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Genetic linkage studies in both bipolar affective disorder (BPAD) and schizophrenia have implicated overlapping regions of chromosome 22q. We previously reported that BPAD pedigrees containing multiple members with psychotic symptoms showed suggestive linkage to chromosome 22q12.3. Now we have tested 189 single nucleotide polymorphisms (SNPs) spanning a 3 Mb region around the linkage peak for association with BPAD in 305 families, unrelated cases, and controls. SNPs were selected in or near genes, resulting in coverage at a density of 1 SNP per 6.7 kb across the 22 annotated genes in the region. The strongest signal emerged from family-based association analysis of an 11-SNP, 54 kb haplotype straddling the gene HMG2L1 and part of TOM1. A 3-marker haplotype of SNPs within TOM1 was associated with BPAD (allele-wise P = 0.0011) and with psychotic BPAD (allele-wise P = 0.00049). As hypothesized, the mean odds ratio for the risk alleles across the region was 1.39 in the psychotic but only 0.96 in the non-psychotic subset. Genotype-wise analyses yielded similar results, but the psychotic/non-psychotic distinction was more pronounced with mean odds ratios of 1.91 versus 0.8. Permutation of genotype-wise results for rs2413338 in HMG2L1 showed an empirical P = 0.037 for the difference between subsets. HMG2L1 is a negative regulator of Wnt signaling, a pathway of interest in psychotic BPAD as it is activated by both mood stabilizer and anti-psychotic medications. Further work is needed to confirm these results and uncover the functional variation underlying the association signal., ((c) 2007 Wiley-Liss, Inc.)

Previous attempts to identify genetic loci conferring risk for late-onset Alzheimer's disease (LOAD) through linkage analysis have observed some regions of linkage in common. However, due to the sometimes-considerable overlap between the samples, some of these reports cannot be considered to be independent replications. In order to assess the strength of the evidence for linkage and to obtain the best indication of the location of susceptibility genes, we have amalgamated three large samples to give a total of 723 affected relative pairs (ARPs). Multipoint, model-free ARP linkage analysis was performed. Genome-wide significant evidence for linkage was observed on 10q21.2 (LOD=3.3) and genome-wide suggestive evidence was observed on 9q22.33 (LOD=2.5) and 19q13.32 (LOD=2.0). One further region on 9p21.3 was identified with an LOD score>1. We observe no evidence to suggest that more than one locus is responsible for the linkage to 10q21.2, although this linked region may harbour more than one susceptibility gene. Evidence of allele-sharing heterogeneity between the original collection sites was observed on chromosome 9 but not on chromosome 10 or 19. Evidence for an interaction was observed between loci on chromosomes 10 and 19. Where samples overlapped, the genotyping consistency was high, estimated to average at 97.3%. Our large-scale linkage analysis consolidates clear evidence for a susceptibility locus for LOAD on 10q21.2.

Purpose: We had previously performed a genome-wide linkage scan for bipolar affective disorder in an Ashkenazi Jewish sample, a population likely to have reduced genetic heterogeneity. This study is a second stage follow-up focusing on regions that showed positive linkage scores in our previous scan but were not fine-mapped at that time., Methods: We genotyped an additional 145 highly polymorphic microsatellites and conducted linkage analyses using standard laboratory and analytical methods., Results: We saw an improvement of the evidence for linkage in most regions, with the most notable change on chromosome 12p13.1-p12.3, where the evidence of linkage is now suggestive. This region harbors the gene encoding the ionotropic glutamate receptor subunit 2B (GRIN2B), a gene that previously yielded evidence for association in a candidate gene study on 323 Ashkenazi Jewish bipolar case-parent trios. We find that the evidence for linkage is significantly correlated with the presence of the putative high-risk allele identified in our candidate gene study., Conclusions: Following up weaker signals can significantly improve linkage signals even after relatively small increases in information content. Our results on chromosome 12p support GRIN2B as a candidate gene for bipolar disorder that needs further investigation.

Background: Exposure to stressful life events increases the risk of developing a psychotic disorder. Moreover, increased reactivity to stress seems to represent part of the vulnerability for psychosis. This study aimed to investigate whether a functional polymorphism in the catechol-O-methyltransferase (COMT Val(158)Met) gene moderates the psychosis-inducing effects of stress., Method: A semi-experimental stress exposure paradigm was used in a sample of 306 genotyped young men (aged 19-24 years), in whom measures of psychotic symptoms were obtained at recruitment in the Greek army (exposed condition) and again after 18 months of military training (unexposed condition)., Results: Stress exposure at army induction was associated with an increased level of psychotic symptoms. In addition, carriers of the COMT Val(158)Met Val allele were more susceptible to the effect of stress on the psychosis outcome than those with the Met/Met genotype (test for interaction: chi2 = 5.02, df = 1, p = 0.025)., Conclusion: The COMT Val(158)Met genotype may moderate the effect of stress on psychotic symptoms.

