Genome-wide association study identifies novel susceptibility loci for migraine in Han Chinese resided in Taiwan

Abstract

Background Susceptibility genes for migraine, despite it being a highly prevalent and disabling neurological disorder, have not been analyzed in Asians by genome-wide association study (GWAS). Methods We conducted a two-stage case-control GWAS to identify susceptibility genes for migraine without aura in Han Chinese residing in Taiwan. In the discovery stage, we genotyped 1005 clinic-based Taiwanese migraine patients and 1053 population-based sex-matched controls using Axiom Genome-Wide CHB Array. In the replication stage, we genotyped 27 single-nucleotide polymorphisms with p < 10 in 1120 clinic-based migraine patients and 604 sex-matched normal controls by using Sequenom. Variants at LRP1, TRPM8, and PRDM, which have been replicated in Caucasians, were also genotyped. Results We identified a novel susceptibility locus (rs655484 in DLG2) that reached GWAS significance level for migraine risk in Han Chinese ( p = 1.45 × 10, odds ratio [OR] = 2.42), and also another locus (rs3781545in GFRA1) with suggestive significance ( p = 1.27 × 10, OR = 1.38). In addition, we observed positive association signals with a similar trend to the associations identified in Caucasian GWASs for rs10166942 in TRPM8 (OR = 1.33, 95% confidence interval [CI] = 1.14-1.54, P = 9.99 × 10; risk allele: T) and rs1172113 in LRP1 (OR = 1.23, 95% CI = 1.04-1.45, P = 2.9 × 10; risk allele: T). Conclusion The present study is the first migraine GWAS conducted in Han-Chinese and Asians. The newly identified susceptibility genes have potential implications in migraine pathogenesis. DLG2 is involved in glutamatergic neurotransmission, and GFRA1 encodes GDNF receptors that are abundant in CGRP-containing trigeminal neurons. Furthermore, positive association signals for TRPM8 and LRP1 suggest the possibility for common genetic contributions across ethnicities.

Association between PRDM16, MEF2D, TRPM8, LRP1 gene polymorphisms and migraine susceptibility in the She ethnic population in China

“…Migraine with aura (n = 52) P [31]; however, other study of the Han Chinese population failed to find a significant association between alleles, genotypes of the two SNPs (rs10166942 and rs111721132) and migraines [27].…”

“…We found that rs4379368 (in c7orf10) and rs13208321 (in FHL5) were potential genetic markers for migraines in the She population [20]. In the present study, four SNPs were chosen based on their association with migraines identified in previous studies [22][23][24][25][26][27][28][29][30][31] as well as in a meta-analysis of 29 GWAS [20]. The rs2651899 SNP is localized to PRDM16, which is associated with myelodysplastic syndromes, acute myeloid leukemia and metabolic syndrome [24].…”

“…We subsequently found that rs4379368 and rs10504861 (near MMP16) were markers for susceptibility to migraines with aura, and that rs12134493 (near TSPAN2 ) is a marker for risk of migraines without aura in the Han population in Fujian Province, China [21], suggesting that the migraine susceptible loci are different between the Han and She populations. Because evidence suggests that SNPs in those four migraine susceptible loci might not be risk factors for migraines in the She population, we wanted to explore whether the four SNPs reported to be associated with migraines in Han Chinese (i.e., rs2651899 in PRDM16 [22][23][24][25][26][27], rs2274316 in MEF2D [23,[28][29][30], rs7577262 in TRPM8 [18,28] and rs11172113 in LRP1 [27][28][29][30][31]) were similarly associated with migraine in the She population, which is already shown to have a high prevalence of migraine. The purpose of the present study was to investigate the four SNPs identified within migraine susceptible loci in Han Chinese for their association with migraine susceptibility in the She population.…”

TRPM8 genetic variant is associated with chronic migraine and allodynia

“…Several single nucleotide polymorphisms (SNPs) associated with migraine susceptibility were recently identified by genome-wide association studies (GWAS) [11]. In our study among the Han Chinese population in Taiwan, several novel variants were identified to be associated with migraine in a two-stage GWAS [12], including rs655484 in disks large homolog 2 (DLG2) and rs3781545 in GDNF family receptor alpha-1 (GFRA1), rs10803531 in G protein-coupled receptor 39 (GPR39), and rs7565931 in uridine phosphorylase 2 (UPP2). Furthermore, the association between migraine and rs10166942 in transient receptor potential melastatin 8 (TRPM8) as well as rs1172113 in low density lipoprotein receptor-related protein 1 (LRP1), the two most replicated SNPs in Caucasians, were also reproduced in our study cohort.…”

“…Other investigated endophenotypes included aura and migrainous features. The candidate genes were chosen based on the findings of our previous migraine GWAS, the only published study in Asians [12]. The current study adopted a two-stage design, including discovery and replication cohorts of patients with migraine.…”