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

BACKGROUND: White matter hyperintensities (WMH), a hallmark imaging feature of small vessel disease, are strongly associated with neurodegenerative and cardiovascular conditions. METHODS: 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. RESULTS: 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 blobulin), 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%). CONCLUSIONS: 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.