Fig. 4: Example of defining GIMs within a genomic region.

At a 2.55-Mb region on chromosome 8 (region 512), metabolite associations fall into four sets (GIMs) acting through three genes (PYCR3, OPLAH or GPT) with known roles in metabolism. a, Four GIMs defined by overlap in the genetic regulation of metabolite sets. Matrices display the −log₁₀(P) (capped at 50) and direction of effect (higher, red; lower, blue) for associations from stepwise conditional models, fitting the variants in the following order: rs3935209, rs2242090, rs11777194, rs10094377, rs35975875, rs10108836, rs11986259, rs34121654. GIM 1: two variants associating with 6-oxopiperidine-2-carboxylic acid and 5-oxoproline; the causal gene is OPLAH, encoding 5-oxoprolinase, which catalyzes the ATP-dependent hydrolysis of 5-oxoproline to glutamic acid (5-oxoproline and the structurally closely related 6-oxopiperidine-2-carboxylic acid associated in this cluster). GIM 2: four variants associating with S-1-pyrroline-5-carboxylate and the unannotated metabolites X-11315 and X-11334; the causal gene is PYCR3, a pyrroline-5-carboxylate reductase that generates proline from S-1-pyrroline-5-carboxylate (the strongest associated metabolite in this cluster). GIM 3: a single variant associating with aspartate; the causal gene is GPT, encoding alanine aminotransferase, which takes alanine as a substrate and produces glutamate, which is one step removed from the associated metabolite aspartate. GIM 4: a single variant associating with the unannotated metabolite X-23639. b, Regional association indicating genomic positions of the associated variants (black lines) and causal genes (in red). c, Manhattan plot of chromosome eight, with the y axis capped at 120 for clarity. All P values presented were derived from linear mixed models.