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FRIPRO-Fri prosjektstøtte

Decoding psychotic disorders into patterns of polygenic pleiotropy

Alternative title: Avdekke mønstre av overlappende polygene risikofaktorer for psykotiske lidelser.

Awarded: NOK 12.0 mill.

Project Number:

324252

Application Type:

Project Period:

2021 - 2025

Funding received from:

Location:

Partner countries:

The relationship between cannabis use and psychiatric disorders has been widely debated. Cannabis is a psychoactive and addictive drug which sometimes produces psychosis-like symptoms. Psychiatric disorders such as schizophrenia and bipolar disorder are characterized by a severely disturbed perception of reality or a state of confusion. We have shown that there are shared genetic factors underlying our susceptibility to both cannabis use and some psychiatric disorders. These findings may indicate that a subgroup of the population is at high risk for both cannabis use and certain psychiatric disorders, based on their genetics. Our genetics play an important role Individuals who use cannabis have a threefold risk of developing psychosis. Lifelong use of cannabis may also lead to the development of bipolar disorder. We know that genetic factors affect an individual's likelihood of using cannabis. We also know that genetic factors play an important role in determining an individual's susceptibility to developing psychiatric disorders. We have shown that some of the genetic variants associated with cannabis use are also linked to psychiatric disorders In other words, there is a genetic link between the use of cannabis and some psychiatric disorders. We explore this genetic link even further with this study. Not only is there a link between the genetic variants. It is actually the same genetic variants that cause a person’s susceptibility to both using cannabis and developing psychiatric disorders, such as schizophrenia and bipolar disorder.

Psychotic disorders (schizohrenia, bipolar and depressive disorder), represent major societal challenges, with large unmet needs. In spite of this, factors that influence disease development and the neurobiological underpinnings are mainly unknown. Recent evidence supports extensive polygenic overlap across psychotic disorders and traits, leading to the polygenic pleiotropy model. This suggests that most associated genetic variants are not unique for a given mental trait or disorder, but influence susceptibility to a wide range of phenotypes. PleioMent will apply innovative methodology designed to test the hypothesis that the distinct genetic architecture of a mental phenotype is determined by the unique patterns of associations among a group of highly pleiotropic genetic variants with the following specific aims: 1) map the ‘polygenic pleiotropy’ architecture of mixed effects across psychotic phenotypes, 2) discover genetic loci associated with multiple brain-related traits and psychotic disorders with multivariate methods, 3) identify brain-related neurodevelopmental trajectories for psychotic disorders and interplay with environmental stressors in a prospective birth cohort PleioMent will develop apply biostatistical tools based on mixture and multivariate models and integrate massive amounts of genotype data with sparse phenotypes enriched by the collection of new critical data (environmental stressors, brain imaging) from a large, deeply phenotyped prospective birth cohort (MoBa). We will apply our novel analytical framework to exploit unprecedented large samples and investigate the brain characteristics (multimodal MRI) of mental dysregulation risk in a longitudinal setting. If successful, this high risk – high gain approach will provide novel insight into the neurodevelopmental processes preceding the emergence of mental psychopathology and psychotic disorders.

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Funding scheme:

FRIPRO-Fri prosjektstøtte

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