Quantitative trait loci mapping and gene network analysis implicate protocadherin‐15 as a determinant of brain serotonin transporter expression

• DOI: 10.1111/gbb.12119
• Publication Date: 2014-01-09T13:48:43Z
• Authors: R. Ye; A. M. D. Carneiro; Q. Han; D. Airey; E. Sanders‐Bush; B. Zhang; L. Lu; R. Williams; R. D. Blakely
• Keywords: Protocadherin; Candidate gene

Presynaptic serotonin (5-hydroxytryptamine, 5-HT) transporters (SERT) regulate 5-HT signaling via antidepressant-sensitive clearance of released neurotransmitter. Polymorphisms in the human SERT gene (SLC6A4) have been linked to risk for multiple neuropsychiatric disorders, including depression, obsessive-compulsive disorder and autism. Using BXD recombinant inbred mice, a genetic reference population that can support discovery novel determinants complex traits, merging collective trait assessments with bioinformatics approaches, we examine phenotypic molecular networks associated protein expression. Correlational analyses revealed network genes significantly mRNA levels. We quantified expression levels identified region- gender-specific quantitative loci (QTLs), one which male midbrain expression, centered on protocadherin-15 (Pcdh15), overlapped QTL Pcdh15 was also only QTL-associated whose both suggesting an unrecognized role cell adhesion development or function neurons. To test this hypothesis, assessed traits functional null line (Pcdh15(av-) (3J) ), studies strong, negative influence these phenotypes. Together, our findings illustrate power multidimensional profiling lines analysis synaptic signaling, that, as case Pcdh15, reveal relationships may underlie mental illness.