Angiotensin converting enzyme polymorphism in schizophrenia and major affective disorder: Population and family-based association studies

Angiotensin converting enzyme (ACE) produces the active octapeptide angiotensin II from the decapeptide angiotensin I, as part of the renin-angiotensin cascade. A prevalent insertion/deletion polymorphism of a 287 nucleotide fragment in the 16th intron of the ACE gene has been found to correlate with plasma ACE activity. Numerous studies have reported a role for this polymorphic site as a risk factor for certain cardiovascular disorders, as well as a phenotype modifier. Angiotensin is a neurotransmitter colocalised with dopamine in limbic areas implicated with psychotic and affective disorders, and ACE has been shown to modulate dopamine turnover in the corpus striatum. We examined the relative frequency of this polymorphic locus in 239 schizophrenia patients, 81 bipolar (BP) disorder patients, and 41 unipolar (UP) disorder patients (all diagnosed according to DSM-IV criteria), compared to a group of 91 ethnically matched healthy control subjects who were screened for a personal and family history of psychiatric illness. An additional group of 61 schizophrenia probands whose parents were available, were also examined, in the context of a haplotype relative risk (HRR) design. We found no significant differences in allele frequencies among the schizophrenia patients compared to controls nor in allele transmission rates in the HRR analysis. Among the affective patients, there was no difference in BP or UP allele or genotype distribution compared to controls. However, comparing both groups of affective patients combined (BP+UP) vs. controls, there was an excess of the DD genotype among the affective patients which was of borderline significance (P = .05). Our results for the schizophrenia patients are in accordance with Arinami et al. [1996], who found similar frequencies of the I/D polymorphism among 292 schizophrenia patients as compared with 579 control Japanese subjects. Arinami et al. [1996] also reported a significant excess of the D allele and DD genotype in 31 BP disorder patients and 34 major depressive disorder patients, and in their combined sample of affective (BP and UP) patients, which was partially supported in our sample. We conclude that it is unlikely this polymorphic site contributes in a substantial manner to the risk of schizophrenia. The role of the I/D polymorphism in affective disorders requires further study.