Exclusion of Linkage Between Schizophrenia and the D2 Dopamine Receptor Gene Region of Chromosome 11q in 112 Irish Multiplex Families

Abstract

• A leading theory hypothesizes that schizophrenia arises from dysregulation of the dopamine system in certain brain regions. As this dysregulation could arise from abnormal expression of D₂dopamine receptors, the D₂receptor gene (DRD2) on chromosome 11q is a candidate locus for schizophrenia. We tested whether allelic variation atDRD2and five surrounding loci cosegregated with schizophrenia in 112 small- to moderate-size Irish families containing two or more members affected with schizophrenia or schizoaffective disorder, defined byDSM-III-R. Evidence of linkage was assessed using varying definitions of illness and modes of transmission. Assuming genetic homogeneity, linkage between schizophrenia and large regions of 11q aroundDRD2could be strongly excluded. Assuming genetic heterogeneity, variation at theDRD2locus could be rejected as a major risk factor for schizophrenia in more than 50% of these families for all models tested and in as few as 25% of the families for certain models. TheDRD2linkage in fewer than 25% of these families could not be excluded under any of the models tested. Our results suggest that the major component of genetic susceptibility to schizophrenia is not due to allelic variation at theDRD2locus or other genes in the surrounding chromosomal region.