@article{TEXTUAL,
      recid = {7477},
      author = {Yazdani, Neema and Parker, Clarissa C. and Shen, Ying and  Reed, Eric R. and Guido, Michael A. and Kole, Loren A. and  Kirkpatrick, Stacey L. and Linn, Jackie E. and Sokoloff,  Greta and Cheng, Riyan and Johnson, W. Evan and Palmer,  Abraham A. and Bryant, Camron D.},
      title = {<i>Hnrnph1</i> Is A Quantitative Trait Gene  for Methamphetamine Sensitivity},
      journal = {PLOS Genetics},
      address = {2015-12-10},
      number = {TEXTUAL},
      abstract = {Psychostimulant addiction is a heritable substance use  disorder; however its genetic basis is almost entirely  unknown. Quantitative trait locus (QTL) mapping in mice  offers a complementary approach to human genome-wide  association studies and can facilitate environment control,  statistical power, novel gene discovery, and  neurobiological mechanisms. We used interval-specific  congenic mouse lines carrying various segments of  chromosome 11 from the DBA/2J strain on an isogenic  C57BL/6J background to positionally clone a 206 kb QTL  (50,185,512–50,391,845 bp) that was causally associated  with a reduction in the locomotor stimulant response to  methamphetamine (2 mg/kg, i.p.; DBA/2J < C57BL/6J)—a  non-contingent, drug-induced behavior that is associated  with stimulation of the dopaminergic reward circuitry. This  chromosomal region contained only two protein coding  genes—heterogeneous nuclear ribonucleoprotein, H1 (Hnrnph1)  and RUN and FYVE domain-containing 1 (Rufy1). Transcriptome  analysis via mRNA sequencing in the striatum implicated a  neurobiological mechanism involving a reduction in  mesolimbic innervation and striatal neurotransmission. For  instance, Nr4a2 (nuclear receptor subfamily 4, group A,  member 2), a transcription factor crucial for midbrain  dopaminergic neuron development, exhibited a 2.1-fold  decrease in expression (DBA/2J < C57BL/6J; p 4.2 x  10<sup>−15</sup>). Transcription activator-like effector  nucleases (TALENs)-mediated introduction of frameshift  deletions in the first coding exon of Hnrnph1, but not  Rufy1, recapitulated the reduced methamphetamine behavioral  response, thus identifying Hnrnph1 as a quantitative trait  gene for methamphetamine sensitivity. These results define  a novel contribution of Hnrnph1 to neurobehavioral  dysfunction associated with dopaminergic neurotransmission.  These findings could have implications for understanding  the genetic basis of methamphetamine addiction in humans  and the development of novel therapeutics for prevention  and treatment of substance abuse and possibly other  psychiatric disorders.},
      url = {http://knowledge.uchicago.edu/record/7477},
}