Updated Genome-Wide Association Study of Intracranial Aneurysms by Genotype Correction and Imputation in Koreans

Abstract

Compared to European, Japanese, and Chinesepopulations, genetic studies on intracranial aneurysms (IAs) in Koreans are lacking. We conducted an updated genome-wide association study (GWAS) to more accurately identify candidate variations predicting IA by genotype correction and imputation than in the first Korean GWAS. We performed a high-throughput imputation of single-nucleotide polymorphisms (SNPs) and genotype missing values for 250 IA and 296 controls. Out of a total of 7,333,746 sites with an imputation R2 score of ≥0.5, 6,105,212 SNPs were analyzed. A high-throughput GWAS was performed after adjusting for clinical variables and 4 principal component analysis values. A total of 39 SNPs reached a significant genome-wide threshold (P<5× 10-8). After pruning by pairwise linkage disequilibrium (r2<0.8), 11 SNPs were consistently associated with IA. Six tagging SNPs, including rs3120004, rs1851347, rs1522095, rs7779989, rs12935558, rs3826442, and rs2440154, showed strong linkage disequilibrium tower tagging haplotype structures. Among them, rs3120004 tagged a large and strong haplotype structure between LOC440704 and RGS18 genes in 1q31.2 (odds ratio,2.34; 95% confidence interval, 1.74-3.14; P=1.4× 10-8). The rs2440154 (SLC47A1, 17p11.2) SNP increased the risk of IA most significantly (odds ratio,2.90; 95% confidence interval, 2.07-4.08; P=8.2× 10-10). The region encompassing rs3826442 (MYH13, 17p13.1) showed a high recombination rate of approximately 70cM/Mbp. Our updated GWAS using high-throughput imputation approaches can be an informative milestone in understanding IA formation via susceptibility loci in this stage before large-scale genome-wide association meta-analysis.