MooDs Phenome Databank and Reverse Phenotyping

Coordinator:    Prof. Dr. Marcella Rietschel                                                                 
Institution: Zentralinstitut für Seelische Gesundheit Mannheim (ZI)                
Bipolar disorder and schizophrenia are heterogeneous disorders, and patients with the same diagnosis can differ with respect to their clinical symptoms and the course of the disease. The present project aimed to identify homogeneous subgroups of patients with these disorders according to their risk genes and symptoms.

In the first pilot study, we analysed combinations of gene variants, rather than single markers that are commonly assessed. Using this approach, we analysed the influence of GABAA receptor genes on psychotic symptoms, which constitute a dimension of bipolar disorder (Breuer et al. 2011). We showed significant gen-wide associations for GABRA1, GABRB2, and GABRG2, which encode the major subunits of the GABAA receptor in the brain.

In the second study, we tested a previously reported association between a variant of the neuregulin 3 gene and attention, which constitutes an endophenotype. Our analysis was not confined to patients diagnosed with schizophrenia, but also included patients with bipolar disorder. In both schizophrenia and bipolar disorder patients, attention differed between those patients who carried a risk allele of this gene and those who did not. These findings replicated previous results and showed that this endophenotype association occurs in patients with either disorder (Meier et al. 2012).

In a study of the neurocan risk allele, a genome-wide significant locus for bipolar disorder (Cichon et al 2011), principal components and genotype association analyses were used to derive main clinical factors from lifetime symptoms and to determine which of these factors were associated with the risk allele. Our analyses revealed that the neurocan risk allele is significantly associated with mania and overactivity. Interestingly, we showed that neurocan mouse mutants had comparable symptoms, i.e., they were hyperactive, frequently took risks, had few depression-like symptoms, and had high saccharin preference. These symptoms normalized after lithium administration (Miro et al. 2012).

Next, we conducted the first genome-wide association study using symptom clusters rather than categorical psychiatric diagnoses. We showed a significant genome-wide association between an intergenic region on chromosome 3q26.1 in the vicinity of the glucose carrier solute carrier family 2, member 2 (SLC2A2) gene and the factor analysis-derived dimension of negative mood delusions. This finding was replicated in a large independent sample (Meier et al. 2012).
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