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A S Bassett

Publications and source records attributed to A S Bassett.

At least 19 recordsLinked to original sources
PubMed2000

Location of a major susceptibility locus for familial schizophrenia on chromosome 1q21-q22.

Schizophrenia is a complex disorder, and there is substantial evidence supporting a genetic etiology. Despite this, prior attempts to localize susceptibility loci have produced predominantly suggestive findings. A genome-wide scan for schizophrenia susceptibility loci in 22 extended families with high rates of schizophrenia provided highly significant evidence of linkage to chromosome 1 (1q21-q22), with a maximum heterogeneity logarithm of the likelihood of linkage (lod) score of 6.50. This linkage result should provide sufficient power to allow the positional cloning of the underlying susceptibility gene.

Chromosome Mapping↗
PubMed2000

Chromosomal abnormalities and schizophrenia.

Schizophrenia is a common and serious psychiatric illness with strong evidence for genetic causation, but no specific loci yet identified. Chromosomal abnormalities associated with schizophrenia may help to understand the genetic complexity of the illness. This paper reviews the evidence for associations between chromosomal abnormalities and schizophrenia and related disorders. The results indicate that 22q11.2 microdeletions detected by fluorescence in-situ hybridization (FISH) are significantly associated with schizophrenia. Sex chromosome abnormalities seem to be increased in schizophrenia but insufficient data are available to indicate whether schizophrenia or related disorders are increased in patients with sex chromosome aneuploidies. Other reports of chromosomal abnormalities associated with schizophrenia have the potential to be important adjuncts to linkage studies in gene localization. Advances in molecular cytogenetic techniques (i.e., FISH) have produced significant increases in rates of identified abnormalities in schizophrenia, particularly in patients with very early age at onset, learning difficulties or mental retardation, or dysmorphic features. The results emphasize the importance of considering behavioral phenotypes, including adult onset psychiatric illnesses, in genetic syndromes and the need for clinicians to actively consider identifying chromosomal abnormalities and genetic syndromes in selected psychiatric patients.

Aneuploidy↗
PubMed1999

Qualitative MRI findings in adults with 22q11 deletion syndrome and schizophrenia.

BACKGROUND: A genetic syndrome associated with schizophrenia, 22q11 deletion syndrome (22qDS), may represent a genetic subtype of schizophrenia (22qDS-Sz). Structural brain changes are common in schizophrenia and may involve developmental anomalies, but there are no data yet for 22qDS-Sz. The objective of this study was to assess brain structure in adults with 22qDS-Sz using magnetic resonance imaging (MRI). METHODS: Brain and arterial MRI scans of 11 adults with 22qDS-Sz (mean age = 28.4 years, SD = 6.5) were systematically assessed by a neuroradiologist for qualitative anomalies. RESULTS: A high frequency of abnormalities were found: T2 white matter bright foci (BF), 90%; developmental midline anomalies, 45%; cerebral atrophy or ventricular enlargement, 54%; mild cerebellar atrophy, 36%; skull base abnormalities, 55%; and minor vascular abnormalities, 36%. CONCLUSIONS: BF and skull base abnormalities, especially in association with neurodevelopmental midline abnormalities, may be distinguishing MRI features for a genetic subtype of schizophrenia involving a deletion on chromosome 22.

Adult↗
PubMed1999

Phenotype of adults with the 22q11 deletion syndrome: A review.

