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doi:10.1534/genetics.105.045658
A more recent version of this article appeared on December 1, 2005.
REGULAR RESEARCH PAPERS |
Two QTLs for prepulse inhibition of startle identified on mouse chromosome 16 using chromosome substitution strains
Tracey L Petryshen 1, Andrew Kirby 2, Ronald P Hammer Jr 3, Shaun Purcell 4, Jonathan B Singer 5, Annie E Hill 6, Joseph H Nadeau 6, Mark J Daly 2 and Pamela Sklar 1*
1 Broad Institute of MIT and Harvard, Center for Human Genetics Research, and Harvard Medical School
2 Broad Institute of MIT and Harvard
3 Tufts University School of Medicine
4 Center for Human Genetics Research, and Harvard Medical School
5 Novartis Institutes for BioMedical Research
6 Case Western Reserve University School of Medicine
* To whom correspondence should be addressed. E-mail: sklar{at}psych.mgh.harvard.edu.
Submitted on May 13, 2005
Revised on June 7, 2005
Accepted on 28 June 2005
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 (QTLs) 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 = 1.6x10-11), 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 = 3.9 and 4.7 (significance threshold LOD = 2.3). The QTLs 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 QTLs 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.
Key Words: consomic, endophenotype, linkage, quantitative trait locus, single nucleotide polymorphism
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