Extended Data Fig. 12. Application of V2G2P to other traits and other cell models.

a. Venn diagram of V2G2P genes for coronary artery disease (CAD), pulse pressure (PP), and mean arterial pressure (MAP) GWAS traits in teloHAEC (using the same ABC-maps and Perturb-seq data, but disease variants for each trait). For MAP, we prioritized program 8 (ECM organization, AQP1, FDR = 0.0135) and program 15 (KLF2, flow response, FDR = 0.0289). For PP we prioritized program 50 (TGFβ response, FDR = 0.0046) and program 29 (EDN1, wound healing, FDR = 0.0316). Several genes in the PP programs are known to regulate vascular tone and stiffness, including FHL2, SMAD3, and TGFB1^153-155.

b. K562 V2G2P programs for mean corpuscular hemoglobin (MCH), mean corpuscular volume (MCV), platelet count (Plt), red blood cell count (RBC), pulse pressure (PP), mean corpuscular hemoglobin concentration (MCHC), average blood glucose level (HbA1c), hemoglobin count (Hb), mean arterial pressure (MAP), diastolic blood pressure (DBP), systolic blood pressure (SBP). Overall, 32 programs were prioritized for 6 GWAS traits, ranging from 27 programs associated with MCH to 2 programs for MCHC. In general, traits that were not relevant to K562 erythroleukemia cells had no K562 programs significantly associated with them (e.g. MAP, DBP & SBP). Programs associated with each trait contained genes related to that trait. For instance, the most significantly-enriched mean corpuscular hemoglobin program was K562 Program 13, which included many hemoglobin genes as well as the known regulators GFI1B¹⁵⁶ and CBFA2T3¹⁵⁷, while variants associated with platelet count showed most significant enrichment in K562 Program 4, which included genes known to be involved in megakaryocyte differentiation and platelet count such as VASP¹⁵⁸ and TPM4¹⁵⁹, and which showed high enrichment of motifs for the known megakaryocyte regulators SP1/3¹⁶⁰.