C causal fraction on LD Scores reproduces SNP-based heritability-based estimates. Figure eight continued on subsequent pageSinnott-Armstrong, Naqvi, et al. eLife 2021;ten:e58615. DOI: https://doi.org/10.7554/eLife.16 ofResearch article Figure eight continuedGenetics and GenomicsFigure supplement 5. Estimates of causal web pages are conservative with respect to SNP concentration within the genome. Figure supplement 6. Effect of distribution of causal web site betas on estimates of causal variant count. Figure supplement 7. Association amongst minor allele TrkC Inhibitor custom synthesis frequency and estimated proportion of causal variants. Figure supplement eight. Effect of minor allele frequency cutoff on the estimates obtained. Figure supplement 9. Parametric causal fraction is robust to population structure. Figure supplement 10. Estimating the impact of inflation mis-specification around the estimated causal variant count. Figure supplement 11. Effect of mis-specification of SNP-based heritability or sample size in the simulation matching strategy. Figure supplement 12. Effect of GWAS covariates on estimates. Figure supplement 13. Effect of bin count on estimates of causal variants. Figure supplement 14. Distributions of (left) total SNP-based heritability of gene expression, or (appropriate) fraction of expression SNP-based heritability driven by cis-effects (Ouwens et al., 2020) for genes in the indicated core pathways, or for all other MsigDB genes not within a core pathway.For every single trait, the fraction of non-null tests increases from low levels inside the lowest LD Score bins to above 50 inside the highest LD Score bins. All round we estimate that about 450 of SNPs are linked to a non-zero impact variant for urate, IGF-1 and male testosterone, and 30 for female testosterone (Figure 8B). These estimates have been robust to halving the sample size from the input GWAS, and have been substantially larger than for randomized traits (simulated by permuting the IGF-1 and urate phenotypes) (Figure 8–figure supplement 1). We next carried out simulations to know how these observations relate for the numbers of causal variants (Figure 8C). To make this identifiable, we assume that a fraction 1 p1 of all SNPs have an impact size which is exactly zero, though the remainer (p1 ) draw their impact size from a single normal distribution with imply zero. Our SIK3 Inhibitor drug purpose is to estimate p1 . We simulated phenotypes for the UK Biobank people assuming a array of values of p1 (Components and procedures). Causal variants have been chosen uniformly at random from among the four.4M SNPs with MAF 1 ; effect sizes had been simulated from a normal distribution with imply zero, and variances set to make the observed SNP heritabilities (0.3 for urate, IGF-1, and male testosterone, and 0.two for female testosterone). We also permitted for any degree of over-inflation of the test statistics (i.e. allowing for an inflation aspect as in Genomic Control [Devlin and Roeder, 1999]) his was crucial for fitting the optimistic ashR estimates at low LD Scores. We then matched the simulations towards the observed ashR final results to approximate the numbers of causal variants. All round, our estimates variety from 0.1 of all 4.4M variants with MAF 1 in female and male testosterone ( 4000 causal web sites) to 0.three of variants for urate ( 12,000 causal sites). These final results imply that all four traits are very polygenic, though considerably significantly less so than height (for which we estimate two , or 80,000 causal internet sites in UK Biobank; Figure 8–figure supplements 2 and 4). Furthermore, there are three reaso.
