Genetic Variants Linked to Lacunar Stroke and White Matter Hyperintensity

Study researchers sought to identify novel associations of loci with lacunar stroke and provide mechanistic insights into this disease.

A dozen loci were found to be associated with lacunar stroke during a pooled genome-wide association study (GWAS), according to study results published in The Lancet Neurology.

Study researchers performed a meta-analysis GWAS using data from magnetic resonance imaging (MRI)-confirmed lacunar stroke (cases: n=2987; control group participants: n=29,540) and TOAST-phenotyped lacunar stroke (cases: n=4351; control group participants: n=225,258). GWAS data of white matter hyperintensity volumes (n=42,310) were used to perform a multitrait analysis. Data were sourced from European, North American, and Australian populations.

Correcting for linkage disequilibrium, the heritability for the MRI-confirmed and non-MRI-confirmed lacunar stroke was 0.065 (standard error [SE], 0.017) and 0.0081 (SE, 0.0025), respectively. The genetic correlation between MRI- and non-MRI-confirmed stroke was 0.61 (SE, 0.21; P =.0033).

A total of 5 loci were associated with lacunar stroke, in which 4 were novel (ULK4, ZCCHC14, ZBTB14-EPB41L3, SPI1-SLC39A13-PSMC3-RAPSN) and 1 was previously associated with intracerebral hemorrhage and lacunar stroke (ICA1L-WDR12-CARF- NBEAL1).

The genetic correlation with lacunar stroke and white matter hyperintensities, accounting for linkage disequilibrium, among the MRI-confirmed and pooled cohorts was 0.46 (SE, 0.10; P =4.6´10-6) and 0.37 (SE, 0.09; P =4.0´10-5), respectively.

The joint analysis identified 3 novel loci (COL4A2, SH3PXD2A, LOX-ZNF474I-LOC100505841, SLC25A44-PMF1-BGLAP) and 4 loci previously associated with white matter hyperintensities (FOXF2- FOXQ1, VTA1-G GPR126, HTRA1ARMS2).

These 12 loci explained 1.4% of the overall heritability of lacunar stroke.

A pathway analysis of these loci identified phosphatidyl-inositol 5 phosphate binding (P =2.2´10-6), extracellular matrix structural constituent (P =6.2´10-6), extracellular matrix constituent conferring elasticity (P =8.9´10-6), middle ear morphogenesis (P =2.3´10-5), and roundabout binding (P =2.7´10-5).

Eleven of the 12 loci were categorized as potential treatment targets.

Lacunar stroke was positively associated with systolic blood pressure (odds ratio [OR], 1.04; P =3.1´10-6), diastolic blood pressure (OR, 1.06; P =3.1´10-5), type 2 diabetes (OR, 1.10; P =.00019), and pulse pressure (OR, 1.04; P =.0025).

These findings may not be generalizable because the genetic samples were sourced from a nondiverse population.

In this pooled GWAS, 12 loci were associated with lacunar stroke. Additional studies are needed to validate these relationships and assess whether any may be therapeutic targets.

Disclosure: Some authors declared affiliations with pharmaceutical, biotech, and/or device companies. Please refer to the original article for a full list of disclosures.


Traylor M, Persyn E, Tomppo L, et al. Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies. Lancet Neurol. 2021;20(5):351-361. doi:10.1016/S1474-4422(21)00031-4