J Korean Neurosurg Soc.  2023 Jul;66(4):409-417. 10.3340/jkns.2022.0026.

Novel Genome-Wide Interactions Mediated via BOLL and EDNRA Polymorphisms in Intracranial Aneurysm

• Hong EP
• Youn DH
• Kim BJ
• Lee JJ
• Nam S
• Yoo H
• Kim HC
• Rhim JK
• Park JJ
• Jeon JP

• KMID: 2543532
• DOI: http://doi.org/10.3340/jkns.2022.0026

Abstract

Objective
: The association between boule (BOLL) and endothelin receptor type A (EDNRA) loci and intracranial aneurysm (IA) formation has been reported via genome-wide association studies. We sought to identify genome-wide interactions involving BOLL and EDNRA loci for IA in a Korean adult cohort.
Methods
: Genome-wide pairwise interaction analyses of BOLL and EDNRA involving 250 patients with IA and 296 controls were performed using the additive effect model after adjusting for confounding factors.
Results
: Among 512575 single-nucleotide polymorphisms (SNPs), 23 and 11 common SNPs suggested a genome-wide interaction threshold (p<1.25×10^-8) involving rs700651 (BOLL) and rs6841581 (EDNRA). Rather than singe SNP effect of BOLL or EDNRA on IA development, they showed a synergistic effect on IA formation via multifactorial pair-wise interactions. The rs1105980 of PTCH1 gene showed the most significant interaction with rs700651 (natural log-transformed odds ratio [lnOR], 1.53; p=6.41×10^-11). The rs74585958 of RYK gene interacted strongly with rs6841581 (lnOR, -19.91; p=1.64×10^-9). Although, there was no direct interaction between BOLL and EDNRA variants, two EDNRA-interacting gene variants of TNIK (rs11925024 and rs1231) and FTO (rs9302654), and one BOLL-interacting METTL4 gene variant (rs549315) exhibited marginal interaction with BOLL gene.
Conclusion
: BOLL or EDNRA may have a synergistic effect on IA formation via multifactorial pair-wise interactions.

Keyword

Boule; Endothelin receptor type A; Genome-wide association study; Intracranial aneurysm

Figure

• 

  Fig. 1. Manhattan plots of genome-wide interactions with (A) rs700651 (BOLL, 2q33.1) and (B) rs6841581 (EDNRA, 4q31.22) and their effect on intracranial aneurysm based on the additive effect model. Red line indicates genome-wide significance threshold (interaction p=1.25×10-8). SNP : single nucleotide polymorphism, ENDRA : endothelin receptor type A.

• 

  Fig. 2. Regional association plots of (A) rs1105980 (PTCH1, 9q22.32) interacting with rs700651 (BOLL, 2q33.1) and (B) rs74585958 (RYK, 3q22.2) interacting with rs6841581 (EDNRA, 4q31.22) at position ±400 kb and the effect on intracranial aneurysm (IA). X-axis indicates the chromosomal position (mega base, Mb) and Y-axis did -log10 transformed p-value and recombination rate, respectively. Purple triangles of rs1105980 (p=6.41×10-11) and rs74585958 (p=6.41×10-9) represent the most significant interactions with BOLL and EDNRA, respectively. Other up or down triangles denote other variants within the target variant ±400 kb regions. Up and down triangles indicate positive and negative effect sizes on IA formation, respectively. Each color shows pair-wise linkage disequilibrium with either rs1105980 or rs74585958. PTCH1 : patched 1, RYK : receptor-like tyrosine kinase.

Reference

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