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BEDREHELSE-Bedre helse og livskvalitet

Identifying the polygenic basis of the human brain and neurodevelopmental disorders

Alternative title: null

Awarded: NOK 5.0 mill.

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Project Period:

2013 - 2018


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Schizophrenia and other severe mental disorders are recognized as leading health problem world-wide and are among the most costly disorders to affect humans. Identifying the underlying pathophysiology is imperative and can lead to major health benefits through better treatment and prevision strategies. The heritability for both mental disorders and brain structure is high but most genetic mechanisms behind are unknown. This project combined new statistical analytical methods with results from world-wide genetic consortia and took advantage of Norwegian brain scan data and human biobank to identify new variants for brain and mental disorders. In a new research study of more than 250,000 people, researchers have found risk factors?for schizophrenia that also affect the cognitive abilities response time, reasoning and general intellectual function. The study can help to increase the understanding of cognitive difficulties in schizophrenia which is necessary to develop new and better treatment for this disorder since cognitive difficulties is believed to be one of the most important reasons why individuals with schizophrenia experience difficulties with participating in work and have a satisfactory social life. This knowledge can help us understand the processes in the brain that give rise to cognitive difficulties in schizophrenia. - In total we found 21 genetic variants that overlap between schizophrenia and cognitive abilities. For 18 of these variants, there was an increased risk of schizophrenia associated with lower cognitive abilities, explains Olav B. Smeland. The study shows that the risk of schizophrenia can contribute to cognitive difficulties, says Ole A. Andreassen. - The study can be an important contribution in the work of understanding cognitive difficulties in schizophrenia. It will be able to facilitate new research that examines how genetic variables affect the brain's function and development, where the goal is to find disease processes we can predict and treat. A similar study found a genetic overlap between schizophrenia and the size of hippocampus, putamen and intracranial volume. In this study, six genetic variants of which three had not previously been identified, were found. This helps to show that schizophrenia contributes to changes in the brain. Both studies are based on long-term cooperation between the Norwegian Center for Research?on Mental Disorders (NORMENT) and the Center for Multimodal Imaging and Genetics at the University of California San Diego and other international partners. Potential volumetric changes in the brain have been an important point in the uncertainty of bipolar disorder (BD). This project led to the identification of patterns in the brain of both schizophrenia and BD patients. BD changes include reduced volumes in limbic structures (hippocampus, amygdala, thalamus) and increased ventricular volume - mainly the pattern of BD on subcortical functions in the brain, while schizophrenia changes include less hippocampus, amygdala, thalamus, accumbens and intracranial volume and greater pallidum and lateral ventricular volume. The findings in this study support previous studies showing volumetric differences in parts of the brain implicated in emotional processing and executive behavior. The findings also provide strong statistical evidence of a lack of difference in the biological signature of bipolar disorder subtypes. Both studies were part of the large international consortium ENIGMA and included patients and healthy controls from all over the world including data from the Norwegian centre for mental disorders (NORMENT), a center of excellence at Oslo university led by Professor Ole A. Andreassen. This is an important step forward in understanding brain abnormalities underlying bipolar disorder, says the principal investigator of the study, professor Ole Andreassen. The findings provide important knowledge, and are currently being followed by new analyses of the cortex.

Severe mental disorders usually starts in adolescence and are major public health problems with unknown pathophysiology. Recently we produced the first genetically-based atlas of the human cortex derived from magnetic resonance imaging (MRI) data of twins using fuzzy clustering. This finding not only confirms that human brain phenotypes are heritable traits but also demonstrates a very clear region-specific genetic pattern in which the cortex can be subdivided into various pleiotropic regions. In this pro ject, we will extend this approach further and apply it to a uniquely large in-house sample with both MRI and single nucleotide polymorphism (SNP) data (n=5,000), in order to generate SNP-based atlases. We will adopt a novel statistical framework develope d by Visscher to examine the contribution of all SNPs to phenotypic variation in aggregate. This approach is analogous to twin modeling which examines aggregate genetic influences on a trait, and captures a much larger portion of heritability than the con ventional genome-wide association study approach. However, neither the twin nor the Visscher methods is informative about specific genetic variants underlying each genetic division.Next, it is well-recognized that neurodevelopmental disorders affect both brain and behavior. We will study genetic variants and mechanisms that are involved in disease or symptom pathogenesis with benefit from incorporating the knowledge of polygenic basis of the brain and neurodevelopmental disorders. Partners include UC San Diego and Univ of Oslo, in addition to Oslo Univ. Hosp and deCODE Genetics. Understanding the polygenic basis of human brain structure will shed insight into the pathogenesis of neurodevelopmental disorders, with potential high impact on personalized medi cine and public health.

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BEDREHELSE-Bedre helse og livskvalitet