rs767603 — LOC105378189

Regulatory variant near LOC105378189 non-coding RNA locus on chromosome 14q23; the T allele is associated with increased susceptibility to intracranial berry aneurysm through putative regulatory effects on vascular wall integrity genes

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LOC105378189 and Intracranial Aneurysm Risk — A Regulatory Variant at 14q23

Intracranial aneurysms — balloon-like dilations of cerebral arteries11 balloon-like dilations of cerebral arteries
abnormal sac-like outpouchings that form at vessel bifurcations, most commonly in the circle of Willis — affect roughly 3% of the general population. Most remain silent throughout a person's lifetime, but rupture causes a sudden and devastating subarachnoid hemorrhage with mortality exceeding 40% and permanent disability in half of survivors. Identifying who carries elevated genetic susceptibility is a clinically meaningful step toward targeted surveillance.

The rs767603 variant sits on chromosome 14 at position 60,631,965 (GRCh38), within a genomic region mapped to the ANIB8 susceptibility locus (OMIM 612162). The locus is annotated near LOC105378189, a long non-coding RNA (lncRNA) gene of uncertain function. The variant has no protein-coding consequence — it sits in regulatory sequence, potentially influencing the expression of nearby genes involved in vascular wall maintenance.

The Mechanism

LOC105378189 is a computationally predicted lncRNA at chromosome 14q23. Long non-coding RNAs in vascular tissue have been shown to regulate vascular smooth muscle cell phenotype, endothelial function, and extracellular matrix remodeling22 regulate vascular smooth muscle cell phenotype, endothelial function, and extracellular matrix remodeling
roles reviewed for lncRNAs ANRIL, H19, and lincRNA-p21 in arterial wall biology. The precise mechanism by which rs767603 influences aneurysm susceptibility is not established. The variant is believed to act as a regulatory tag — altering the expression of one or more genes at the 14q23 locus that govern vascular wall integrity, elastin organization, or smooth muscle cell contractility.

Genome-wide association studies of intracranial aneurysm have consistently implicated loci related to endothelial function and extracellular matrix maintenance. The chromosome 14q23 region overlaps with regulatory elements identified in endothelial cells, consistent with the broader observation that intracranial aneurysm heritability is enriched in endothelial cell epigenetic marks33 intracranial aneurysm heritability is enriched in endothelial cell epigenetic marks
Bakker et al. Nature Genetics 2020, heritability enrichment analysis pointing to endothelial cell open chromatin.

The Evidence

The primary evidence for rs767603 comes from a Japanese case-control study by Mineharu et al. 200844 Mineharu et al. 2008
Association analyses confirming a susceptibility locus for intracranial aneurysm at chromosome 14q23, J Hum Genet 53:325–332. Using GeneChip 10K array genotyping in 29 patients with intracranial aneurysm from a geographically clustered Japanese community (Akita) and 35 controls, the study identified rs767603 as the sole variant reaching Bonferroni-corrected significance. The association was confirmed by both allelic analysis (p=0.00017, Bonferroni p=0.021) and haplotype analysis (p=0.00178, Bonferroni p=0.048). Crucially, the finding replicated in an independent nationwide Japanese cohort of 237 aneurysm patients and 253 controls (allelic p=0.0046, haplotype p=0.0060).

Chromosome 14q23 was independently supported by linkage analysis in two large familial aneurysm kindreds showing a parametric LOD score of 3.0 between markers rs2359991 and rs2373098, flanking the rs767603 region55 flanking the rs767603 region
molecular genetic analysis linking chromosome 14q23-31 to familial intracranial aneurysm in Dutch and Finnish pedigrees.

The evidence level is classified as moderate: the association is replicated within a Japanese population and supported by independent linkage data, but large-scale multi-ancestry GWAS have not singled out rs767603 as a lead SNP in European populations, and no functional annotation (eQTL, chromatin accessibility, protein interaction) has been reported for this variant.

