eQTS can also identify pathways known to be associated with monogenic diseases. For example, the PGSs for serine, glycine, the glycine derivative N-acetylglycine and creatine56,57 were negatively associated with the expression of PHGDH, PSAT1 and AARS (P<5.3×10−7). The PGSs for these traits are driven by SNPs near CPS1 (2q34), PHGDH (1p12) and PSPH (7p11.2) (Supplementary Table 16–18) that influence expression of PHGDH and PSAT1 in trans. We nominally replicated these trans-eQTLs in scRNA-seq data (absolute average Z>1.96 across tested cell types, part of the 729 trans-eQTLs replicating in the scRNA-seq data; Supplementary Table 4, Figure 6e), suggesting that this eQTS is driven by multiple genetic loci, but independent of cell-type-composition. PHGDH and PSAT1 encode enzymes that regulate the synthesis of serine and, in turn, glycine46, while N-acetylglycine and creatine form downstream of glycine47 (Figure 6f). Mutations in PSAT1 and PHGDH can result in monogenic conditions with defective serine biosynthesis, which are characterized by low concentrations of serine and glycine in blood and severe neuronal manifestations48–50. Unexpectedly, the PGS for higher levels of these amino acids was associated with lower expression of PHGDH, PSAT1 and AARS, implying the presence of a negative feedback loop that controls serine synthesis.
