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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Intergenerational Transmission of Internalizing and Externalizing Psychopathological Spectra: A Genome-Wide Complex Trait Study

Alternative title: Intergenerasjonel overføring av risiko for vanlige psykiske lidelser: En longitudinell utvidet barn-av-tvilling kohortstudie

Awarded: NOK 9.3 mill.

Mental disorders affect 10-20% of children and adolescents worldwide, and are one of the leading causes for disability in adults. Common mental disorders (CMD) in both children (e.g. anxiety disorders, depression, conduct disorder, and ADHD) and adults (e.g. anxiety disorders, depression, substance use disorders, antisocial personality disorder, and adult ADHD) can be divided into an Internalizing and an Externalizing spectrum. Externalizing disorders are characterized by a general risk for disinhibitory behavior, and from adolescence also include disorders such as substance use- and antisocial behavior disorders. Internalizing disorders include disorders such as major depressive disorder, generalized anxiety disorder, and different phobias. There is a strong association between CMD in parents and children, and a CMD in parents is found to be the most important risk factor for the same disorder in children. Associations between CMD in parents and children could be due to three different modes of intergenerational transmission of risk: 1) risk genes shared among family members, 2) risk environments shared among family members, and 3) direct effect of CMD in parents which leads to CMD in children. The objective of this project is to prospectively study genetic and environmental modes of intergenerational transmission of risk from CMD and alcohol use in parents to CMD in children. Our aim is thereby to contribute to clarifying the causal mechanisms underlying these disorders. Such knowledge is a necessary foundation for the development of effective prevention and treatment strategies. Theories and claims about causal processes involved in CMD shape and guide public policy with regard to, prevention efforts, and treatment. It is therefore of great importance to clarify the underlying etiological mechanisms. Researchers in the project have studied how different forms of psychopathology can be explained by one single risk factor. This factor is best described by the personality trait of Neuroticism. The project have developed novel methods for estimating how heritable traits in parents influence children´s mental health. These models combine both pedigree and genotype data, and shop how the same phenomenon can be described sing fundamentally different methods. The project aims to include aims for studying mechanisms for parent-offspring associations closer by including parental use of psychopharmaceuticals as putative mediatiors for intergenerational effects of mental health. This will contribute to a better understanding of mechanism for associations that cannot be attributed to genetic transmission. Collaborators in the project have participated in a large-scale meta-study (n=42 998) on the manifestation of genetic risk for adult mental disorders on child and adolescent mental disorders. This is an important breakthrough and an invaluable foundation for following analyses on genetic and environmental transmission of risk. Affiliated researchers have used the children-of-methods developed in the project to publish studies of intergenerational transmission of risk within both externalizing and internalizing spectra from pregnancy to school age. The project has produced the software ?svcmr? (structured variance component models with relationship matrices). Svcmr is a novel approach to estimation of genetic and environmental variance components by using large pedigree matrices for the entire population. This is an integration of genetic methods oft used in animal studies into structural equation models oft used in human research, such that all relationships in the population can be used and the analysis time is drastically reduced. Svcmr makes available multivariate genetic research on large registry data such as in the Nordic countries. Svcmr is freely available as public domain software. A major milestone in the project has been reached by publishing a version of M-GCTA which can utilize triadic genomic data fra mother, fathers, and offspring: Trio-GCTA. This is a novel method that index all direct and indirect genetic effects in a family. The project has in addition to the method article published two articles on anxiety and depression and one article on ADHD in children where variants of this method in used. The method provides groundbreaking estimates of the total effect of parents’ heritable traits on children’s mental health through the environment “genetic nurture” and derived genotyped-environment correlation. The method has evoked considerable interest and several international research groups are currently using it in collaboration with researchers in the project. The postdoc in the project was for Trio-GCTA nominated in 2022 to the Fulker Award established by the Behavior Genetics Association. Results from the project has been a major contributing factor for the principal investigator receiving an European Research Council Consolidator Grant in 2022.

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Knowledge on causality is the sine qua non of prevention. However, the causal mechanisms for mental disorders are largely unknown. The strongest predictor of a mental disorder in childhood is to have a parent with the same disorder. We will move beyond the conventional study of associations and directly address the causality of intergenerational transmission of risk for psychopathology. Associations between psychopathology in parents and children could be due to three different modes of intergenerational transmission of risk: 1) risk genes shared among family members, 2) risk environments shared among family members, and 3) direct effect of psychopathology in parents (direct environmental). We will use an exceptional multi-generational dataset comprising DNA markers from complete families; genetically informative extended pedigrees; and measures of psychopathology and normal personality in mothers, fathers, and children. We will therefore be able to use both molecular genetic analyses of genomic similarity in unrelated individuals and quantitative genetic analyses of extended pedigrees. We aim to estimate genetic, shared environmental, and direct environmental modes of intergenerational transmission of risk for psychopathology, the genetic correlation between mental disorders in parents and mental disorders in children, and the impact of genomic and phenotypic similarity in parents on prevalence and heritability of mental disorders. First, this project will increase our understanding of core aspects of psychopathology. Second, and most importantly, it will point to prevention strategies that are likely to be successful or unsuccessful. Policy on prevention and treatment are guided by theories and claims about causal processes. It is therefore of the highest importance to clarify the underlying etiological mechanisms through empirical evidence. Prevention and intervention based on either genetic or environmental knowledge on causality could be very different indeed.

Publications from Cristin

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FRIMEDBIO-Fri prosj.st. med.,helse,biol

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