Originally published as Genetics Published Articles Ahead of Print on July 5, 2005.

Genetics, Vol. 171, 1895-1904, December 2005, Copyright © 2005
doi:10.1534/genetics.105.045658

Two Quantitative Trait Loci for Prepulse Inhibition of Startle Identified on Mouse Chromosome 16 Using Chromosome Substitution Strains

Tracey L. Petryshen^*,, Andrew Kirby, Ronald P. Hammer, Jr., Shaun Purcell, Sinead B. O'Leary^*, Jonathan B. Singer^*,**,1, Annie E. Hill, Joseph H. Nadeau^,, Mark J. Daly^*, and Pamela Sklar^*,,2

^* Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research and Department of Psychiatry, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts 02114, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, Departments of Psychiatry and Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111, ^** Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106 and Center for Computational Genomics and Systems Biology, Case Western Reserve University School of Medicine and Center for Human Genetics, University Hospitals of Cleveland, Cleveland, Ohio 44106

² Corresponding author: Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, 185 Cambridge St., 6th Fl., Boston, MA 02114. 
E-mail: sklar{at}psych.mgh.harvard.edu

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 F₂ 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.

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