Supplement: Pregnancy, Chromosomes, and Receptors

1 However, a systematic statistical meta-analytic approach indicates less evidence for DISC1 and RGS4 (see 2 In the past the interpersonal environment of the family was thought to play a role in susceptibility, but this does not appear to be the case. Nonetheless, some differences in expressed emotion within families are associated with differences in severity of illness in the patients. The second half of the 20th century also saw the development of biochemical hypotheses for schizophrenia

By | December 1, 2007

1 However, a systematic statistical meta-analytic approach indicates less evidence for DISC1 and RGS4 (see 2 In the past the interpersonal environment of the family was thought to play a role in susceptibility, but this does not appear to be the case. Nonetheless, some differences in expressed emotion within families are associated with differences in severity of illness in the patients.

The second half of the 20th century also saw the development of biochemical hypotheses for schizophrenia. The most prominent was the dopamine hypothesis that Carlsson and Lindqvist originally put forth in 1963; it was based on the biochemical effects of treatment with the first antipsychotic drugs, which had been introduced only in 1952. Animal studies lent support to what became a building block of antipsychotic drug discovery - the search for dopamine receptor blockers - and treatment, and Carlsson shared a Nobel Prize for this and other research in 2002.


At this time multiple classes of dopamine receptors are known. Genetic mutations in dopamine receptors have also been discovered and have been applied to comparisons of patients and controls for decades. At first there appeared to be no association between these genetic changes and susceptibility to schizophrenia, but as evidence accumulated from studies of thousands of normal controls and patients with schizophrenia, a pattern emerged. Examination and reanalysis of meta-analyses has implicated three dopamine receptors that have genetic variants consistently associated with schizophrenia: DRD1, DRD2, and DRD4 (dopamine receptors 1, 2, and 4). Other evidence also implicates DRD3. Other specific genes, based on biochemical hypotheses, also have strong evidence for association with schizophrenia.

The overall picture for schizophrenia is now quite promising. The genes associated with schizophrenia vulnerability are also related to treatment in the case of dopamine receptors. This suggests that treatments might be tailored to the susceptibility variants, and that the tailored treatments would be more effective in patients who had the specific variants. It also suggests that new treatment approaches might be developed from translational research based on the more recently developed gene-disease associations. Finally, it invites research on prevention based on precautionary care of women through deterrence of viral infections during pregnancy, and improvements in obstetric delivery.

Elliot S. Gershon is Foundations Fund Professor of Psychiatry and Human Genetics at the University of Chicago.

Table 1. Environmental traumas associated with schizophrenia

Event Age at event
Influenza infection In utero second trimester of pregnancy
Starvation In utero second trimester of pregnancy
Traumatic brain injury Throughout life



Table 2. Genes statistically associated with schizophrenia susceptibility

Symbol Full Name Chromosome
MTHFR 5,10-methylenetetrahydrofolate reductase 1
DRD4 Dopamine D4 receptor 11
DRD2 dopamine receptor D2 11
DRD1 dopamine receptor D1 5
DAO D-amino-acid oxidase 2
IL1B interleukin 1, beta proprotein 2
TPH1 Tryptophan hydroxylase 1 11
TP53 Tumor protein p53 17
HP Haptoglobin 16
DAOA D-Aminoacid Activator 13
DTNBP1 Dystrophin binding protein 1 (Dystrobrevin) 6
COMT Catechol O-methyltransferase 22


1. N. Norton, H.J. Williams, M.J. Owen, "An update on the genetics of schizophrenia," Curr Opin Psychiat, 19:158-64, 2006.
2. D. Malaspina et al., "Traumatic brain injury and schizophrenia in members of schizophrenia and bipolar disorder pedigrees," Am J Psychiat, 158:440-6, 2001.

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