22q11 deletion syndrome (22qDS) is due to microdeletions of chromosome region 22q11.2. Little is known about the phenotype of adults. We reviewed available case reports of adults (age >/=18 years) with 22qDS and compared the prevalence of key findings to those reported in a large European survey of 22qDS (497 children and 61 adults) [Ryan et al., 1997: J. Med. Genet. 34:798-804]. Fifty-five studies reported on 126 adults (83 women, 40 men, 3 unknown sex), mean age 29.6 years (SD = 8.7 years). Compared with the European survey, adults with 22qDS reviewed had a lower rate of CHD, 30% versus 75%; chi(2) = 88.65, df = 1, P < 0.0001, but higher rates of identified palate anomalies, 88% versus 15%; chi(2) = 37.45, df = 1, P < 0.0001, and learning difficulties, 94% versus 79%; chi(2) = 12.13, df = 1, P = < 0.0008. The most common finding reported was minor facial anomalies. Few reports provided details of minor physical anomalies. Psychiatric conditions were more prevalent, 36% versus 18%; chi(2)= 5.71, df = 1, P < 0.02, than in the survey: 60% of reviewed adults were transmitting parents (72% mothers) ascertained following diagnosis of affected offspring. They had lower rates of CHD, cleft palate, and psychiatric disorders but similar rates of learning disabilities, and other palate and facial anomalies compared with adults ascertained by other methods. The results suggest that learning disabilities and facial and palate anomalies may be key findings in 22qDS adults, but that ascertainment is a key factor in the observed phenotype. Comprehensive studies of adults with 22qDS identified independently of familial transmission are necessary to further delineate the phenotype of adults and to determine the natural history of the syndrome.

Abnormalities, Multiple↗
PubMed1999

22q11 deletion syndrome: a genetic subtype of schizophrenia.

Schizophrenia is likely to be caused by several susceptibility genes and may have environmental factors that interact with susceptibility genes and/or nongenetic causes. Recent evidence supports the likelihood that 22q11 Deletion Syndrome (22qDS) represents an identifiable genetic subtype of schizophrenia. 22qDS is an under-recognized genetic syndrome associated with microdeletions on chromosome 22 and a variable expression that often includes mild congenital dysmorphic features, hypernasal speech, and learning difficulties. Initial evidence indicates that a minority of patients with schizophrenia (approximately 2%) may have 22qDS and that prevalence may be somewhat higher in subpopulations with developmental delay. This paper proposes clinical criteria (including facial features, learning disabilities, hypernasal speech, congenital heart defects and other congenital anomalies) to aid in identifying patients with schizophrenia who may have this subtype and outlines features that may increase the index of suspicion for this syndrome. Although no specific causal gene or genes have yet been identified in the deletion region, 22qDS may represent a more homogeneous subtype of schizophrenia. This subtype may serve as a model for neurodevelopmental origins of schizophrenia that could aid in delineating etiologic and pathogenetic mechanisms.

Chromosome Deletion↗
PubMed1999

Linkage of familial schizophrenia to chromosome 13q32.

Over the past 4 years, a number of investigators have reported findings suggestive of linkage to schizophrenia, with markers on chromosomes 13q32 and 8p21, with one recent study by Blouin et al. reporting significant linkage to these regions. As part of an ongoing genome scan, we evaluated microsatellite markers spanning chromosomes 8 and 13, for linkage to schizophrenia, in 21 extended Canadian families. Families were analyzed under autosomal dominant and recessive models, with broad and narrow definitions of schizophrenia. All models produced positive LOD scores with markers on 13q, with higher scores under the recessive models. The maximum three-point LOD scores were obtained under the recessive-broad model: 3.92 at recombination fraction (theta).1 with D13S793, under homogeneity, and 4.42 with alpha=.65 and straight theta=0 with D13S793, under heterogeneity. Positive LOD scores were also obtained, under all models, for markers on 8p. Although a maximum two-point LOD score of 3.49 was obtained under the dominant-narrow model with D8S136 at straight theta=0.1, multipoint analysis with closely flanking markers reduced the maximum LOD score in this region to 2. 13. These results provide independent significant evidence of linkage of a schizophrenia-susceptibility locus to markers on 13q32 and support the presence of a second susceptibility locus on 8p21.

Canada↗
PubMed1998

No evidence for linkage of the CHRNA7 gene region in Canadian schizophrenia families.

