title: Genome-wide-associated variants in migraine susceptibility: a replication study from North India.
abstract: OBJECTIVE
  Genome-wide association studies (GWAS) have identified various migraine susceptibility variants. We aim to replicate 5 GWAS-associated polymorphisms (rs1835740, LRP1 rs11172113, TRPM8 rs10166942, PRDM16 rs2651899, and TGFBR2 rs7640453) in the North Indian population. Furthermore, we checked the single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium (LD) with the selected variants. We also undertook to predict the functional effect (in silico) of the variants.
  
  
  METHODS
  The study included 340 migraineurs and 200 controls. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), amplification-refractory mutation system (ARMS)-PCR, and Taqman. Logistic regression was used for association analysis. LD plot was prepared using genotyping data retrieved from ENCODE and HapMart. Functional effect was predicted by functional SNP (F-SNP)and FastSNP.
  
  
  RESULTS
  We did not observe any significant effect of the variant genotype or allele of the first migraine GWAS associated marker, rs1835740. However, significance was observed in case of heterozygous genotype for total migraineurs and migraine without aura (MO). We suggest potential protective effect of LRP1 rs11172113 polymorphism in migraine susceptibility. PRDM16 rs2651899 variant genotype and allele showed a protective effect on migraine and MO susceptibility. On the other hand, TRPM8 rs10166942 and TGFBR2 rs7640543 variants did not have significant influence on migraine susceptibility in the North Indian population. Most of the selected SNPs (except LRP1 rs11172113) and some of the SNPs in strong LD were predicted to affect transcriptional regulation. Functional effect of LRP1 rs11172113 variant could not be predicted, but another SNP in the same LD block was found to affect transcription factor binding sites.
  
  
  CONCLUSIONS
  We report significant influence of rs1835740, LRP1 rs11172113 and PRDM16 rs2651899 polymorphisms on migraine susceptibility in the North Indian population. Finally, we present the first replication study of GWAS-associated polymorphisms in a population other than European.
authors.affiliation: Department of Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences (SGPGIMS), Lucknow, India.
authors.forename: Jayashri
authors.initials: J
authors.lastname: Ghosh
authors.forename: Sunil
authors.initials: S
authors.lastname: Pradhan
authors.forename: Balraj
authors.initials: B
authors.lastname: Mittal
mesh_terms: D000328:Adult; D004261:DNA Replication / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D007194:India / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
keywords: genome-wide association studies; linkage disequilibrium; migraine; replication; susceptibility