Background: Aspects of cognitive function and schizotypy have been proposed as potential endophenotypes for schizophrenia. It is unknown whether the expression of these endophenotypes at the population level is modulated by the genetic variability of candidate susceptibility genes for schizophrenia., Methods: We examined the potential impact of 18 single nucleotide polymorphisms (SNPs) within the DTNBP1, NRG1, DAOA/G32, and DAAO genes, on cognition and self-rated schizotypy, in a representative population of 2243 young male military conscripts. Single SNP and haplotype associations were evaluated., Results: The DTNBP1 SNPs rs2619522 and rs760761 exhibited several single marker associations, the minor alleles being associated with lower attention capacity but also a decrease in positive and paranoid schizotypy scores. The DTNBP1 haplotype load had borderline associations with nonverbal IQ, paranoid schizotypy, and sustained attention. For individual NRG1 polymorphisms, isolated but weak signals of association were noted with sustained attention and working memory but not schizotypy. The risk allele of functional SNP8NRG243177 was associated with reduced spatial working memory capacity. An isolated effect of DAAO haplotype variability was noted on negative and disorganization schizotypy. No convincing association of DAOA/G32 variability was detected., Conclusions: The DTNBP1 and, less so, NRG1 and DAAO variants might exert gene-specific modulating effects on schizophrenia endophenotypes at the population level.

We previously reported linkage to chromosome 8q24 in bipolar disorder (BP) with a LOD of 3.32. We fine mapped the locus with SNPs and tested for association with BP in families with evidence of linkage to the region. We genotyped 249 informative SNPs over 3.4 Mb in an initial sample of 155 nuclear families (352 affected offsprings), and followed up the best findings by genotyping six of the most significantly associated SNPs in a replication sample of 103 nuclear families (231 affected offsprings). We used FBAT and GIST for association tests. Two clusters of SNPs emerged with the strongest evidence of association. The first consisted of three SNPs, approximately 3 kb 5' from the gene ST3GAL1. These SNPs were associated with BP in the initial sample by FBAT (best P = 0.001) and GIST (best P = 0.05) and associated in the replication sample by FBAT (best P = 0.04). The second cluster consisted of four SNPs (one of which was not genotyped in the replication sample), approximately 480 kb 5' of ST3GAL1 in a relative gene desert. These SNPs were associated with BP in the initial sample by FBAT (best P = 0.007) and GIST (best P = 0.03), and marginally associated in the replication sample by FBAT (best P = 0.07) and GIST (P = 0.04). ST3GAL1 belongs to a family of glycosyltransferase proteins, several members of which are highly expressed in the brain and involved in neurogenesis. Several other interesting candidate genes are also located nearby. The congruence of findings across methods and samples suggests further investigation is warranted in these two targeted regions.

Individuals with schizotypal personality disorder or high scores in questionnaires measuring schizotypy are at high risk for the development of schizophrenia and they also share some of the same phenotypic characteristics such as eye-tracking dysfunction (ETD). The question arises whether these individuals form a distinct high-risk group in the general population or whether schizotypy and ETD co-vary in the general population with no distinct cutoff point for a high-risk group. A large sample of military conscripts aged 18-25 were screened using oculomotor, cognitive and psychometric tools for the purposes of a prospective study on predisposing factors for the development of psychosis. Schizotypy measured using the perceptual aberration scale (PAS) and the schizotypal personality questionnaire (SPQ), anxiety and depression, measured using the Symptom Checklist 90-R, had no effect on pursuit performance in the total sample. Small groups of individuals with very high scores in schizotypy questionnaires were then identified. These groups were not mutually exclusive. The high PAS group had higher root-mean-square error scores (a quantitative measure for pursuit quality) than the total sample, and the high disorganized factor of SPQ group had lower gain and higher saccade frequencies in pursuit than the total sample. The presence of significant differences in pursuit performance only for predefined high schizotypy groups favors the hypothesis that individuals with high schizotypy might present one or more high-risk groups, distinct from the general population, that are prone to ETD as that observed in schizophrenia.

