Shared Genetic Factors

The utility of current diagnostic entities for genetic studies seems limited, since psychiatric diagnoses incompletely cover the patients' prodromal phase, age-of-onset, severity of illness, long-term course, and impairment. In particular, psychiatric diagnoses do not offer much information about a patient's response to treatment and prognosis. Evidence from quite a number of studies suggests significant interrelationships between vulnerability to major psychiatric disorders, resilience factors, medical comorbidity, and the time course of recovery under antidepressants and antipsychotics. Shared genetic factors appear to increase or decrease the likelihood for developing the disorders, as they appear to support or impede recovery. Quantitative, syndrome-oriented approaches to psychopathology replace the dichotomy of the diagnostic schema by dimensional quantities and allow one to evaluate "psychopathological similarity" between patients across diagnostic boundaries.

Support from Molecular-Genetic Studies

Several previous investigations have suggested that the gene for the α7-nicotinic receptor may play a role in the pathogenesis of schizophrenia and may be responsible for heavy smoking among schizophrenic patients. In a study of 129 healthy controls and 127 schizophrenic, schizoaffective and bipolar patients, we aimed (1) to confirm the potential association between schizophrenia and the α7-nicotinic receptor, (2) to test the diagnostic specificity of α7-receptor subunits with respect to psychiatric diagnoses, and (3) to investigate potential receptor differences between smokers and nonsmokers in the general population. Our analysis included the two dinucleotide polymorphisms D15S1360 and L76630 that are localized in a genomic fragment containing the α7-nicotinic receptor gene CHRNA7. Highly significant differences (p < 0.0001) between the allele distributions of patients and controls were detected for these two markers, with all three diagnostic subgroups contributing to the discrimination. An independently ascertained replication sample of 24 patients confirmed this finding (Table).

Unresolved Methodological Issues

The genetic analysis of complex disorders influenced by multiple genes as well as multiple non-genetic factors is a still unresolved methodological issue. Standard phenotype-to-genotype research strategies enable the localization of genes coding for traits influenced by a few major genes. Yet these strategies have not been successful in elucidating the genetic background of complex disorders. Thus, if (1) the contributions of single loci are small, (2) the single loci are, by themselves, neither necessary nor sufficient for developing the phenotype, (3) significant interactions between the loci are involved, and (4) there exist different pathways to the phenotype in ethnically different populations, detecting genes by these strategies may be very difficult or impossible. Unknown population admixture can also substantially reduce the power of studies that aim to link phenotype to genotype.

References