title: OTTO: a new strategy to extract mental disease-relevant combinations of GWAS hits from individuals.
abstract: Despite high heritability of schizophrenia, genome-wide association studies (GWAS) have not yet revealed distinct combinations of single-nucleotide polymorphisms (SNPs), relevant for mental disease-related, quantifiable behavioral phenotypes. Here we propose an individual-based model to use genome-wide significant markers for extracting first genetic signatures of such behavioral continua. 'OTTO' (old Germanic=heritage) marks an individual characterized by a prominent phenotype and a particular load of phenotype-associated risk SNPs derived from GWAS that likely contributed to the development of his personal mental illness. This load of risk SNPs is shared by a small squad of 'similars' scattered under the genetically and phenotypically extremely heterogeneous umbrella of a schizophrenia end point diagnosis and to a variable degree also by healthy subjects. In a discovery sample of >1000 deeply phenotyped schizophrenia patients and several independent replication samples, including the general population, a gradual increase in the severity of 'OTTO's phenotype' expression is observed with an increasing share of 'OTTO's risk SNPs', as exemplified here by autistic and affective phenotypes. These data suggest a model in which the genetic contribution to dimensional behavioral traits can be extracted from combinations of GWAS SNPs derived from individuals with prominent phenotypes. Even though still in the 'model phase' owing to a world-wide lack of sufficiently powered, deeply phenotyped replication samples, the OTTO approach constitutes a conceptually novel strategy to delineate biological subcategories of mental diseases starting from GWAS findings and individual subjects.
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.|DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Ehrenreich
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Mitjans
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medicine, Greifswald, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Van der Auwera
authors.affiliation: Computational Systems Biology, German Center for Neurodegenerative Diseases, Göttingen, Germany.
authors.forename: T P
authors.initials: TP
authors.lastname: Centeno
authors.affiliation: Clinical Neuroscience, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Begemann
authors.affiliation: Department of Psychiatry and Psychotherapy, University Medicine, Greifswald, Germany.
authors.forename: H J
authors.initials: HJ
authors.lastname: Grabe
authors.affiliation: DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.|Computational Systems Biology, German Center for Neurodegenerative Diseases, Göttingen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Bonn
authors.affiliation: DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Göttingen, Germany.|Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors.forename: K-A
authors.initials: KA
authors.lastname: Nave
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011618:Psychotic Disorders / Q000235:genetics; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics*