Two quantitative trait loci for prepulse inhibition of startle identified on mouse chromosome 16 using chromosome substitution strains.
Prepulse inhibition (PPI) of acoustic startle is a genetically complex quantitative phenotype of considerable medical interest due to its impairment in psychiatric disorders such as schizophrenia. To identify quantitative trait loci (QTL) involved in mouse PPI, we studied mouse chromosome substitution strains (CSS) that each carry a homologous chromosome pair from the A/J inbred strain on a host C57BL/6J inbred strain background. We determined that the chromosome 16 substitution strain has elevated PPI compared to C57BL/6J (P = 1.6 x 10(-11)), indicating that chromosome 16 carries one or more PPI genes. QTL mapping using 87 F(2) intercross progeny identified two significant chromosome 16 loci with LODs of 3.9 and 4.7 (significance threshold LOD is 2.3). The QTL were each highly significant independently and do not appear to interact. Sequence variation between B6 and A/J was used to identify strong candidate genes in the QTL regions, some of which have known neuronal functions. In conclusion, we used mouse CSS to rapidly and efficiently identify two significant QTL for PPI on mouse chromosome 16. The regions contain a limited number of strong biological candidate genes that are potential risk genes for psychiatric disorders in which patients have PPI impairments.
Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Broad Institute of Harvard, 185 Cambridge Street, Cambridge, MA 02139, USA.
Tracey L
TL
Petryshen
Andrew
A
Kirby
Ronald P
RP
Hammer
Shaun
S
Purcell
Sinead B
SB
O'Leary
Jonathan B
JB
Singer
Annie E
AE
Hill
Joseph H
JH
Nadeau
Mark J
MJ
Daly
Pamela
P
Sklar
D000818:Animals; D002874:Chromosome Mapping; D033481:Chromosomes, Mammalian / Q000235:genetics*; D019295:Computational Biology; D003433:Crosses, Genetic; D014644:Genetic Variation; D008126:Lod Score; D051379:Mice; D008810:Mice, Inbred C57BL; D040641:Quantitative Trait Loci; D013216:Reflex, Startle / Q000235:genetics* / Q000502:physiology