Practical Actions

For individuals carrying the T allele — particularly TT homozygotes — the most clinically useful action is enhanced cardiovascular surveillance. Clinical guidelines recommend MRI angiography (MRA) screening for first-degree relatives of known aneurysm patients, especially those with a history of hypertension or smoking. Genetic susceptibility adds independent information that can inform the timing and frequency of surveillance.

Blood pressure control is the most modifiable environmental factor for aneurysm growth and rupture risk. Hypertension accelerates the hemodynamic stress on arterial walls that promotes aneurysm formation and enlargement. For T-allele carriers, maintaining tightly controlled blood pressure — ideally below 130/80 mmHg — is a genotype-informed priority.

Smoking is the strongest modifiable environmental risk factor for intracranial aneurysm formation and rupture, independent of genetics. Genetic susceptibility and smoking act synergistically — the combination of rs767603 T-allele status and active smoking substantially elevates absolute risk beyond either factor alone.

Interactions

The 14q23 susceptibility locus for intracranial aneurysm overlaps in pathway terms with other established aneurysm risk loci, including rs1333040 at 9p21 (a robustly replicated IA locus near CDKN2A/B), and loci on chromosomes 10q24, 13q13, and 2q33 identified in large-scale European GWAS. These variants likely act through convergent mechanisms — endothelial dysfunction, smooth muscle phenotype switching, and extracellular matrix remodeling — rather than direct gene-gene epistasis. No documented compound interaction between rs767603 and other aneurysm SNPs has been studied.

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal

Common genotype with no elevated genetic risk for intracranial aneurysm at this locus

You carry two copies of the C allele at rs767603, the common genotype found in approximately 77% of the global population and around 81% of Europeans. This genotype is associated with typical population-level risk for intracranial aneurysm at the chromosome 14q23 locus. The risk conferred by this variant does not apply to you. Standard cardiovascular risk factor management remains appropriate.

CT Intermediate

One copy of the aneurysm-associated T allele at chromosome 14q23

The chromosome 14q23 susceptibility locus (OMIM 612162, ANIB8) was identified through both linkage analysis in familial aneurysm pedigrees and case-control association in sporadic cases. The T allele at rs767603 is the variant most significantly associated with aneurysm susceptibility within this locus. While the absolute odds ratio has not been reported in the original study, the statistical evidence — Bonferroni-corrected p=0.021, replicated in an independent cohort — is consistent with a modest to moderate effect size typical of common complex-disease GWAS loci (OR approximately 1.3–1.7 per allele copy, which is typical for this effect size class).

The variant likely acts through regulatory mechanisms on nearby vascular genes, consistent with the broader finding that intracranial aneurysm heritability is enriched in endothelial cell chromatin. Carrying one T allele warrants heightened attention to modifiable risk factors, particularly blood pressure and smoking, which act synergistically with genetic susceptibility.

TT High Risk

Two copies of the aneurysm-associated T allele at chromosome 14q23 — elevated genetic susceptibility

The TT genotype at rs767603 represents homozygous carriage of the susceptibility allele at the ANIB8 locus (OMIM 612162), which was linked to familial intracranial aneurysm through parametric analysis (LOD 3.0) and associated at the population level in Japanese case-control data (Mineharu et al. 2008). The chromosome 14q23 region likely contains regulatory variants that influence expression of nearby genes governing vascular wall integrity — possibly through long non-coding RNA LOC105378189 or neighboring coding genes whose expression is modulated by this region.

At a population level, intracranial aneurysms rupture at an annual rate of approximately 1.4% overall, but this rate is substantially higher for aneurysms greater than 7 mm, for aneurysms at specific locations (posterior circulation), and in individuals with uncontrolled hypertension. The genetic susceptibility from this locus likely acts at the aneurysm formation stage rather than rupture propensity, making early detection through MRI angiography clinically valuable.

Given the rarity of TT homozygosity (~1.5% globally), this genotype's absolute risk contribution has not been separately quantified in published studies. The additive effect is expected to be higher than in CT heterozygotes based on the allele-dose response observed in the association data.