic influences identified at eight independent genomic loci across different chromosomes. The findings suggest alterations in metabolite levels in individuals with migraine, with fatty acids playing a potentially protective role against migraine and a specific lipid metabolite identified as a potential therapeutic target for migraine.