A genetic study of decreased language lateralization and left-handedness as possible endophenotypes for psychosis.

Hypothesis: Schizophrenia is a severe psychiatric disorder with a 1% lifetime risk. Recent research has focused on dissecting the genetic underpinnings of the disorder. However, although large genetic studies have identified several disease genes, only a few associations have been reproduced and no genes of large effect have been found. This relative lack of success might partially result from the broad and variable clinical picture of the disorder. An additional explanation can be found in the high genetic heterogeneity of the large patient samples that have been studied. One strategy to tackle these problems is to investigate a well-defined vulnerability model related to fundamental aspects of the disease. Such a model (an endophenotype) is likely to be determined by fewer genes than the full schizophrenia phenotype itself. In addition, an endophenotype can also be studied in healthy subjects displaying the trait of interest. Decreased language lateralization is a possible endophenotype for schizophrenia. While language function is generally lateralized to the left-hemisphere in healthy subjects, functional MRI studies have consistently shown a more bilateral pattern of language representation in schizophrenia patients, present throughout the course of the disease. Healthy monozygotic co-twins of schizophrenia patients also have decreased language lateralization, which can therefore be regarded a genetically determined predisposition for schizophrenia. In addition, there is some evidence that decreased lateralization is an oligogenic trait. These characteristics: being genetically determined, possibly oligogenic and consistently associated with schizophrenia make decreased language lateralization a suitable endophenotype for schizophrenia. Language lateralization is related to hand-preference. While almost 100% of right-handed individuals have left hemispheric language lateralization, left-handers show larger variability with up to 30% of the individuals having right or bilateral lateralization. As such, decreased language lateralization can be efficiently studied in left-handed subjects. In this project we will apply an endophenotype approach to find genetic regions potentially involved in schizophrenia. The endophenotype, decreased language lateralization, will be measured in large families from a unique Dutch population isolate. Main goal: We aim to identify genetic regions for decreased language lateralization, an endophenotype for schizophrenia, in an attempt to unravel part of the genetic underpinnings of schizophrenia. Method: A sample of normal subjects from the village of Urk, a population isolate within the Netherlands, will be investigated. Urk, a former island characterized by religious endogamy, is among the most traditional communities in the Netherlands with the highest birth rate and a low average marital age. The current population has rapidly grown in the last century and stems from a small number of founder families. Families from Urk are large and frequently interconnected. As a result, genetic variation is low, allowing genetic linkage analysis in a relatively small number of subjects. We aim to include 35 large families with multiple left-handed subjects, from which a mean of 15 subjects per family will expectedly participate. In all subjects hand-preference is measured by questionnaire, language lateralization is measured with a mobile transcranial Doppler device and DNA is collected for genome wide linkage analysis. The genetic regions involved in language lateralization that show up from this analysis will be tested for association with schizophrenia in a large and readily genotyped patient cohort (n>800). Role of the AGIKO candidate: The PhD student designed the study and wrote the protocol. He arranged the essential contacts on Urk, learned how to perform functional transcranial Doppler measurements and was responsible for recruitment of all subjects. The PhD student performed the major part of the data collection with regards to hand-preference questionnaires, DNA sampling as well as functional transcranial Doppler measurements. After completion of the sample, the PhD student will perform the genetic analyses. Hereafter he will write up the findings for publication. Benefit: The results of this study will provide unique insights into molecular pathways involved in language lateralization. When association with schizophrenia is found, it may provide knowledge of one of the mechanisms leading to schizophrenia and unravel a functional gene related to the etiology of schizophrenia.