Pleiotropy data resource as a primer for investigating co-morbidities/multi-morbidities and their role in disease

Abstract

Most current biomedical and protein research focuses only on a small proportion of genes, which results in a lost opportunity to identify new gene-disease associations and explore new opportunities for therapeutic intervention. The International Mouse Phenotyping Consortium (IMPC) focuses on elucidating gene function at scale for poorly characterized and/or under-studied genes. A key component of the IMPC initiative is the implementation of a broad phenotyping pipeline, which is facilitating the discovery of pleiotropy. Characterizing pleiotropy is essential to identify gene-disease associations, and it is of particular importance when elucidating the genetic causes of syndromic disorders. Here we show how the IMPC is effectively uncovering pleiotropy and how the new mouse models and gene function hypotheses generated by the IMPC are increasing our understanding of the mammalian genome, forming the basis of new research and identifying new gene-disease associations.

Fig. 1

Correspondence between physiological systems and IMPC procedures. The thickness of the lines corresponds to the number of IMPC parameters associated with the physiological system (note that the same parameter can be counted more than once when it is associated with more than one physiological system; see Supp Table 1 for details)

Fig. 2

Frequency distribution of the degree of gene pleiotropy showing extensive pleiotropy for 7590 genes studied by the IMPC; 4862 (77%) of the genes affect two or more phenotypes or traits. Degree of pleiotropy here is equivalent to the number of traits

Fig. 3

Pleiotropy across physiological systems and in relation to the effect size of the gene on the trait. Co-occurrence matrix of genes by physiological system for viable homozygotes (a) and heterozygotes (b), assessed with the early adult phenotyping pipeline, and lethal homozygotes (c), assessed with the embryo pipeline. Relationship between the total effect size of gene-trait associations in Euclidean distance versus the degreed of pleiotropy (d)

Fig. 4

Selected traits of mouse models for Mendelian disease identified using the IMPC translational pipeline. Gp9^{tm1.1(KOMP)Vlcg} homozygotes have decreased platelet number (a) and increased platelet volume (b). Fam53b^{tm1b(EUCOMM)Hmgu} homozygotes have decreased red blood cell number (c) and increased red blood cell volume (d). Rnf216^{tm1b(EUCOMM)Wtsi} homozygotes are infertile; histopathology images show epididymal aspermia and testicular degeneration and atrophy and lack of spermatogenesis in the mutants, while the wild types are unaffected (e)