Uncovering Novel Atrial Fibrillation Genetics Through Pleiotropic Overlap with Life’s Essential 8

Figures

• 

  Figure 1. Flowchart of the study. The figure illustrates the overall workflow of the study, including data sources and analytical procedures. In the colocalization panel, the blue star denotes the causal variant, and the associated grey area represents the pleiotropic loci.

• 

  Figure 2. Genetic Correlations between AF and LE8 components. The plot displays the genetic correlation (rg) between AF and each LE8 trait from linkage disequilibrium score (LDSC) regression. Thirty traits are arranged on the outer ring and color-coded by their LE8 component in the legend. Bar length represents the magnitude of rg, with direction outward and inward indicating positive and negative correlations, respectively. The rg values are provided at bar tips. Statistically significant genetic correlations are determined by Bonferroni correction as 0.05/30, resulting in a significance threshold of p < 1.67 × 10−3, denoted by the asterisks (*) in the bar tips.

• 

  Figure 3. Pleiotropy and colocalized loci between AF and LE8 components. (A) The distribution of pleiotropic loci across chromosomes and AF-LE8 trait pairs identified by conditional false discovery rate (condFDR) approach. The horizontal bar plot displays the count of loci across chromosomes 1–22 labeled in the x-axis. The exact numbers of total counts within each chromosome are labeled above each vertical bar. The vertical bar plot represents the count of loci in each AF-LE8 pair with different colors as defined in the legend. (B) The fold enrichment of pleiotropy between AF and LE8 components from condFDR. The heatmap illustrates the fold enrichment, calculated as the ratio of the −log10(PAF) cumulative distribution of SNPs conditional on PLE8 thresholds <0.1, <0.01, and <0.001 for each LE8 component to the cumulative distribution of all SNPs for that LE8 component, with colors ranging from blue (lower enrichment) to red (higher enrichment). (C) The distribution of 137 distinct colocalized regions containing colocalized loci across AF-LE8 trait pairs identified by colocalization analysis. The horizontal bar plot illustrates the count of loci that colocalize with AF and at least one LE8…

• 

  Figure 4. Prioritization of candidate genes from colocalized loci between AF and LE8 components. This figure illustrates the evidence of gene prioritization and the confirmation of novel AF-associated genes. The innermost circle displays the functional genomics evidence of candidate genes and fills the cells in dark blue if they rank highest in V2G score or PoPS score, or have the smallest SmultiXCAN p value within their locus. Prioritized genes meeting simultaneously the three criteria above are highlighted in blue of the font. The second circle presents the previous AF evidence for the confirmation of novel AF-associated genes. The cells in the second circle in light gray means that the genes were supported in the evidence of HuGE, GWAS catalog, or L2G (see Section 2 for details). And novel AF-associated genes lacking all three are filled in light green in the cells of “Novel discovery”. Genes designated as both prioritized and novel AF genes are labeled in red of the font, while other candidate genes are in black. The third circle illustrates the specific LE8 components of colocalized loci harboring the specific candidate gene.

• 

  Figure 5. Pathway enrichment of candidate genes. (A) Enrichment results for all candidate genes. (B) Enrichment results for novel AF candidate genes. (C) Enrichment results for candidate genes from AF-BP colocalized loci. (D) Enrichment results for candidate genes from AF-SBP colocalized loci. (E) Enrichment results for candidate genes from AF-DBP colocalized loci. (F) Enrichment results for candidate genes from AF-PP colocalized loci. In each panel, bars represent the highlighted pathways after multiple testing correction (p < 0.05) via the g:SCS method and clustering by g:profiler.

• 

  Figure 6. Tissue Enrichment of candidate genes. (A) Enrichment results for all candidate genes. (B) Enrichment results for novel AF-associated candidate genes. (C) Enrichment results for candidate genes identified from AF-SBP and/or AF-DBP colocalized loci. (D) Enrichment results for candidate genes identified from AF-PP colocalized loci. In each panel, circles represent upregulation of genes in the tissues on the x-axis, while triangles represent downregulation. Symbol size is proportional to the number of enriched genes in each tissue, with larger symbols indicating a greater number of genes, and color denotes the tissue category in the legend. The dashed line indicates the significance threshold of p < 0.05. Data points above this dashed line represent statistically significant differences in the tissue. The top five genes in upregulated tissues and the top five genes in downregulated tissues are labeled, respectively.

• 

  Figure 7. Associations of shared genetic variants with AF and CVDs risk in the UK Biobank. (A) Associations of AF-LE8-PRS with AF and CVDs. (B) Associations of AF-BP-PRS with AF and CVDs. In each panel, HR and 95% CI were used to describe the risk of each disease, with the forest plot and values presented. The asterisks (*) next to the disease name indicate statistical significance at the Bonferroni-corrected level (p < 3.13 × 10−3).