Statistical analysis
We conducted colocalization analysis of genetic associations forACE gene expression in brain cortex tissue and AD liability
within +/-20kb of the ACE gene using coloc,8 a
Bayesian method for colocalization. We also assessed for three-way
colocalization with SBP using the HyPrColoc method9(Hypothesis Prioritisation for multi-trait Colocalization), to
investigate whereby AD risk, cortical ACE expression and blood
pressure share a common causal variant. The single-nucleotide
polymorphism (SNP) with the greatest posterior probability from
colocalization analysis of cortical ACE expression and AD risk
represents the genetic proxy most likely to simulate the effect of
cerebral cortex ACE modulation on AD risk. We then employ a MR paradigm
to explore whether this variant is associated with other
neurodegenerative traits. Finally, the effect of SBP on AD risk was
explored in an MR analysis using an instrument comprising of genetic
variants from across the genome. Full details are given in Supplementary
Methods.