Neuropeptide S as a potential risk locus for migraine in the Portuguese population

ABSTRACT Objective The most common forms of migraine are complex disorders characterized by significant clinical diversity. The genetic basis of migraine has been the subject of many studies but remains largely unknown. We present the first pilot genome-wide association study (GWAS) integrating a polygenic risk score (PRS) in the Portuguese population, designed to identify migraine susceptibility risk loci through a case-control study, in order to unravel population-specific variants. Methods Genotyping was conducted on 380 individuals using the Applied Biosystems Axiom™ PMDA array. A vast dataset of 8,031,293 single-nucleotide polymorphisms (SNPs) was available, providing a comprehensive scope for GWAS analysis. PRS models were created and tested on subsets of the genotyping data, and the optimal statistical significance threshold was assessed. Results We detected nine risk loci corresponding to nine lead SNPs ( ZNF385D , YTHDF3 , NPS , RAP1A/INKA2 , CTA-481E9.4/CTA-481E9.3 , AC092079.1 , PPHLN1 , SMYD3 and AL355597.1 (near ADARB2 )). Additionally, eleven variants, without any previous association to pathogenicity in migraine, were highlighted by the chosen PRS model. Among our results, a new locus within the NPS gene, representing a novel association with migraine, is a potential new target directly related to recent and effective migraine treatments. Conclusions These findings reinforce the importance of neurotransmitter release and synaptic transmission, as well as the involvement of vascular components, in migraine pathophysiology. This work underscores that GWAS can provide novel, clinically valuable insights into populational and disease-associated genetic landscapes, enabling therapeutic developments and bolstering personalized medicine strategies.