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Clinical Charcterization (phenomics)

In this WP we will perform phenotypic characterisation that will enable a detailed sub-classification defining separate, cross-disorder, endo- or extreme phenotypes, which may correlate more closely to specific genetic risk variants and environmental risk profiles. This will be done in our present samples as well as in additional case-control and family samples recruited. Furthermore, we aim to identity early clinical precursors for development of mental disorders in individuals at high risk. The three main objectives are outlined below.

1.1 Phenotypic characterisation using clinical and register-based information:

Specific diagnoses; symptom dimensions; suicidal behaviour; severity; course and functional outcomes; psychiatric and somatic comorbidity; treatment response; cognitive function

Cross-disorder phenotypes

In addition to the register-based information, many patients have already participated in our clinical studies, and the available data is exhaustive and allows a more accurate classification of phenotypes. We have detailed data on psychopathology and global functioning for 1500 patients with schizophrenia, 500 bipolar disorder and 300 patients with depression.

Similarly suicidal behaviour will be analysed as a separate phenotype. In several clinical samples, data on suicidal ideation and behaviour were collected at several time points.

Co-morbidity

In many cases, concurrent co-morbidity between psychiatric and physical disorders are likely to be explained by life style factors or adverse effects of medication, but several genetic findings indicate that co-morbidity can also be caused by common genetic factors. In order to analyse concurrent and lifetime co-morbidity, we will link the genetic information with the Danish Psychiatric Central Research Register, the Danish National Hospital Register and, as proxy measure, data from the Medicinal Product Statistics. In addition to that, para-clinical data from the National Indicator Project for 5,000 schizophrenia patients will be used to model proxy measures for diabetes, hypertension, and hypercholesterolemia in this disorder.

Treatment response

Understanding the genetic variation affecting response to e.g. antipsychotics is important in order to develop diagnostic tests to match individual patients to the most effective and safe medication and to understand the specific effects and adverse reactions. E.g. response vs non-response to antipsychotic, antidepressant, anticonvulsant or lithium treatment in cases with schizophrenia or affective disorders will be used as phenotype. Treatment response will be estimated by examining the risk of re-hospitalization and drug discontinuation by linking national databases of hospitalization, and psychopharmacological prescriptions.

Pattern of course

Within each of the five disorders clinical presentation, course and outcome vary greatly, and more precise outcome measures are likely to facilitate identification of aetiology. Therefore, across disorders, we will model register-based data as to define severe recurrent patterns versus benign courses and outcomes as a phenotype, utilizing data on hospitalisations, ability to work or study vs disability pension, high vs low level of social functioning (GAF) and institutional stay. After being controlled for substance abuse and other confounding factors, these subgroups can serve as proxy measures for dimensions such as cognitive functioning and negative symptoms.

Cognitive function and brain imaging

Cognitive functioning, structural and functional brain alteration can serve, as endophenotypes that can help understand pathogenesis. We have neurocognitive data in samples of 1000 patients with schizophrenia, 100 at ultra high risk for transition to psychosis, 300 with depression and 100 healthy controls.

In addition, a subset of individuals, carrying (low frequency) variants found to convey high effect on disease risk, will be subjected to fMRI.

1.2 Additional sampling of new clinical cases

Additional cases of the five disorders in the Faroe Islands will be ascertained with comprehensive clinical profiling to obtain total national cohorts.

Saliva samples will be collected from all members of the cross-disorder multiplex families and individuals carrying high-risk mutations will be clinically examined.

1.3. Identification of early precursors for development of mental disorders in individuals at high-risk

We aim to identify early clinical precursors of schizophrenia and bipolar disorder to establish a basis for future primary preventive interventions in the premorbid phase, and to analyse the influences of genetic risk and environmental factors on psychopathology, cognition, neuromotor, and psychosocial development. The Danish high risk and resilience study- VIA 7 will closely examine 400 children with 0, 1 or 2 parents with schizophrenia or bipolar disorder at age 7, 11 and 15 to determine the influence of specific risks and confounding or mediating factors on cognition, behaviour, psychopathology, neuromotor development, brain development (MRI-scans) and psychophysiology.

Moreover, micro-deletions and -duplications in the genome has recently been shown to confer high risk of schizophrenia and other brain disorders. Carriers of such genomic abnormalities are at ultra-high risk of developing disease and constitute etiologically, homogenous populations that are unique in studies of complex disease.  Clinical profiling of 250 children carrying such de-novo high-risk variations will be conducted. Register information and interviews with teachers and carers will provide data on environmental exposures during pregnancy and upbringing.

More information on VIA 7 (in Danish).

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