When is a human developmental disorder a “multifactorial trait

This article [attached] just came to my attention––largely because it won the “Toxicol Sci Best Paper” Award for 2o14.     Isoniazid (INH), the mainstay therapeutic for tuberculosis infection, has been associated with rare but serious hepatotoxicity in the clinic. However, the mechanisms underlying inter-individual variability in response to this drug have remained elusive. A genetically diverse mouse population model, in combination with a systems-biology approach, was used to identify transcriptional changes, INH-responsive metabolites, and gene variants that contribute to the liver response in genetically sensitive individuals.     Following three days of oral INH, sensitive mouse strains developed severe microvesicular steatosis, compared with corresponding vehicle control-treated mice. Genes involved in mitochondrial dysfunction were enriched among liver transcripts altered by INH treatment. Genes associated with INH treatment and susceptibility to INH-caused hepatic steatosis included:  apolipoprotein A-IV, lysosomal-associated membrane protein-1, and choline phosphotransferase-1. These alterations were accompanied by metabolomic  changes––including decreased levels of glutathione and the choline metabolites, betaine and phosphocholine––suggesting that oxidative stress and diminished lipid export may additionally contribute to INH-induced steatosis.     Finally, genome-wide association mapping revealed that polymorphisms in perilipin-2 were linked to increased triglyceride levels following INH treatment––implicating a role for  inter-individual differences in lipid packaging in individuals susceptible to INH-induced steatosis. Taken together, these data suggest that INH-induced steatosis is caused by not one, but multiple, events involving lipid retention in livers of genetically-sensitive individuals. This study also underscores the value of using a mouse diversity panel––to investigate clinically relevant diseases caused by environmental toxicants including drugs.     DwN                 Church RJ, Wu H, Mosedale M, Sumner SJ, Pathmasiri W, Kurtz CL, Pletcher MT, Eaddy JS, Pandher K, Singer M, Batheja A, Watkins PB, Adkins K, and Harrill AH.  A systems biology approach utilizing a mouse diversity panel identifies genetic differences influencing isoniazid-induced microvesicular steatosis.  Toxicol Sci 2o14; 140, 481-492.

When is a human developmental disorder a “multifactorial trait” (i.e. hundreds of genes contributing to the phenotype) and when is it “oligogenic” (i.e. just a handful of genes at most contributing to the phenotype?) 

Congenital heart disease (CHD) is a leading cause of childhood morbidity in the developed world. There are few prevalent clinical risk factors and––although it is possible that up to 90% of risk for CHD may be “predominantly genetic” (i.e. specific genes perturbed by in utero conditions including exposure to drugs/environmental toxicants, or due to entropy (i.e. chaos during development)––the number of genes clinically associated with disease appears to be surprisingly small.

Rather than grouping disparate CHD phenotypes, as most other studies have done, authors of the attached paper have studied a single specific malformation––the atrioventricular septal defect (AVSD). Instead of recurrent variation in a handful of genes, they observed de novo and inherited variation in 19 genes associated with human disease, syndromic loci, and genes implicated in cardiac development by mouse knockout studies. The number of loci identified, … support the longstanding hypothesis of a complex oligogenic inheritance for a single malformation.

PLoS Genet 2o16; 12: e1005963

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