Interspecies trait genetics reveals association of Adcy8 with mouse avoidance behavior and a human mood disorder

Annetrude J G de Mooij-van Malsen; Hein A van Lith; Hugo Oppelaar; Judith Hendriks; Marina de Wit; Elzbieta Kostrzewa; Gerome Breen; David A Collier; Berend Olivier; Martien J Kas

doi:10.1016/j.biopsych.2009.06.016

Interspecies trait genetics reveals association of Adcy8 with mouse avoidance behavior and a human mood disorder

Annetrude J G de Mooij-van Malsen, Hein A van Lith, Hugo Oppelaar, Judith Hendriks, Marina de Wit, Elzbieta Kostrzewa, Gerome Breen, David A Collier, Berend Olivier, Martien J Kas

Research output: Contribution to journal › Article › Academic › peer-review

49 Citations (Scopus)

Abstract

BACKGROUND: Identifying susceptibility genes for endophenotypes by studying analogous behaviors across species is an important strategy for understanding the pathophysiology underlying psychiatric disorders. This approach provides novel biological pathways plus validated animal models critical for selective drug development. One such endophenotype is avoidance behavior.

METHODS: In the present study, novel automated registration methods for longitudinal behavioral assessment in home cages are used to screen a panel of recently generated mouse chromosome substitution strains that are very powerful in quantitative trait loci (QTL) detection of complex traits. In this way, we identified chromosomes regulating avoidance behavior (increased sheltering preference) independent of motor activity levels (horizontal distance moved). Genetic information from the mouse QTL-interval was integrated with that from the homologous human linkage region for a mood disorder.

RESULTS: We genetically mapped a QTL for avoidance behavior on mouse chromosome 15, homologous with a human genome region (8q24) linked to bipolar disorder. Integrating the syntenic mouse QTL-interval with genotypes of 1868 BPD cases versus 14,311 control subjects revealed two associated genes (ADCY8 and KCNQ3). Adenylyl cyclase 8 (Adcy8) was differentially expressed in specific brain regions of mouse strains that differ in avoidance behavior levels. Finally, we showed that chronic infusion of the human mood stabilizer carbamazepine (that acts via adenylyl cyclase activity) significantly reduced mouse avoidance behavior, providing a further link between human mood disorders and this mouse home cage behavior.

CONCLUSIONS: Our data suggest that Adcy8 might encode a translational behavioral endophenotype of bipolar disorder.

Original language	English
Pages (from-to)	1123-30
Number of pages	8
Journal	Biological Psychiatry
Volume	66
Issue number	12
DOIs	https://doi.org/10.1016/j.biopsych.2009.06.016
Publication status	Published - 15-Dec-2009
Externally published	Yes

Keywords

Adenylyl Cyclases
Animals
Chromosome Mapping
Chromosomes, Mammalian
Escape Reaction
Female
Gene Expression Profiling
Genetic Predisposition to Disease
Genotype
Humans
KCNQ3 Potassium Channel
Mice
Mice, Inbred C57BL
Mice, Transgenic
Models, Genetic
Mood Disorders
Motor Activity
Oligonucleotide Array Sequence Analysis
Phenotype
Polymorphism, Single Nucleotide
Quantitative Trait Loci

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title = "Interspecies trait genetics reveals association of Adcy8 with mouse avoidance behavior and a human mood disorder",

abstract = "BACKGROUND: Identifying susceptibility genes for endophenotypes by studying analogous behaviors across species is an important strategy for understanding the pathophysiology underlying psychiatric disorders. This approach provides novel biological pathways plus validated animal models critical for selective drug development. One such endophenotype is avoidance behavior.METHODS: In the present study, novel automated registration methods for longitudinal behavioral assessment in home cages are used to screen a panel of recently generated mouse chromosome substitution strains that are very powerful in quantitative trait loci (QTL) detection of complex traits. In this way, we identified chromosomes regulating avoidance behavior (increased sheltering preference) independent of motor activity levels (horizontal distance moved). Genetic information from the mouse QTL-interval was integrated with that from the homologous human linkage region for a mood disorder.RESULTS: We genetically mapped a QTL for avoidance behavior on mouse chromosome 15, homologous with a human genome region (8q24) linked to bipolar disorder. Integrating the syntenic mouse QTL-interval with genotypes of 1868 BPD cases versus 14,311 control subjects revealed two associated genes (ADCY8 and KCNQ3). Adenylyl cyclase 8 (Adcy8) was differentially expressed in specific brain regions of mouse strains that differ in avoidance behavior levels. Finally, we showed that chronic infusion of the human mood stabilizer carbamazepine (that acts via adenylyl cyclase activity) significantly reduced mouse avoidance behavior, providing a further link between human mood disorders and this mouse home cage behavior.CONCLUSIONS: Our data suggest that Adcy8 might encode a translational behavioral endophenotype of bipolar disorder.",

keywords = "Adenylyl Cyclases, Animals, Chromosome Mapping, Chromosomes, Mammalian, Escape Reaction, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Genotype, Humans, KCNQ3 Potassium Channel, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Genetic, Mood Disorders, Motor Activity, Oligonucleotide Array Sequence Analysis, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci",

author = "{de Mooij-van Malsen}, {Annetrude J G} and {van Lith}, {Hein A} and Hugo Oppelaar and Judith Hendriks and {de Wit}, Marina and Elzbieta Kostrzewa and Gerome Breen and Collier, {David A} and Berend Olivier and Kas, {Martien J}",

year = "2009",

month = dec,

day = "15",

doi = "10.1016/j.biopsych.2009.06.016",

language = "English",

volume = "66",

pages = "1123--30",

journal = "Biological Psychiatry",

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publisher = "ELSEVIER SCIENCE INC",

