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

R. Ye, A. M.D. Carneiro, Q. Han, D. Airey, E. Sanders-Bush, B. Zhang, Lu Lu, Robert Williams, R. D. Blakely

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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 the discovery of novel determinants of complex traits, merging collective trait assessments with bioinformatics approaches, we examine phenotypic and molecular networks associated with SERT gene and protein expression. Correlational analyses revealed a network of genes that significantly associated with SERT mRNA levels. We quantified SERT protein expression levels and identified region- and gender-specific quantitative trait loci (QTLs), one of which associated with male midbrain SERT protein expression, centered on the protocadherin-15 gene (Pcdh15), overlapped with a QTL for midbrain 5-HT levels. Pcdh15 was also the only QTL-associated gene whose midbrain mRNA expression significantly associated with both SERT protein and 5-HT traits, suggesting an unrecognized role of the cell adhesion protein in the development or function of 5-HT neurons. To test this hypothesis, we assessed SERT protein and 5-HT traits in the Pcdh15 functional null line (Pcdh15av-3J), studies that revealed a strong, negative influence of Pcdh15 on these phenotypes. Together, our findings illustrate the power of multidimensional profiling of recombinant inbred lines in the analysis of molecular networks that support synaptic signaling, and that, as in the case of Pcdh15, can reveal novel relationships that may underlie risk for mental illness. Midbrain expression networks showing genes that correlate positively (green circles) or negatively with Slc6a4 or Tph2.

Original languageEnglish (US)
Pages (from-to)261-275
Number of pages15
JournalGenes, Brain and Behavior
Volume13
Issue number3
DOIs
StatePublished - Mar 1 2014

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Serotonin Plasma Membrane Transport Proteins
Gene Regulatory Networks
Quantitative Trait Loci
Serotonin
Mesencephalon
Brain
Genes
Messenger RNA
Obsessive-Compulsive Disorder
Population Genetics
Autistic Disorder
Computational Biology
Cell Adhesion
Antidepressive Agents
Neurotransmitter Agents
Proteins
Depression
Phenotype
Gene Expression
Neurons

All Science Journal Classification (ASJC) codes

  • Genetics
  • Neurology
  • Behavioral Neuroscience

Cite this

Quantitative trait loci mapping and gene network analysis implicate protocadherin-15 as a determinant of brain serotonin transporter expression. / Ye, R.; Carneiro, A. M.D.; Han, Q.; Airey, D.; Sanders-Bush, E.; Zhang, B.; Lu, Lu; Williams, Robert; Blakely, R. D.

In: Genes, Brain and Behavior, Vol. 13, No. 3, 01.03.2014, p. 261-275.

Research output: Contribution to journalArticle

Ye, R. ; Carneiro, A. M.D. ; Han, Q. ; Airey, D. ; Sanders-Bush, E. ; Zhang, B. ; Lu, Lu ; Williams, Robert ; Blakely, R. D. / Quantitative trait loci mapping and gene network analysis implicate protocadherin-15 as a determinant of brain serotonin transporter expression. In: Genes, Brain and Behavior. 2014 ; Vol. 13, No. 3. pp. 261-275.
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