Multi-trait association studies discover pleiotropic loci between Alzheimer’s disease and cardiometabolic traits

Figures

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  Fig. 1. Bivariate GWAS analysis workflow. Starting with all the SNPs that were in both GWAS summary statistics files, we performed a bivariate GWAS and filtered the bivariate significant loci based on their single-trait P values. For the locus discovery experiment, we removed loci that were in LD (1 kG EUR r2 > 0.2) or within 500 kb of a known AD or the cardiometabolic trait being tested according to the GWAS Catalog (dotted line arrows). The filtration steps were followed by trait-trait colocalization to confirm there was evidence of a shared causal SNP between the signals at each locus. Finally, we performed single-tissue-eQTL analysis to identify candidate causal genes for each locus

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  Fig. 2. ACE locus. a Pleiotropic signal between DBP, SBP, and AD at the ACE locus, and the eQTL signal for ACE in kidney cortex and cerebellum. b Flowchart of our hypothesized mechanism as to how tissue-specific expression of ACE could mediate the blood pressure (BP) and AD pleiotropic signal at this locus. c Diagram of a hypothesized mechanism by which increased kidney expression of ACE could alter renin expression and thus lead to reduce BP through the feedback loops of the renin-angiotensin system

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  Fig. 3. DOCK4 locus. Evidence that supports rs144867634 being the causal variant for the pleiotropic signal at the DOCK4 locus. a In silico evidence that rs144867634 alters DOCK4 splicing. The variant is at the splice junction and is predicted to alter splicing by Human Splice Finder 3 (HSP3) and ASVIPA. b Single-cell mouse kidney data show that Dock4 is expressed by proximal convoluted tubule cells (PT) (128 PT cells of 26,482 assayed have clear evidence of expressing Dock4) and distal convoluted tubule cells (DCT) (27 DCT cells of 8544 assayed have clear evidence of expressing Dock4) (Park et al. 2018). c Mouse brain single-cell data show that Dock4 expression is reduced in microglia when mice have a neuroinflammatory response induced by endotoxin lipopolysaccharide (LPS) injections (Srinvasan et al. 2016)