ausblenden:
Schlagwörter:
Migraine, aura, genome-wide, association, gene-based, pleiotropy
Zusammenfassung:
Introduction It is unclear whether patients diagnosed according to
International Classification of Headache Disorders criteria for migraine
with aura (MA) and migraine without aura (MO) experience distinct
disorders or whether their migraine subtypes are genetically related.
Aim Using a novel gene-based (statistical) approach, we aimed to
identify individual genes and pathways associated both with MA and MO.
Methods Gene-based tests were performed using genome-wide association
summary statistic results from the most recent International Headache
Genetics Consortium study comparing 4505 MA cases with 34,813 controls
and 4038 MO cases with 40,294 controls. After accounting for
non-independence of gene-based test results, we examined the
significance of the proportion of shared genes associated with MA and
MO.
Results We found a significant overlap in genes associated with MA and
MO. Of the total 1514 genes with a nominally significant gene-based p
value (p(gene-based)0.05) in the MA subgroup, 107 also produced
p(gene-based)0.05 in the MO subgroup. The proportion of overlapping
genes is almost double the empirically derived null expectation,
producing significant evidence of gene-based overlap (pleiotropy)
(p(binomial-test) = 1.5x10(-4)). Combining results across MA and MO, six
genes produced genome-wide significant gene-based p values. Four of
these genes (TRPM8, UFL1, FHL5 and LRP1) were located in close proximity
to previously reported genome-wide significant SNPs for migraine, while
two genes, TARBP2 and NPFF separated by just 259bp on chromosome
12q13.13, represent a novel risk locus. The genes overlapping in both
migraine types were enriched for functions related to inflammation, the
cardiovascular system and connective tissue.
Conclusions Our results provide novel insight into the likely genes and
biological mechanisms that underlie both MA and MO, and when combined
with previous data, highlight the neuropeptide FF-amide peptide encoding
gene (NPFF) as a novel candidate risk gene for both types of migraine.
