Heritability of circle of Willis variations in families with intracranial aneurysms

Abstract

Background: Intracranial aneurysms more often occur in the same arterial territory within families. Several aneurysm locations are associated with specific circle of Willis variations. We investigated whether the same circle of Willis variations are more likely to occur in first-degree relatives than in unrelated individuals.

Methods: We assessed four circle of Willis variations (classical, A1-asymmetry, incomplete posterior communicating artery and fetal circulation) in two independent groups of families with familial aneurysms and ≥2 first-degree relatives with circle of Willis imaging on MRA/CTA. In each (index) family we determined the proportion of first-degree relatives with the same circle of Willis variation as the proband and compared it to the proportion of first-degree relatives of a randomly selected unrelated (comparison) family who had the same circle of Willis variation as the index family's proband. Concordance in index families and comparison families was compared with a conditional logistic events/trials model. The analysis was simulated 1001 times; we report the median concordances, odds ratios (ORs), and 95% confidence intervals (95%CI). The groups were analysed separately and together by meta-analysis.

Results: We found a higher overall concordance in circle of Willis configuration in index families than in comparison families (meta-analysis, 244 families: OR 2.2, 95%CI 1.6-3.0) mostly attributable to a higher concordance in incomplete posterior communicating artery (meta-analysis: OR 2.8, 95%CI 1.8-4.3). No association was found for the other three circle of Willis variations.

Conclusions: In two independent groups of families with familial aneurysms, the incomplete PcomA variation occurred more often within than between families suggesting heritability of this circle of Willis variation. Further studies should investigate genetic variants associated with circle of Willis formation.

Fig 1. The four categories of circle of Willis variations used in this study.

Classical circle of Willis was defined as A1, P1 and PcomA diameters >0.8 mm, with no asymmetric A1s and no fetal posterior circulation. A1 asymmetry was defined as a difference in diameter of the A1 segments of >33%. Incomplete PcomA was defined as a uni- or bilateral PcomA diameter <0.8 mm. Finally, fetal posterior circulation was defined as a PcomA diameter >10% larger than the P1 diameter on the same side. A1 = proximal segment of anterior cerebral artery; P1 = proximal segment of posterior cerebral artery; PcomA = posterior communicating artery.