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

Abstract

Objective: Compared to European, Japanese, and Chinese populations, 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.

Methods: 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.

Results: 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 70 cM/Mbp.

Conclusions: 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.

Keywords: Genome-wide association study; High-through imputation; Intracranial aneurysm.