Schizophrenia patients demonstrate a deficiency in the filtering of sensory information, and one specific measure involves a response to the second of a pair of auditory stimuli. A neurophysiological measure of this consists of the electroencephalographic response to pairs of auditory signals, emitted fractions of a second apart. Schizophrenic patients and some of their unaffected relatives show a failure of inhibition of a second tone if it occurs 50 msec after the first. A recent genome scan indicated that the gating defect is linked to the alpha 7 neuronal nicotinic acetyl choline receptor gene on chromosome 15. We genotyped 5 schizophrenia families with a total of 96 subjects with a dinucleotide polymorphic marker located less than 120 kb from the first exon of the alpha 7 neuronal nicotinic acetylcholine receptor gene. Linkage analysis was undertaken using parametric and nonparametric statistical methods. The results of the parametric analysis showed negative lod scores under both narrow and broad diagnosis (lod = -3.6 and -4.8, respectively, at theta = 0), and dominant and recessive modes of transmission of the disease. Nonparametric analysis using GENEHUNTER produced nonsignificant NPL scores (NPL = -0.4 and -0.3 for broad and narrow diagnoses, respectively). In summary, we did not find any evidence that the alpha 7 neuronal nicotinic acetylcholine receptor gene (CHRNA7) is linked to schizophrenia. However, we have not been able to assess the P50 measures in these families.

Chromosomes, Human, Pair 15↗
PubMed1998

22q11 deletion syndrome in adults with schizophrenia.

Genetic syndromes associated with deletions at chromosome 22q11 generally have been diagnosed during childhood based on a constellation of physical features. To investigate a reported association of velocardiofacial syndrome with psychotic disorders in adults, we assessed subjects with DSM-IV schizophrenia or schizoaffective disorder who were referred with two or more syndromal features (palatal, cardiac, facial, or other congenital anomalies, and/or learning difficulties). We report on 10 subjects (5 men and 5 women), mean age 27.2 (SD 6.0) years, who were found to have a 22q11 deletion at locus D22S75 using fluorescence in-situ hybridization (FISH). The mean age at onset of psychosis was 19.6 (SD 4.6) years. Symptoms and course of the psychotic illnesses were unremarkable, but additional signs such as temper outbursts were common. These adult subjects had significantly fewer major palatal (P = .0001) and conotruncal cardiac (P = .05) anomalies but the same high rate of learning difficulties as a sample with deletion 22q11 ascertained through a pediatric clinic [Lindsay et al. (1995): Am J Med Genet 57:514-522]. Minor congenital features and rate of transmitted cases were similar to those previously reported. These results replicate the association of a 22q11 deletion syndrome with schizophrenia and confirm the importance of ascertainment in influencing the phenotype found. The findings support a developmental gene in the 22q11 deletion region causing a complex phenotype which may include significant behavioral components that emerge over time. We support using the term "22q11 deletion syndrome (22DS)," which would encompass physical and psychiatric features, and could also be applied to describe a genetic subtype of schizophrenia.

Abnormalities, Multiple↗
PubMed1998

Paternal transmission and anticipation in schizophrenia.

Recent studies have observed anticipation (earlier age at onset (AAO) or increased disease severity in successive generations) in familial schizophrenia. In other disorders, where the molecular mechanism (repeat expansion) is known, anticipation varies in degree depending on the sex of the transmitting parent. We investigated parental sex effects on anticipation in schizophrenia, using a familial sample of affected two-generation pairs in which anticipation had previously been demonstrated using the median intergenerational difference (MID) in AAO. A Wilcoxon rank sum test for independent samples was used to determine whether MID in AAO was significantly different for paternal and maternal transmission. Results suggested that in a sample of 127 parent-offspring pairs, anticipation was greater with paternal than with maternal transmission (MID = 18 and 14 years, respectively, P = 0.05). Paternal effects were strongest in 39 parent-offspring pairs with early-onset offspring (< or = 21 years) (MID = 22 and 17 years, respectively, for paternal and maternal transmission, P = 0.01). However, assessment of the effect of possible selection biases suggests that preferential ascertainment of late-onset fathers may have exerted important effects. While the results support possible paternal effects, further studies are needed to draw firm conclusions about true parent-of-origin effects on anticipation in familial schizophrenia.

Adolescent↗
PubMed1997

Absence of linkage for schizophrenia on the short arm of chromosome 5 in multiplex Canadian families.

