Robert Freedman

Human Dopamine Transporter Gene Not Linked to Schizophrenia in Multigenerational Pedigrees

A large body of data suggests that perturbations in brain dopaminergic transmission play a role in the pathogenesis of schizophrenia. Recently, the gene for the human dopamine transporter has been cloned and polymorphisms have been identified. Because mutations of the dopamine transporter gene might underlie the cause of schizophrenia in a subset of families, we undertook a linkage analysis between schizophrenia in 9 families and a dopamine transporter gene polymorphism. Evidence of linkage was not found in most families assuming autosomal dominant or recessive inheritance.

Linkage analysis of schizophrenia: the D1 dopamine receptor gene and several flanking DNA markers

Alterations in dopaminergic activity may play an important role in the pathogenesis of schizophrenia. The central effects of dopamine are mediated by at least five G protein-coupled receptors, D1, D2, D3, D4 and D5. The D1 receptor maps to 5q35.1 and it identifies an Eco RI as well as a Taq I RFLP. In the present study we undertook a linkage analysis between the D1 receptor RFLPs and schizophrenia in 9 multigenerational families in which segregation of disease was consistent with autosomal dominant inheritance and reduced penetrance. Several flanking DNA markers were also analyzed as the D1 receptor RFLPs were relatively uninformative in our families. Pairwise analyses of schizophrenia and several flanking markers indicate that inheritability of this region is unlikely to be involved in the pathogenesis of schizophrenia in the 9 families studied.

Schizophrenia and glutamate receptor genes

Nine multiplex schizophrenia familes were genotyped with polymorphisms for the GLUR5 and NMDAR1 glutamate receptor subunit genes. Using the lod score technique, evidence of linkage was not found assuming either dominant or recessive transmission. Similarly, the non-parametric sib pair test did not yield significant evidence of linkage.

Linkage analysis between schizophrenia and index simple-sequence repeat loci for chromosome 21

Nine multiplex schizophrenia families were genotyped with seven highly polymorphic microsatellite loci used in the construction of an index map of chromosome 21. Assuming either autosomal dominant or recessive transmission, evidence of linkage was not found. In addition, the nonparametric sib-pair test did not yield significant evidence of linkage.