Genetic influences on human brain structure - Implications for intellectual ability and schizophrenia liability

Abstract

This thesis describes research that was conducted to explore the genetic and environmental factors contributing to associations between human brain structure and behavioral phenotypes, i.e., intellectual ability and schizophrenia liability. To achieve this, structural equation twin modeling methods were applied to neuroimaging and behavioral data obtained from adult monozygotic and dizygotic healthy twins and twins discordant for schizophrenia. In chapter 2 and chapter 3 of this thesis, we have investigated the shared genetic component between regional grey matter volume and intellectual ability. The importance of subcortical structures in intellectual ability, especially implicating the thalamus, was highlighted. Also, it was shown that grey matter regions implicated in intelligence form a densely connected network and that the volume of these areas is influenced by a genetic factor that influences intellectual ability independently of genes acting on total brain volume. These results indicate that researching specific brain regions implicated in intellectual ability may yield novel genetic variants for this trait. Chapter 4 shows that topological aspects of the structural brain network are considerably genetically determined. The heritability of these topological aspects could not be explained by global characteristics of white matter structure such as volume and microstructural directionality, suggesting that graph theoretical measures of brain structure may provide new insight in the genetic mechanisms that promote the development of brain connectivity. In chapter 5 and chapter 6, results are presented showing that white matter integrity and schizophrenia liability are partly influenced by shared genes. Our findings further indicate that the genetic overlap between separate structural brain phenotypes (white matter integrity and cortical thickness) and schizophrenia liability is influenced by independent genetic factors. Also, variation in intellectual ability is found to predict a substantial part of schizophrenia liability through shared genes. The overlap between brain structure and schizophrenia was estimated to be through a direct association, independent of variation in intellectual ability. This suggests that studying different heritable aspects of brain structure in relation to schizophrenia liability may provide important and independent clues about the development of this etiologically heterogeneous disorder.