The first example is a missense variant (A296T; rs32536342) in the fumarate hydratase mitochondrial enzyme located on chromosome 1 at 175.60 Mb (Fh1; Fig. 3a). Fh1 catalyses the hydration of fumarate to malate in the tricarboxylic acid (TCA) cycle and has been linked to renal cell cancer18. The missense variant in the lyase 1 domain is associated with a ∼1.4-fold effect on expression of Fh1 across many tissues, including midbrain, hypothalamus, striatum and spleen (Fig. 3b). This variant is strongly associated with Fh1 mRNA expression, as well as the expression of other mitochondrial genes, including Mrpl50, Sirt3 and Dlst (Fig. 3c). Expression PheWAS shows that the Fh1 locus modulates mRNA expression levels of 113 mitochondrial proteins, in addition to eight genes linked to renal necrosis, and seven genes involved in mTOR signalling, consistent with the known role of FH1 in renal cancer (Supplementary Data 16). Interestingly, four mitochondrial genes, Hspd1, Hspa9, Clpx and Lonp1 that all encode components of the mitochondrial unfolded protein response (UPRmt) (ref. 19)—a still poorly characterized mitochondrial stress response pathway in mammals—show strong association with Fh1
