Genomic variants in an inbred mouse model predict mania-like behaviors

• Published in: PloS one Vol. 13; no. 5; p. e0197624
• Main Authors: Saul, Michael C, Stevenson, Sharon A, Zhao, Changjiu, Driessen, Terri M, Eisinger, Brian E, Gammie, Stephen C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.05.2018; Public Library of Science (PLoS)
• Subjects: Affective disorders; Alleles; Analysis; Animal models; Animals; Annotations; Basic Helix-Loop-Helix Transcription Factors - genetics; Behavior; Bioinformatics; Biology; Biology and Life Sciences; Bipolar disorder; Bipolar Disorder - genetics; Capsaicin receptors; Construction; Disease Models, Animal; Disorders; DNA Helicases - genetics; Female; Filtration; Gene expression; Gene frequency; Gene regulation; Genes; Genetic aspects; Genetic variation; Genomes; Genotyping; Inbreeding; Male; Medicine and Health Sciences; Mental depression; Mental disorders; Mental health; Mice; Mice, Inbred ICR - genetics; Mice, Inbred Strains - genetics; Mice, Inbred Strains - psychology; Nerve Tissue Proteins - genetics; Nuclear Proteins - genetics; Pharmacology; Phenotypes; Polymorphism, Genetic - genetics; Population genetics; Proteins; Psychiatry; Research and Analysis Methods; Risk factors; Schizophrenia; Sequence Alignment; Sequence Analysis, DNA; Strains (organisms); Transcription; Transcription Factors - genetics; TRPV Cation Channels - genetics; United States; United States > US; Wisconsin
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0197624

Contemporary rodent models for bipolar disorders split the bipolar spectrum into complimentary behavioral endophenotypes representing mania and depression. Widely accepted mania models typically utilize single gene transgenics or pharmacological manipulations, but inbred rodent strains show great potential as mania models. Their acceptance is often limited by the lack of genotypic data needed to establish construct validity. In this study, we used a unique strategy to inexpensively explore and confirm population allele differences in naturally occurring candidate variants in a manic rodent strain, the Madison (MSN) mouse strain. Variants were identified using whole exome resequencing on a small population of animals. Interesting candidate variants were confirmed in a larger population with genotyping. We enriched these results with observations of locomotor behavior from a previous study. Resequencing identified 447 structural variants that are mostly fixed in the MSN strain relative to control strains. After filtering and annotation, we found 11 non-synonymous MSN variants that we believe alter protein function. The allele frequencies for 6 of these variants were consistent with explanatory variants for the Madison strain's phenotype. The variants are in the Npas2, Cp, Polr3c, Smarca4, Trpv1, and Slc5a7 genes, and many of these genes' products are in pathways implicated in human bipolar disorders. Variants in Smarca4 and Polr3c together explained over 40% of the variance in locomotor behavior in the Hsd:ICR founder strain. These results enhance the MSN strain's construct validity and implicate altered nucleosome structure and transcriptional regulation as a chief molecular system underpinning behavior.