A VNTR for the human dopamine transporter gene (DAT-1) has been localized to chromosome 5p15.3. Silverman et al. [1996] found evidence for genetic linkage of the D5S111 locus, located just centromeric to DAT-1, to schizophrenia and related disorders in a large Hispanic family. We evaluated five markers on 5p, including D5S111 and the DAT-1 VNTR, in five multiplex schizophrenic families, assuming autosomal dominant transmission (subjects assessed n = 122, DNAs available n = 96, individuals with schizophrenia and schizoaffective disorder n = 36, broader spectrum disorders n = 14). LOD scores were negative across all families for all markers tested, and overall LOD scores were strongly negative (<-2.0, theta = 0) across all five families for each of the markers typed. Thus, there is no evidence to support the linkage of markers in this region of chromosome 5 to schizophrenia in this sample of families.

Canada↗
PubMed1997

The New York High-Risk Project. Prevalence and comorbidity of axis I disorders in offspring of schizophrenic parents at 25-year follow-up.

BACKGROUND: The New York High-Risk Project is a study of offspring of patients with schizophrenia (HRSz group) or affective illness (HRAff group) and psychiatrically normal parents (NC group) observed prospectively from childhood to adulthood. We herein present lifetime prevalence and comorbidity rates of Axis I disorders in subjects and their siblings from sample A of the project. METHODS: Schedule for Affective Disorders and Schizophrenia-Lifetime Version interviews conducted with the offspring in adulthood were used to obtain diagnoses of Axis I disorders. RESULTS: Schizophrenia and unspecified psychoses occurred only in the HRSz group. However, schizoaffective and psychotic affective disorders occurred equally in the HRSz and HRAff groups. Total rates of psychosis in these groups were significantly higher than in the NC group. All groups had similar rates of nonpsychotic affective and substance abuse disorders. The HRAff group, however, had significantly more total affective illness than the NC group and tended to have more anxiety disorders than the other groups. Comorbidity rates in the HRSz and HRAff groups were nearly twice those of the NC group. CONCLUSIONS: The familial liabilities to schizophrenia and affective disorders show specificities and commonalities, differing markedly from each other in their expression of some disorders and sharing others. Patterns of comorbidity are generally, although not entirely, similar to these liabilities.

Adolescent↗
PubMed1997

NCAM and schizophrenia: genetic studies.

The hypothesis of a neurodevelopmental dysfunction being involved in the etiology of schizophrenia is suggested by the observation of morphological alterations in the brains of schizophrenia patients. These alterations may be caused by defects in neural cell differentiation or migration, which could lead to disrupted neuronal circuitry and to the schizophrenia symptomatology. The neural cell adhesion molecule (NCAM) plays a major role in cell migration and axon outgrowth, and is involved in synaptic plasticity mechanisms implicated in adult cognitive functions. Altered levels of the NCAM polysialylated form, PSA-NCAM, in the brain of schizophrenia patients have been reported, and are supportive of a role for this molecule in the disorder. To investigate the possible involvement of the NCAM gene in schizophrenia, we conducted a comprehensive genetic study, which included linkage analysis and an association study employing the Haplotype Relative Risk (HRR) design in nuclear families. Our results indicate that structural alterations in the NCAM gene are unlikely to play a major role in schizophrenia, although a function for the NCAM molecule in the etiology of the disease remains an intriguing hypothesis.

Adult↗
PubMed1997

Use of a quantitative trait to map a locus associated with severity of positive symptoms in familial schizophrenia to chromosome 6p.

A number of recent linkage studies have suggested the presence of a schizophrenia susceptibility locus on chromosome 6p. We evaluated 28 genetic markers, spanning chromosome 6, for linkage to schizophrenia in 10 moderately large Canadian families of Celtic ancestry. Parametric analyses of these families under autosomal dominant and recessive models, using broad and narrow definitions of schizophrenia, produced no significant evidence for linkage. A sib-pair analysis using categorical disease definitions also failed to produce significant evidence for linkage. We then conducted a separate sibpair analysis using scores on positive-symptom (psychotic), negative-symptom (deficit), and general psychopathology-symptom scales as quantitative traits. With the positive symptom-scale scores, the marker D6S1960 produced P = 1.2 x 10(-5) under two-point and P = 5.4 x 10(-6) under multipoint analyses. Using simulation studies, we determined that these nominal P values correspond to empirical P values of .034 and .0085, respectively. These results suggest that a schizophrenia susceptibility locus on chromosome 6p may be related to the severity of psychotic symptoms. Assessment of behavioral quantitative traits may provide increased power over categorical phenotype assignment for detection of linkage in complex psychiatric disorders.

