TDT: Advantages & disadvantages for mapping studies of schizophrenia

Association studies of schizophrenia using unrelated controls are prone to artifacts due to population sub-structure. Family based analyses such as the Transmission Disequilibrium Test (TDT) are therefore currently preferred. However, the TDT imposes restrictions regarding family structure and parental genotype. This limits its usefulness, as shown in our ongoing studies. We evaluated 168 simplex families consisting of patients with schizophrenia (DSM-IV criteria) and available parents at the following candidate genes /regions: cPLA2, DRD1, DRD3, hSKCaS, DCP1, CHRNA7, D22S278 and chromosome 6p21.3. We did not detect significant preferential transmission of any allele from heterozygous parents to affected offspring. The requirement of heterozygoous parents for the TDT, as well as exclusion of families with single homozygous parents resulted in substantial numbers of exclusions. For example, only 58 parental genotypes were included when a restriction fragment length polymorphism (RFLP) at DRD3 was investigated using the computer software MCETDT. Haplotype based TDT analysis using '3,4', a short tandem repeat polymorphism (STRP) localized <1 kb from the DRD3 RFLP did not increase informativeness. It may be advisable to use the TDT in conjunction with analysis using unrelated controls. This is illustrated with respect to DCP1, for which we examined a bi-allelic polymorphism simultaneously among two independent sets of unrelated controls.