title: Large-scale phenome analysis defines a behavioral signature for Huntington's disease genotype in mice.
abstract: Rapid technological advances for the frequent monitoring of health parameters have raised the intriguing possibility that an individual's genotype could be predicted from phenotypic data alone. Here we used a machine learning approach to analyze the phenotypic effects of polymorphic mutations in a mouse model of Huntington's disease that determine disease presentation and age of onset. The resulting model correlated variation across 3,086 behavioral traits with seven different CAG-repeat lengths in the huntingtin gene (Htt). We selected behavioral signatures for age and CAG-repeat length that most robustly distinguished between mouse lines and validated the model by correctly predicting the repeat length of a blinded mouse line. Sufficient discriminatory power to accurately predict genotype required combined analysis of >200 phenotypic features. Our results suggest that autosomal dominant disease-causing mutations could be predicted through the use of subtle behavioral signatures that emerge in large-scale, combinatorial analyses. Our work provides an open data platform that we now share with the research community to aid efforts focused on understanding the pathways that link behavioral consequences to genetic variation in Huntington's disease.
authors.affiliation: PsychoGenics Inc., Tarrytown, New York, USA.
authors.forename: Vadim
authors.initials: V
authors.lastname: Alexandrov
authors.affiliation: PsychoGenics Inc., Tarrytown, New York, USA.
authors.forename: Dani
authors.initials: D
authors.lastname: Brunner
authors.affiliation: PsychoGenics Inc., Tarrytown, New York, USA.
authors.forename: Liliana B
authors.initials: LB
authors.lastname: Menalled
authors.affiliation: PsychoGenics Inc., Tarrytown, New York, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kudwa
authors.affiliation: PsychoGenics Inc., Tarrytown, New York, USA.
authors.forename: Judy
authors.initials: J
authors.lastname: Watson-Johnson
authors.affiliation: PsychoGenics Inc., Tarrytown, New York, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Mazzella
authors.affiliation: PsychoGenics Inc., Tarrytown, New York, USA.
authors.forename: Ian
authors.initials: I
authors.lastname: Russell
authors.affiliation: PsychoGenics Inc., Tarrytown, New York, USA.
authors.forename: Melinda C
authors.initials: MC
authors.lastname: Ruiz
authors.affiliation: PsychoGenics Inc., Tarrytown, New York, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Torello
authors.affiliation: PsychoGenics Inc., Tarrytown, New York, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Sabath
authors.affiliation: PsychoGenics Inc., Tarrytown, New York, USA.
authors.forename: Ana
authors.initials: A
authors.lastname: Sanchez
authors.affiliation: PsychoGenics Inc., Tarrytown, New York, USA.
authors.forename: Miguel
authors.initials: M
authors.lastname: Gomez
authors.affiliation: PsychoGenics Inc., Tarrytown, New York, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Filipov
authors.affiliation: PsychoGenics Inc., Tarrytown, New York, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Cox
authors.affiliation: PsychoGenics Inc., Tarrytown, New York, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Kwan
authors.affiliation: PsychoGenics Inc., Tarrytown, New York, USA.
authors.forename: Afshin
authors.initials: A
authors.lastname: Ghavami
authors.affiliation: PsychoGenics Inc., Tarrytown, New York, USA.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ramboz
authors.affiliation: CHDI Management/CHDI Foundation, Princeton, New Jersey, USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Lager
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Vanessa C
authors.initials: VC
authors.lastname: Wheeler
authors.affiliation: CHDI Management/CHDI Foundation, Princeton, New Jersey, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Aaronson
authors.affiliation: CHDI Management/CHDI Foundation, Princeton, New Jersey, USA.
authors.forename: Jim
authors.initials: J
authors.lastname: Rosinski
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Marcy E
authors.initials: ME
authors.lastname: MacDonald
authors.affiliation: CHDI Management/CHDI Foundation, Princeton, New Jersey, USA.
authors.forename: David
authors.initials: D
authors.lastname: Howland
authors.affiliation: CHDI Management/CHDI Foundation, Princeton, New Jersey, USA.
authors.forename: Seung
authors.initials: S
authors.lastname: Kwak
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002874:Chromosome Mapping / Q000379:methods; D016678:Genome / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D000071058:Huntingtin Protein / Q000235:genetics*; D006816:Huntington Disease / Q000235:genetics*; D051379:Mice / Q000145:classification / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: C506812:Htt protein, mouse; D000071058:Huntingtin Protein