Canada↗
PubMed1997

A comprehensive method of assessing routine CT scans in schizophrenia.

Morphological brain abnormalities are common in schizophrenia, although the aetiological and clinical significance of these findings is largely unknown. Substantial between-subject variability suggests that large samples are needed to study the full implications of brain pathomorphology. Computerized tomography (CT) is frequently used routinely in schizophrenia, and large numbers of scans are available for study. This article describes the development and statistical properties of a rapid and simple method of assessing CT scans. The CT Rating Scale for Schizophrenia (CTRSS) is minimally affected by variability in scanning procedures, is reliable, and accurately estimates area and volumetric measures of brain spaces. By promoting the comprehensive assessment of large numbers of routinely obtained scans, the CTRSS would allow the investigation of variables that may systematically affect results (e.g. gender and age) and variables with low prevalence. The CTRSS provides a useful adjunct to technologically more sophisticated methods of assessment such as magnetic resonance imaging (MRI).

Adult↗
PubMed1997

Anticipation or ascertainment bias in schizophrenia? Penrose's familial mental illness sample.

Several studies have observed anticipation (earlier age at onset [AAO] in successive generations) in familial schizophrenia. However, whether true anticipation or ascertainment bias is the principal originating mechanism remains unclear. In 1944 L. S. Penrose collected AAO data on a large, representative sample of familial mental illness, using a broad ascertainment strategy. These data allowed examination of anticipation and ascertainment biases in five two-generation samples of affected relative pairs. The median intergenerational difference (MID) in AAO was used to assess anticipation. Results showed significant anticipation in parent-offspring pairs with schizophrenia (n = 137 pairs; MID 15 years; P = .0001) and in a positive control sample with Huntington disease (n = 11; P = .01). Broadening the diagnosis of the schizophrenia sample suggested anticipation of severity of illness. However, other analyses provided evidence for ascertainment bias, especially in later-AAO parents, in parent-offspring pairs. Aunt/uncle-niece/nephew schizophrenia pairs showed anticipation (n = 111; P = .0001), but the MID was 8 years and aunts/uncles had earlier median AAO than parents. Anticipation effects were greatest in pairs with late-AAO parents but remained significant in a subgroup of schizophrenia pairs with early parental AAO (n = 31; P = .03). A small control sample of other diseases had MID of 5 years but no significant anticipation (n = 9; P = .38). These results suggest that, although ascertainment-bias effects were observed in parent-offspring pairs, true anticipation appears to be inherent in the transmission of familial schizophrenia. The findings support investigations of unstable mutations and other mechanisms that may contribute to true anticipation in schizophrenia.

Adolescent↗
PubMed1996

Reproductive fitness in familial schizophrenia.

BACKGROUND: Reproductive fitness is an important factor in understanding inheritance in genetic disorders. The purpose of this study was to determine whether fitness is reduced in familial schizophrenia (FS) and if fitness in siblings differs from the norm. METHOD: The number of offspring in 36 subjects with RDC schizophrenia or schizoaffective disorder (SZ) and their 101 siblings from large FS families was compared with age-adjusted census figures. RESULTS: Fitness in the SZ group was significantly reduced: 23% of expected in males and 51% of expected in females. Fitness of unaffected siblings was within census expectations. However, female siblings with schizophrenia spectrum features had increased fitness over census norms. Reduced fitness was correlated with low marital rates, poor functioning and positive symptoms. CONCLUSIONS: These results indicate that reduced fitness is an important genetic force in FS and is likely inherent to the illness. Sex differences are important and would need to be considered when examining maternal and paternal transmission of schizophrenia. The results support a proposed high mutation rate for schizophrenia, consistent with a dynamic mutation mechanism.

Adolescent↗