Fig. 2. Noncoding rare variants associated with human quantitative traits represent a substantial fraction of putative causal variants.

a, Enrichment of variants within the regulatory region in variants with high PPI. The vertical axis indicates the OR of variants in each PPI bin within the DHS/CFP or not in comparison with the variants with the lowest PPI bin (0–0.1). The error bars indicate the 95% CIs. The circles and stars indicate noncoding and coding variants, respectively. b, Higher predicted pathogenicity of noncoding putative causal variants. The vertical axis indicates the disease impact score predicted from its sequence changes (Methods). The box plot shows the median value as the centerline; the box boundaries show the first and third quartiles and the whiskers extend 1.5 times the interquartile range. c, A rare Japanese-specific noncoding variant rs146018792 in CCND3 strongly associated with MCV and MCH is in the CFP of the myeloid cell line K562. d, β estimates, PPI and AAF of rs146018792. The error bar for the β estimates indicates the 95% CI. The number of individuals included in the analysis is shown after the trait names. e, Distribution of the absolute β estimates of associations with a PPI > 0.9. The dashed line shows the median absolute β estimate of protein-truncating associations (median |β_PTV | = 0.261). The colored dots indicate large effect associations with |β| > 0.261. f, Distribution of the MAFs of associations with a PPI > 0.9. The colored dots indicate the large effect associations defined in e. g, Proportion of population-specific variants within each PPI bin. The y axis indicates the fraction of variants found in only one population in each indicated PPI bin. The color indicates the population in which the variants were found. The AAF was obtained from the gnomAD dataset. The number of individuals included in the association analysis is found in Supplementary Table 1; the abbreviations for the phenotypes are found in Supplementary Table 2.