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Objective: The author examined the chromosomal linkage method as an approach to the genetic basis of schizophrenia and bipolar disorder. Method: Comparisons were conducted of recent meta-analyses of genome scans of schizophrenia and bipolar disorder and of the three largest (N>300) sibling pair studies of schizophrenia and schizoaffective disorder and a comparable study of bipolar illness. Results: Recent meta-analyses have not identified consistent sites of linkage. The three largest studies of schizophrenia fail to agree on a single locus, no commonality with bipolar illness has been demonstrated, and there is no replicable support for any of the current candidate genes. Discussion: An alternative to the concept that DNA sequence variation lies in 'multiple genes of small effect' is the hypothesis that the variation is epigenetic but related to the genetic transition ('the speciation event') that separated Homo sapiens from a prior hominid species. This hypothesis draws attention to the chromosomal rearrangement (the Xq21.3/Yp translocation) that occurred some 6 million years ago in the hominid lineage and subsequent rearrangements, including a paracentric inversion, that have taken place within the translocated segment. Here it is argued that the most recent of these events is relevant to specifically human characteristics, including language. The gene pair protocadherin X and Y within this region is under new selective pressure and is in a novel (epigenetic) situation with respect to X inactivation. Conclusions: Epigenetic variation associated with chromosomal rearrangements that occurred in the hominid lineage and that relates to the evolution of language could account for predisposition to schizophrenia and schizoaffective and bipolar disorder and failure to detect such variation by standard linkage approaches.

Objective: Biometrical model fitting was applied to clinical data from twins to investigate whether operationally defined schizophrenic, schizoaffective, and manic syndromes share genetic risk factors. Method: Seventy-seven monozygotic and 89 same-sex dizygotic twin pairs in which the proband met the Research Diagnostic Criteria (RDC) for lifetime-ever schizophrenic, schizoaffective, or manic syndrome were ascertained from the Maudsley Twin Register in London. The syndromes were defined nonhierarchically. Correlations in liability were calculated for each syndrome in the monozygotic and dizygotic pairs and across the three pairings of schizophrenic-manic, schizophrenic-schizoaffective, and schizoaffective-manic syndromes both within probands and within pairs. For the three syndromes considered together, an independent pathway model was fitted. Results: The model fitting showed significant genetic correlations between all three syndromes. There was evidence of both common and syndrome-specific genetic contributions to the variance in liability to the schizophrenic and manic syndromes, but the genetic liability to the schizoaffective syndrome was entirely shared in common with the other two syndromes. In contrast, environmental liability to the schizoaffective syndrome was not shared with the other syndromes. Conclusions: If diagnostic hierarchies are relaxed, there is a degree of overlap in the genes contributing to RDC schizophrenic, schizoaffective, and manic syndromes. Supplementing the traditional approach of assigning a single main lifetime diagnosis with information on within-person comorbidity of psychotic syndromes may provide valuable information about the familial aggregation of psychotic symptoms.

Since psychosis occurs across widely differing social and climatic regions without great variation in incidence or type, it is thought to have a genetic link which is relatively independent of environmental factors. If so, then progress in our understanding of psychosis will only occur when a ''psychosis gene'' is found. A commonly used genetic research strategy is linkage analysis. Linkage refers to the tendency of alleles (genetic variations) to be inherited together. Two alleles placed closely together on a chromosome are more likely to be inherited together than are two alleles which are set further apart. This knowledge allows genetic variations to serve as linked markers for other genes when their existence and location have been tagged. Once the linkage between a disease and a marker locus becomes well established, the linkage defines specific genetic disorders that can be mapped to a well understood region of the human chromosome. This information can then be used to predict disease susceptibility. Another research approach is to use what knowledge we have about the disease process to identify a possible or candidate gene. Both strategies should proceed in parallel. Recent diagnostic advances have led to the emergence of a candidate gene which determines brain symmetry (brain changes in schizophrenia and related psychoses have been shown to be asymmetrical). It is hoped that linkage strategies in concert with continuing work in identifying candidate genes will eventually provide clues to the location of a psychosis gene. (Consumer Summary produced by Reliance Medical Information, Inc.)

