Extended Data Figure 5 |. A framework for constructing polygenic scores that include rare variants.

The framework consists of two steps: a, choosing genes to include in the polygenic score, based on their association p-value and annotation, and b, defining weights for rare variants, based on the masks that include them and the aggregate effect sizes observed for the masks. a, We explored three methods for choosing genes, based on their strength of HbA1C association (blue boxes) and evidence of acting through erythrocytic pathways (red). “GLYCEMIC set” indicates genes located within a glycemic gene set enriched (at p≤0.05) for HbA1C rare variant associations, while “RBC set” indicates genes located within an erythrocytic gene set enriched (at p≤0.05) for HbA1C rare variant associations (the specific gene sets are shown in Figure 2). “HbA1C LOCUS” and “RBC LOCUS” indicates genes located within 125kb of a common variant HbA1C or RBC association, respectively. The two negative controls included only genes that failed the erythrocytic pathway filters (“Excluded”) and applied either the HbA1C association strength filters for the loose gene set (control 1) or the association strength filters for the relaxed gene set (control 2). b, We explored three methods for weighting variants (Methods): the aggregate effect size of the strictest mask that contained the variant (nested), the aggregate effect size of variants unique to the strictest mask that contained the variant (unique), or the aggregate effect size of a weighted burden test for the gene multiplied by the specific weight of the variant (weighted).