title: Hnrnph1 Is A Quantitative Trait Gene for Methamphetamine Sensitivity.
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 10-15). 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.
authors.affiliation: Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts, United States of America.|NIGMS Ph.D. Program in Biomolecular Pharmacology, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Massachusetts, United States of America.
authors.forename: Neema
authors.initials: N
authors.lastname: Yazdani
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Clarissa C
authors.initials: CC
authors.lastname: Parker
authors.affiliation: Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts, United States of America.|Graduate Program in Bioinformatics, Boston University, Boston, Massachusetts, United States of America.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Reed
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Guido
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Loren A
authors.initials: LA
authors.lastname: Kole
authors.affiliation: Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Kirkpatrick
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Jackie E
authors.initials: JE
authors.lastname: Lim
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Greta
authors.initials: G
authors.lastname: Sokoloff
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Riyan
authors.initials: R
authors.lastname: Cheng
authors.affiliation: Division of Computational Biomedicine, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: W Evan
authors.initials: WE
authors.lastname: Johnson
authors.affiliation: Department of Human Genetics, The University of Chicago, Chicago, Illinois, United States of America.|Department of Psychiatry and Behavioral Neuroscience, The University of Chicago, Chicago, Illinois, United States of America.
authors.forename: Abraham A
authors.initials: AA
authors.lastname: Palmer
authors.affiliation: Laboratory of Addiction Genetics, Department of Pharmacology and Experimental Therapeutics and Department of Psychiatry, Boston University School of Medicine, Boston, Massachusetts, United States of America.
authors.forename: Camron D
authors.initials: CD
authors.lastname: Bryant
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage; D002874:Chromosome Mapping; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D055106:Genome-Wide Association Study; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008694:Methamphetamine / Q000008:administration & dosage; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D009435:Synaptic Transmission / Q000187:drug effects / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000697:Central Nervous System Stimulants; D034441:Heterogeneous-Nuclear Ribonucleoproteins; C539883:Nr4a2 protein, mouse; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D012333:RNA, Messenger; C423617:Rufy1 protein, mouse; D008694:Methamphetamine