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Chunk #10 — Results — Simulations with mismatched reference LD

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Functionally informed fine-mapping and polygenic localization of complex trait heritability.
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We performed 19 experiments, described in detail in Table 3, in the Supplementary Note and in Supplementary Table 7. We quantified how mismatched reference LD impacts fine-mapping performance via the maximum number of assumed causal SNPs per locus (denoted as L) that maintains FDR<0.05 at a PIP=0.95 threshold. Based on these experiments we provide fine-mapping best-practice recommendations: (1) PolyFun + SuSiE should ideally use in-sample LD from the GWAS target sample, with L=10; (2) PolyFun + SuSiE can alternatively use a non-overlapping LD reference panel from the target population spanning ≥10% of the target sample size, with L=10; (3), PolyFun + SuSiE can be used without an LD reference panel by specifying L=1. We caution that using an LD reference panel with even subtle population differences with L>1 may lead to false positive results; (4) PolyFun + SuSiE can be used in the presence of related individuals in the target sample (but these results apply to the typical levels of relatedness observed in UK Biobank); and (5) PolyFun + SuSiE should include as many well-imputed SNPs from the target locus