!Research Questions!
1.Do shared genetic variants influence !both! cardiovascular (CVDs: coronary artery disease, heart failure) and neurological diseases (dementia, brain MRI phenotypes)?
2.Which pathways (e.g., lipid metabolism, neuroinflammation) mediate cardio-cerebral pleiotropy?
3.Can a !polygenic risk score (PRS)!! integrating shared signals improve comorbidity risk prediction?
!Objectives!
1.!Identify shared loci! via cross-trait GWAS of CVDs (ICD-10 codes) and brain MRI phenotypes (hippocampal volume [Field ID: 25010-25011], WMH volume [Field ID: 25781].
2.!Test causal mechanisms! with bidirectional Mendelian randomization (MR):
1.Hypertension ! WMH progression ! cognitive decline;
2.Genetic correlations via LD Score Regression.
3.!Annotate pathways! using gene-based (MAGMA) and cell-type enrichment (GTEx/eQTL).
4.!Develop clinical PRS! to predict dementia in high-risk CVD subgroups (Cox regression).
!Scientific Rationale!
Cardiovascular and neurological diseases share epidemiological links (e.g., hypertension ! dementia), but their !shared genetic architecture! is uncharacterized. UK Biobank’s !multi-omics data-including:
!!Whole-genome sequencing! (n=500,000) for cross-trait genetic analysis;
!!Brain MRI! (n=100,000) to quantify cerebrovascular damage (e.g., WMH);
!!Longitudinal health records! (linked to NHS) tracking comorbidities over 30 years;
!!Proteomics! (5,400 plasma proteins) revealing shared pathways (e.g., neuroinflammation).
This enables robust discovery of !pleiotropic variants! and !causal pathways, aligning with UK Biobank’s mission to transform disease prevention.
