title: Genetic analysis of albuminuria in collaborative cross and multiple mouse intercross populations.
abstract: Albuminuria is an important marker of nephropathy that increases the risk of progressive renal and chronic cardiovascular diseases. The genetic basis of kidney disease is well-established in humans and rodent models, but the causal genes remain to be identified. We applied several genetic strategies to map and refine genetic loci affecting albuminuria in mice and translated the findings to human kidney disease. First, we measured albuminuria in mice from 33 inbred strains, used the data for haplotype association mapping (HAM), and detected 10 genomic regions associated with albuminuria. Second, we performed eight F(2) intercrosses between genetically diverse strains to identify six loci underlying albuminuria, each of which was concordant to kidney disease loci in humans. Third, we used the Oak Ridge National Laboratory incipient Collaborative Cross subpopulation to detect an additional novel quantitative trait loci (QTL) underlying albuminuria. We also performed a ninth intercross, between genetically similar strains, that substantially narrowed an albuminuria QTL on Chromosome 17 to a region containing four known genes. Finally, we measured renal gene expression in inbred mice to detect pathways highly correlated with albuminuria. Expression analysis also identified Glcci1, a gene known to affect podocyte structure and function in zebrafish, as a strong candidate gene for the albuminuria QTL on Chromosome 6. Overall, these findings greatly enhance our understanding of the genetic basis of albuminuria in mice and may guide future studies into the genetic basis of kidney disease in humans.
authors.affiliation: Novartis Institute for BioMedical Research, 1 Health Plaza, Bldg. 437, Rm. 4331, East Hanover, NJ 07936, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Thaisz
authors.forename: Shirng-Wern
authors.initials: SW
authors.lastname: Tsaih
authors.forename: Minjie
authors.initials: M
authors.lastname: Feng
authors.forename: Vivek M
authors.initials: VM
authors.lastname: Philip
authors.forename: Yunyu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Liane
authors.initials: L
authors.lastname: Yanas
authors.forename: Susan
authors.initials: S
authors.lastname: Sheehan
authors.forename: Lingfei
authors.initials: L
authors.lastname: Xu
authors.forename: Darla R
authors.initials: DR
authors.lastname: Miller
authors.forename: Beverly
authors.initials: B
authors.lastname: Paigen
authors.forename: Elissa J
authors.initials: EJ
authors.lastname: Chesler
authors.forename: Gary A
authors.initials: GA
authors.lastname: Churchill
authors.forename: Keith
authors.initials: K
authors.lastname: Dipetrillo
mesh_terms: D000419:Albuminuria / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D003433:Crosses, Genetic; D015870:Gene Expression; D056726:Genetic Association Studies; D006239:Haplotypes; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D040641:Quantitative Trait Loci; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism
chemical_list: D011965:Receptors, Glucocorticoid; C568746:glucocorticoid-induced transcript 1 protein, mouse