COMMON DISEASE PHENOTYPES – EQTLS AND COPY
NUMBER VARIATION STUDIES IN RODENTS AND HUMANS
Tim Aitman
MRC Clinical Sciences Centre and Imperial College London, UK
Since the advent of human whole genome association studies, some have questioned
whether rodent genetic studies are still of value. If one can track down the genes in
humans, what are the advantages of studying disease genetics in animal models? Using
integrated genomic approaches, our studies have mapped and identified disease genes for
defective insulin action and fatty acid metabolism in spontaneously hypertensive rats
(SHR), and for autoimmune glomerulonephritis in Wistar Kyoto rats and have found
corresponding human disease phenotypes. The SHR insulin resistance gene, Cd36, causes
defects in insulin action and fatty acid metabolism in rats and humans and may be a cause
of human type 2 diabetes. Cd36 deficiency, common in some human populations, may be
a cause of resistance to therapy with the thiazolidinedione group of anti-diabetes drugs.
More recent expression QTL (eQTL) studies in SHR have yielded candidate genes and
pathways for cardiac hypertrophy and inflammation in SHR and humans. Our studies of
glomerulonephritis showed that gene copy number variation (CNV) at the Fcgr3 locus is
a cause of autoimmune kidney disease in both rats and humans. FCGR3B deficiency in
humans is associated with a range of human systemic autoimmune diseases, including
systemic lupus erythematosus and ANCA-positive vasculitis. These studies show that
FCGR3B copy number variation plays an important role in the development of systemic
autoimmunity, and more generally implicate gene copy number variation as a cause of
common human disease. Our studies in rats and humans suggest that, in the post-genome
era, rodent genetic studies will continue to provide important insights into the genes,
pathways and evolutionary mechanisms underlying common human disease.