For the past 80 years, scientific attempts to preserve the theory that schizophrenia and affective (mood) disorders are unrelated have failed. Recent genetic evidence supports the hypothesis that these disorders represent a continuum, and that the mechanisms behind them are genetic. Post-mortem examinations comparing schizophrenics with age-matched controls demonstrated structural changes in the brains of schizophrenics that were not found in other types of psychotic disorders. In most humans, particularly right-handed humans, structures in the left temporal lobe, which encompass areas responsible for speech and communication, are larger than those located in the right temporal lobe. The left temporal lobe of schizophrenic brains was slightly smaller than those of matched comparisons. If such asymmetry is specific to schizophrenia, then the schizophrenic disease process may be linked to mechanisms that produce this lack of symmetry in the human brain, so that the gene for cerebral dominance may also be the human psychosis gene. Furthermore, the genetic locus for psychiatric disease is within the exchange regions of the sex-linked (X and Y) chromosomes. This type of 'pseudoautosomal' (exchange between X and Y chromosomes) genetic transmission has been firmly established by molecular studies. A characteristic feature of pseudoautosomal transmission is same-sex concordance (sibling pairs will be of the same sex more often than expected). The fact that schizophrenic siblings have high same-sex concordance and share a piece of chromosome at the psychosis locus inherited from a carrier parent offers strong molecular evidence of sex-linked inheritance. It is posited that psychoses may be related to aberrations of late evolutionary development associated with increases in brain weight over time as man evolved from primates. Thus, while the cerebral dominance gene may permit evolutionary developments, psychosis may reflect a disadvantageous product of the evolutionary process. (Consumer Summary produced by Reliance Medical Information, Inc.)

Objective: Impaired olfactory identification ability has previously been demonstrated in patients with schizophrenia. This study assessed olfactory function in psychotic and nonpsychotic members of multigenerational families with familial schizophrenia to determine whether deficits were present in both groups. Method: The University of Pennsylvania Smell Identification Test was administered birhinally to three groups of subjects aged less than 65 years: 19 psychotic and 27 nonpsychotic members of families with familial schizophrenia and 43 age-and sex-matched healthy volunteers. Results: Nonpsychotic family members had significantly higher mean University of Pennsylvania Smell Identification Test scores than psychotic family members but were impaired relative to the healthy volunteer group. These group differences could not be accounted for by age, sex, or smoking habit. Fifty-eight percent of the psychotic and 34% of the nonpsychotic family members performed in the microsmic (impaired) range, compared to 9% of the healthy volunteers. Conclusions: Impaired olfactory deficits may aggregate in families with schizophrenia and may be indicative of a genetic predisposition to psychosis. (Am J Psychiatry 2001; 158:1286-1290)

Objective: The association between stressful life events and the onset of major depression decreases as the number of previous depressive episodes increases. How do genetic risk factors for major depression impact on this 'kindling' phenomenon? In particular, do those at high genetic risk exhibit an increase in the speed of kindling, or are they 'prekindled'? Method: Using discrete-time survival analysis, the authors examined the interaction between genetic risk, number of previous depressive episodes, and life event exposure in the prediction of episodes of major depression in female-female twin pairs from a population-based registry. The twins were interviewed four times over a 9-year period, producing 92,521 person-months of exposure. Results: The decline in the association between stressful life events and risk for major depression as the number of previous depressive episodes increased was strongest in those at low genetic risk and was weak to absent in those at high genetic risk. In the absence of previous depressive episodes, those at high genetic risk frequently experienced depressive episodes without major environmental stressors. Conclusions: Genetic risk factors for depression produce a 'prekindling' effect rather than increase the speed of kindling. The 'kindled' state, wherein depressive episodes occur with little provocation, may be reached by two pathways: many previous depressive episodes, perhaps driven by multiple adversities, and high genetic risk. (Am J Psychiatry 2001; 158:582-586)

Objective: The mutation responsible for Huntington's disease is an elongated and unstable trinucleotide (CAG) repeat on the short arm of chromosome 4. Psychotic symptoms are more common in patients with Huntington's disease than in the general population. This study explored the relationship of psychosis in Huntington's disease patients with the number of CAG repeats and family history of psychosis. Method: Forty-four patients with Huntington's disease, 22 with and 22 without psychotic symptoms, were recruited from two university-affiliated medical genetics clinics in Seattle and Vancouver, B.C. Psychiatric assessments of the subjects were made through chart review, and diagnoses were validated by structured interviews in a subset of patients. The demographic and clinical characteristics of the psychotic and nonpsychotic patients were compared. Results: The two groups did not differ in demographic and clinical characteristics, except that subjects with psychosis were significantly more likely than nonpsychotic subjects to have a first-degree relative with psychosis. In eight of nine families in which Huntington's disease probands with psychosis had a first-degree relative with psychosis, the relative's psychosis cooccurred with Huntington's disease. In the Huntington's disease probands with psychosis, the onset of psychosis correlated with the onset of the neurological symptoms of Huntington's disease, and the age at onset of psychosis was lower in probands with a higher number of CAG repeats. Conclusions: Patients with Huntington's disease and psychotic symptoms may have a familial predisposition to develop psychosis. This finding suggests that other genetic factors may influence susceptibility to a particular phenotype precipitated by CAG expansion in the Huntington's disease gene. (Am J Psychiatry 2000; 157:1955-1959)

In the 16 January 2002 issue of the Lancet, Boer et al (1) reported that psychotic illness in Prader-Willi syndrome (PWS) is associated with chromosome 15 maternal uniparental disomy. Here, [...]

Alzheimer's patients with psychosis are more likely to have family members who develop the condition, said Dr. Robert A. Sweet and his colleagues at the University of Pittsburgh. In a [...]