Investigation into the genetics of schizophrenia has been ongoing for the better part of a century. Researchers believe that identifying susceptibility genes for schizophrenia will ultimately lead to improvements in prevention and treatment. Significant progress has been made within the past year in particular, and recent findings regarding chromosomal deletion syndrome, attentional abnormalities, and spectrum boundaries appeared in the September issue of the American Journal of Psychiatry.

SCHIZOPHRENIA PHENOTYPE IN 22Q11 DELETION SYNDROME

Anne S. Bassett, MD, of the Centre for Addiction and Mental Health in Toronto, and colleagues investigated the schizophrenia phenotype in 24 patients with 22q11 deletion syndrome (22qDS) and schizophrenia (22qDS-schizophrenia), a rare but relatively homogenous genetic subtype of schizophrenia associated with a microdeletion on chromosome 22. Those with 22qDS have a genetically high risk for schizophrenia. Standard measures of signs, symptoms, and the course of schizophrenia were assessed in 16 adults with 22qDS-schizophrenia who did not meet criteria for mental retardation and in 46 adults with schizophrenia without evidence of 22qDS from a community familial sample.

The researchers found no significant difference in age at onset, lifetime, or cross-sectional core positive and negative schizophrenic symptoms or in global functioning between the two groups of patients with schizophrenia. Patients with 22qDS-schizophrenia had higher excitement subscale scores and less lifetime substance use than did the comparison patients with schizophrenia, but no significant difference in anxiety-depression symptom severity was found between the groups.

“These findings indicate that the core clinical schizophrenia phenotype would not distinguish individuals with a 22qDS subtype from those with schizophrenia who did not have the 22qDS subtype,” Dr. Bassett’s team reported. “The results provide further support for the utility of 22qDS-schizophrenia as a neurodevelopmental model of schizophrenia as well as support for prospective studies of individuals with 22qDS to help identify precursors of schizophrenia.”

DEFICIENT ATTENTIONAL MODULATION OF THE STARTLE RESPONSE

Attentional deficits have already been identified as an abnormality that individuals with schizotypal personality disorder share with schizophrenia patients. Erin A. Hazlett, PhD, of the Mount Sinai School of Medicine in New York City, and colleagues sought to examine automatic sensorimotor gating and controlled attentional modulation of the startle eye blink response in unmedicated participants with schizotypal personality disorder. Eighteen unmedicated patients with schizotypal personality disorder and 16 healthy individuals were assessed. The participants performed a selective attention task involving the presentation of attended, ignored, and novel tones that served as prepulse tones. Acoustic startle probes were presented at short and long lead intervals after the onset of tones and occasionally during the intertone interval.

“The comparison subjects showed greater prepulse inhibition and prepulse facilitation during the attended than the ignored prepulses, demonstrating early and later attentional modulation of startle eye blink response,” Dr. Hazlett’s team reported. “In contrast, the subjects with schizotypal personality disorder failed to show this pattern. Subjects with schizotypal personality disorder have deficits in controlled attentional processing, as indexed by modification of the startle eye blink response, that are similar to those observed in patients with schizophrenia.”

GENETIC BOUNDARIES OF THE SCHIZOPHRENIA SPECTRUM

Data from the Finnish Adoptive Family Study of Schizophrenia was used by Pekka Tienari, MD, of the University of Oulu in Finland, and colleagues to examine clinical phenotypes of schizophrenia spectrum disorders in adopted-away offspring of mothers with schizophrenia spectrum disorders. Participants were 190 adoptees at broadly defined genetic high risk who had biological mothers with schizophrenia spectrum disorders, including a subgroup of 137 adoptees at narrowly defined high risk whose mothers had DSM-III-R schizophrenia. These high-risk groups, followed to a median age of 44 years, were compared diagnostically with 192 low-risk adoptees whose biological mothers had either a nonschizophrenia-spectrum diagnosis or no lifetime psychiatric diagnosis.

The investigators found that in adoptees whose mothers had schizophrenia, the mean lifetime age-corrected morbid risk for narrowly defined schizophrenia was 5.34%, compared with 1.74% for low-risk adoptees, a “marginally nonsignificant” difference. In adoptees whose mothers had schizophrenia spectrum disorders, the mean age-corrected morbid risk for a schizophrenia spectrum disorder was 22.46%, compared with 4.36% for low-risk adoptees, a “significant” difference, according to the researchers. Within the array of schizophrenia spectrum disorders, schizotypal personality disorder was found significantly more often in high-risk than in low-risk adoptees. The frequency of the group of nonschizophrenic nonaffective psychoses collectively differentiated high-risk and low-risk adoptees. However, the frequencies of the separate disorders within this category did not. The two groups were not differentiated by the prevalence of paranoid personality disorder and of affective disorders with psychotic features.

“In adopted-away offspring of mothers with schizophrenia spectrum disorders, the genetic liability for schizophrenia-related illness (with the rearing contributions of the biological mothers disentangled) is broadly dispersed,” Dr. Tienari’s team noted. “Genetically oriented studies of schizophrenia-related disorders and studies of genotype-environment interaction should consider not only narrowly defined, typical schizophrenia but also schizotypal and schizoid personality disorders and nonschizophrenic nonaffective psychoses.”

THE LAST WORD

In an accompanying editorial, Kenneth S. Kendler, MD, of the Medical College of Virginia of Virginia Commonwealth University in Richmond, stated, “[T]hese three papers provide good examples of the range of research questions in the vibrant field of the genetics of schizophrenia.… If some of these ‘gene discoveries’ for schizophrenia turn out to be true, as evidence is increasingly suggesting, we will have a new set of particularly exciting tasks before us.”

—Colby Stong

Suggested Reading
Bassett AS, Chow EWC, AbdelMalik P, et al. The schizophrenia phenotype in 22q11 deletion syndrome. Am J Psychiatry. 2003;160:1580-1586.
Hazlett EA, Levine J, Buchsbaum MS, et al. Deficient attentional modulation of the startle response in patients with schizotypal personality disorder. Am J Psychiatry. 2003;160:1621-1626.
Kendler KS. The genetics of schizophrenia: chromosomal deletions, attentional disturbances, and spectrum boundaries. Am J Psychiatry. 2003;160:1549-1553.
Tienari P, Wynne LC, Läksy K, et al. Genetic boundaries of the schizophrenia spectrum: evidence from the Finnish adoptive family study of schizophrenia. Am J Psychiatry. 2003;160:1587-1594.

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