(a) Structure of the Fh1 gene showing lyase 1 and fumarase c domains, the former of which contains a missense mutation. (b) Combined eQTL mapping of Fh1 mRNA across 15 tissues. The eigenvalues associated with the first principal component map to Fh1 with a likelihood ratio statistic of >20. The solid red line represents genome-wide significance. The red triangle indicates the genomic position of Fh1. (c) Manhattan plot of an expression phenome scan of molecular traits linked to the Fh1 locus in midbrain. The y-axis shows the −log10 q values of association, and the x-axis shows positions of 55,681 assays generated using Agilent SurePrint array. (d) QTL heat map of mRNAs involved in the unfolded protein response. The x-axis lists mouse chromosome numbers. Each horizontal line represents the QTL map for a single transcript in midbrain. Transcripts are grouped into three major categories—genes involved in the canonical UPRmt, cytoplasmic heat shock response (HSR) and unfolded protein response in the endoplasmic reticulum (UPRer). A subset of UPRmt genes at the top are strongly modulated by the Fh1 locus on Chr 1 (the intense colours to the upper left). In contrast, none of the UPRer subsets are modulated by Fh1. (e) Principal component analysis plot for six UPRmt transcripts (left). The first two components explain ∼67% of the variance in expression in hypothalamus. There is significant correlation between UPRmt expression and Fh1 (P=5 × 10−8; Pearson product-moment correlation coefficient) (right). (f) Validation that fumarate hydratase selectively controls the UPRmt in C. elegans. The left-most pair of images demonstrates effects of the fum-1 RNAi knockdown on hsp-6::gfp signal—a marker of UPRmt induction. The middle and right panels demonstrate that the fum-1 knockdown does not induce either the UPRer (hsp-4::gfp), or the cytoplasmic heat shock response (hsp-16.2::gfp). (g) Manhattan plot of a phenome scan. The y-axis shows the −log10 q values of ∼4,230 phenotypes, and the x-axis shows the 15 phenotypic categories.