Genetics of Cognitive Endophenotypes in Schizophrenia : a Family-Based Study

Abstract

Schizophrenia is a highly heritable, though complex disease; multiple genes and environmental factors influence its development. Most of these genes have small effects on schizophrenia. Therefore, the localization and identification of genes for schizophrenia has been difficult. An alternative method is to measure characteristics related to schizophrenia that are less complex phenomena, so-called endophenotypes. If endophenotypes are less complex clinically and genetically than schizophrenia itself, it may be easier to find the underlying genes. Because of the link between endophenotype and schizophrenia, a gene linked to an endophenotype may also be involved in schizophrenia. The main objective of these studies was to unravel the genetic characteristics of promising endophenotypes for schizophrenia and to apply these in genetic research. We investigated the heritable characteristics of 13 candidate endophenotypes for schizophrenia, including neuropsychological, psychophysiological, and personality traits, in 25 multigenerational families (180 subjects) with multiple members affected with schizophrenia. Contrary to expectations, only five of 13 measures showed moderate within-family correlations and equivalent heritability estimates between 0.37 and 0.54: sensorimotor gating, openness, verbal fluency, early visual perception, and spatial working memory. Notably, several other popular candidate endophenotypes showed low familial correlations, including verbal memory, neuroticism, and P50. Segregation analysis showed that a simple mode of transmission fitted best to just two endophenotypes: openness and sensorimotor gating. In the second study, we quantified potential overlapping genetic and environmental contributions among the heritable endophenotypes for schizophrenia. The results suggested that intelligence strongly overlaps genetically with a known cognitive endophenotype for schizophrenia, i.e., spatial working memory. Intelligence may thus be a promising endophenotype for genetic research in schizophrenia, even though the underlying genetic mechanism may still be complex. Other endophenotypes, i.e., sensorimotor gating and openness, appeared to represent separate genetic entities. In the third study, we performed a genome-wide linkage scan using the heritable endophenotypes in a subset of the families. The linkage results were combined with information about biological functions of positional candidate genes and independent data of gene expression in brain tissue of schizophrenia patients, guiding us towards the NTRK3 gene as a susceptibility gene for schizophrenia. In the fourth study, we searched for heritable oscillatory phenotypes, EEG, to be used in linkage analysis. Theta activity at occipital sites appeared to be the most heritable of the measured frequency bands. Linkage peaks were observed with suggestive evidence, including the locus for DTNBP1. Contrary to expectations, EEG was not more powerful than previously investigated cognitive endophenotypes in the same linkage sample. Summarizing, the results described in this thesis suggest that: i) not all candidate endophenotypes are heritable; ii) both shared and distinct genetic contributions underlie these heritable endophenotypes; iii) the studied heritable endophenotypes are linked with suggestive evidence to a number of genetic loci; iv) and NTRK3 is a susceptibility gene for schizophrenia. These studies are an example of how phenotype analysis in pedigrees, linkage mapping, gene expression data in brain tissue, and association testing in cases and controls can be used jointly in order to study the genetic basis for complex neuropsychiatric traits.