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TY - JOUR

T1 - Interspecies trait genetics reveals association of Adcy8 with mouse avoidance behavior and a human mood disorder

AU - de Mooij-van Malsen, Annetrude J G

AU - van Lith, Hein A

AU - Oppelaar, Hugo

AU - Hendriks, Judith

AU - de Wit, Marina

AU - Kostrzewa, Elzbieta

AU - Breen, Gerome

AU - Collier, David A

AU - Olivier, Berend

AU - Kas, Martien J

PY - 2009/12/15

Y1 - 2009/12/15

N2 - BACKGROUND: Identifying susceptibility genes for endophenotypes by studying analogous behaviors across species is an important strategy for understanding the pathophysiology underlying psychiatric disorders. This approach provides novel biological pathways plus validated animal models critical for selective drug development. One such endophenotype is avoidance behavior.METHODS: In the present study, novel automated registration methods for longitudinal behavioral assessment in home cages are used to screen a panel of recently generated mouse chromosome substitution strains that are very powerful in quantitative trait loci (QTL) detection of complex traits. In this way, we identified chromosomes regulating avoidance behavior (increased sheltering preference) independent of motor activity levels (horizontal distance moved). Genetic information from the mouse QTL-interval was integrated with that from the homologous human linkage region for a mood disorder.RESULTS: We genetically mapped a QTL for avoidance behavior on mouse chromosome 15, homologous with a human genome region (8q24) linked to bipolar disorder. Integrating the syntenic mouse QTL-interval with genotypes of 1868 BPD cases versus 14,311 control subjects revealed two associated genes (ADCY8 and KCNQ3). Adenylyl cyclase 8 (Adcy8) was differentially expressed in specific brain regions of mouse strains that differ in avoidance behavior levels. Finally, we showed that chronic infusion of the human mood stabilizer carbamazepine (that acts via adenylyl cyclase activity) significantly reduced mouse avoidance behavior, providing a further link between human mood disorders and this mouse home cage behavior.CONCLUSIONS: Our data suggest that Adcy8 might encode a translational behavioral endophenotype of bipolar disorder.

AB - BACKGROUND: Identifying susceptibility genes for endophenotypes by studying analogous behaviors across species is an important strategy for understanding the pathophysiology underlying psychiatric disorders. This approach provides novel biological pathways plus validated animal models critical for selective drug development. One such endophenotype is avoidance behavior.METHODS: In the present study, novel automated registration methods for longitudinal behavioral assessment in home cages are used to screen a panel of recently generated mouse chromosome substitution strains that are very powerful in quantitative trait loci (QTL) detection of complex traits. In this way, we identified chromosomes regulating avoidance behavior (increased sheltering preference) independent of motor activity levels (horizontal distance moved). Genetic information from the mouse QTL-interval was integrated with that from the homologous human linkage region for a mood disorder.RESULTS: We genetically mapped a QTL for avoidance behavior on mouse chromosome 15, homologous with a human genome region (8q24) linked to bipolar disorder. Integrating the syntenic mouse QTL-interval with genotypes of 1868 BPD cases versus 14,311 control subjects revealed two associated genes (ADCY8 and KCNQ3). Adenylyl cyclase 8 (Adcy8) was differentially expressed in specific brain regions of mouse strains that differ in avoidance behavior levels. Finally, we showed that chronic infusion of the human mood stabilizer carbamazepine (that acts via adenylyl cyclase activity) significantly reduced mouse avoidance behavior, providing a further link between human mood disorders and this mouse home cage behavior.CONCLUSIONS: Our data suggest that Adcy8 might encode a translational behavioral endophenotype of bipolar disorder.

KW - Adenylyl Cyclases

KW - Animals

KW - Chromosome Mapping

KW - Chromosomes, Mammalian

KW - Escape Reaction

KW - Female

KW - Gene Expression Profiling

KW - Genetic Predisposition to Disease

KW - Genotype

KW - Humans

KW - KCNQ3 Potassium Channel

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Models, Genetic

KW - Mood Disorders

KW - Motor Activity

KW - Oligonucleotide Array Sequence Analysis

KW - Phenotype

KW - Polymorphism, Single Nucleotide

KW - Quantitative Trait Loci

U2 - 10.1016/j.biopsych.2009.06.016

DO - 10.1016/j.biopsych.2009.06.016

M3 - Article

C2 - 19691954

SN - 1873-2402

VL - 66

SP - 1123

EP - 1130

JO - Biological Psychiatry

JF - Biological Psychiatry

IS - 12

ER -

Interspecies trait genetics reveals association of Adcy8 with mouse avoidance behavior and a human mood disorder

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