2023-07-12

Finemapping in Alzheimer’s Disease

Presentation by Teresa Lin

• Finemapping using SuSiE
• Adding functional annotations can improve fine-mapping (?)

Polygenic Risk Score (PRS)

• still not used in clinical setting.
• low transferability.
• differences in LD structure, allele frequency and causal effect size.

Pipeline

Summary stat \(\rightarrow\) functional finemapping (PolyFun), [use baseline annotations (187), Roadmap (90), DeepSea (75), Glass lab (10), Enformer (66), Glass lab Enformer (6)] \(\rightarrow\) statistical finemapping (SuSiE) \(\rightarrow\) PRS, PLINK (clumping + p-threshold) / PolyFun-pred \(\leftarrow\) adsp genotype/phenotype.

Baseline annotations \(\rightarrow\) MAF bins, LD-related annotations for common and rare SNPs.

Roadmap \(\rightarrow\) DNase, H3K27ax, H3K4me3, H3k4me1

Glass lab \(\rightarrow\) Microglia ATAC-Seq, Neuron H3K27ax, microglia enhancer ATAC-Seq, microglia H3K4me3, oligodendrocyte H3K27ac

Glass lab Enformer \(\rightarrow\) Neuron enhancer, microglia enhancer, microglia enhancer ATAC-Seq, etc.

PRS-CS: continuous shrinkage prior

\[ \beta_j \sim \mathcal{N}\left( 0, \Psi_j \right), \quad \Psi_j ~ G \]