Alternate approach to stroke phenotyping identifies a genetic risk locus for small vessel stroke

Area of Science:

• Genetics
• Neurology
• Stroke Research

Background:

• Ischemic stroke (IS) is a major cause of mortality, with established subtypes like cardioembolic stroke (CES), large artery stroke (LAS), and small vessel stroke (SVS).
• Existing subtyping systems, such as TOAST and CCS, show only moderate agreement, complicating genetic studies.
• Genome-wide association studies (GWAS) require precise phenotypes for accurate genetic discovery in IS.

Purpose of the Study:

• To compare two novel approaches for combining existing IS subtyping systems (TOAST and CCS) into phenotypes suitable for GWAS.
• To evaluate the performance of these combined phenotypes in identifying genetic associations for IS subtypes.

Main Methods:

• Utilized the NINDS Stroke Genetics Network (SiGN) dataset (11,477 IS cases, 28,026 controls).
• Defined two combined phenotypes: 'intersect' (requiring agreement between CCS and TOAST) and 'union' (requiring assignment by either system).
• Performed GWAS using original subtypes, intersect, and union phenotypes.

Main Results:

• The 'intersect' phenotype yielded a smaller sample size but reduced potential misclassification.
• Heritability was consistently higher for the 'intersect' phenotype across all subtypes compared to other methods.
• Stronger effects were observed for known IS variants using the 'intersect' phenotype.
• A novel variant (rs10029218:G>A) was identified as associated with small vessel stroke (SVS) using the 'intersect' phenotype.

Conclusions:

• Combining IS subtyping systems, particularly the 'intersect' approach, enhances the power to detect genetic associations in IS.
• This refined phenotyping strategy increases the likelihood of discovering novel genetic variants contributing to ischemic stroke.
• The findings support the use of combined subtyping for future genetic research in stroke.