Genetic Dissection of Plasma Proteins and Blood Pressure in Small Vessel Disease

White matter hyperintensities (WMH), a hallmark imaging feature of small vessel disease, are strongly associated with neurodegenerative and cardiovascular conditions.

We performed bidirectional and mediation Mendelian randomization analyses using summary statistics from GWAS (genome-wide association studies) of 9 large cohorts of plasma proteins (n=997-35 559), blood pressure (n=1 028 980), and WMH (n=21 381). The inverse-variance-weighted method or Wald ratio was applied as the primary Mendelian randomization approach, with false discovery rate correction and independent replication. We further integrated Mendelian randomization with PheWAS (phenome-wide association studies) to prioritize WMH risk factors and assess mediation via systolic blood pressure and diastolic blood pressure.

Eighteen plasma proteins were genetically associated with WMH, 13 of which were replicated. Thirteen antihypertensive target genes were also linked to WMH burden, including ADRB3, AOC1 (amine oxidase copper containing 1), SHBG (sex hormone binding globulin), and KCNH2 (potassium voltage-gated channel subfamily H member 2), which influenced both systolic blood pressure and diastolic blood pressure. Mendelian randomization-PheWAS highlighted systolic blood pressure and diastolic blood pressure as the top-ranked WMH risk factors among 21 976 traits. Antihypertensive drug targets, including angiotensin II receptor blockers, β-blockers, calcium channel blockers, and diuretics, were significantly associated with WMH burden. Mediation analysis showed that systolic blood pressure partially mediated TFPI's effect (3.04%), and diastolic blood pressure mediated the effects of ACP1 (acid phosphatase 1) (2.74%) and LAMC1 (laminin subunit gamma 1; 4.94%).

The findings outline protein- and blood pressure-centered mechanisms in small vessel disease, highlighting proteins and antihypertensive targets as biomarkers and therapeutic entry points for precision intervention.