Low-copy repeats (LCRs) are genomic features that affect chromosome stability and can produce disease-associated rearrangements. We describe members of three families with deletions in 10q22.3-q23.31, a region harboring a complex set of LCRs, and demonstrate that rearrangements in this region are associated with behavioral and neurodevelopmental abnormalities, including cognitive impairment, autism, hyperactivity, and possibly psychiatric disease. Fine mapping of the deletions in members of all three families by use of a custom 10q oligonucleotide array-based comparative genomic hybridization (NimbleGen) and polymerase chain reaction-based methods demonstrated a different deletion in each family. In one proband, the deletion breakpoints are associated with DNA fragments containing noncontiguous sequences of chromosome 10, whereas, in the other two families, the breakpoints are within paralogous LCRs, removing approximately 7.2 Mb and 32 genes. Our data provide evidence that the 10q22-q23 genomic region harbors one or more genes important for cognitive and behavioral development and that recurrent deletions affecting this interval define a novel genomic disorder.

Alzheimer's disease (AD) is a disabling neurodegenerative disorder with onset commonly in late life. Three genes have been identified causing earlier onset AD, and a fourth has been shown to be a risk factor for late onset AD (LOAD), while many more yet unrecognized genes are thought to contribute to susceptibility. Many studies have reported linkage to LOAD on human chromosome 10, where we have identified a parent of origin effect [Bassett SS, Avramopoulos D, Perry RT, Wiener H, Watson B Jr, Go RC, Fallin MD. Am J Med Genet B Neuropsychiatr Genet 141:537-540, (2006), Bassett SS, Avramopoulos D, Fallin D. Am J Med Genet 114:679-686, (2002)]. In this paper, we report on a gene in this region that shows reduced expression with increasing age, reduced expression in females across ages, and further reduction in LOAD patients. In concordance with the observed parent of origin effect on the linkage, this reduction is more pronounced in patients with an affected mother. We discovered this gene while studying the alkaline ceramidase gene (ASAH2); it is a partial paralog of ASAH2, and we call it ASAH2L. It is the result of a partial duplication of ASAH2 on chromosome 10q11.23, just downstream from the sequence with promoter activity. ASAH2L has a polymorphic start codon with a single nucleotide change of the original ASAH2 sequence plus other putative translation start sites that might produce novel proteins. It is expressed in all the tissues we tested including the brain and is an interesting example of the generation of a new gene. Comparison of primate and other mammal genomes suggests that ASAH2L is human specific. Further research would be necessary to determine the function of the ASAH2L transcript and explore any possible involvement in neurodegeneration.

Background: Mirroring schizophrenia, specific dimensions of schizotypy are related to cognitive dysfunction. The relation of schizotypy and state psychopathology to cognitive performance and its link to catechol-O-methyltransferase (COMT) val(158) met genotype variations was studied in a large sample of young men., Methods: State psychopathology and schizotypy were assessed with self-rated questionnaires. Cognitive performance was assessed with tests of reasoning ability, sustained attention, and verbal and spatial working memory. Subjects were genotyped for the val(158) met polymorphism of the gene for COMT (low enzymatic activity met/met, intermediate met/val, and high val/val)., Results: The val/val group had higher scores in measures of state psychopathology as well as negative and disorganized schizotypy dimensions, whereas there was no effect of COMT genotype on cognitive performance measures. Structural equation modeling showed that cognitive performance accuracy but not speed decreased with increasing negative schizotypy, increased with increasing paranoid schizotypy, and was not affected by state psychopathology. Increasing val loading resulted in a dose-dependent increase in the factor loading for the relation between negative schizotypy and cognitive performance accuracy., Conclusions: Different schizotypal phenotypes had opposing relations to cognitive performance in the population. COMT genotype modulated the relation between the negative schizotypal phenotype and cognitive performance.

The beta2-adrenergic receptor is part of the catecholamine system, and variants at two polymorphic sites in the gene coding for the receptor (ADRB2) confer increased activity. Overstimulation of this receptor may alter brain development, and has been linked to autism in non-identical twins. The objective of this study was to determine whether alleles in ADRB2 are associated with diagnosis of autism in the Autism Genetic Resource Exchange (AGRE) population. Three hundred and thirty-one independent autism case-parent trios were included in the analysis. Subjects were genotyped at activity-related polymorphisms rs1042713 (codon 16) and rs1042714 (codon 27). Association between autism and genotypes at each polymorphic site was tested using genotype-based transmission disequilibrium tests, and effect modification by family and pregnancy characteristics was evaluated. Sensitivity to designation of the proband in each family was assessed by performing 1000 repeats of the analysis selecting affected children randomly. A statistically significant OR of 1.66 for the Glu27 homozygous genotype was observed. Increased associations with this genotype were observed among a subset of Autism Diagnostic Observation Schedule confirmed cases and a subset reporting experience of pregnancy-related stressors. In conclusion, the Glu27 allele of the ADRB2 gene may confer increased risk of autism and shows increased strength with exposure to pregnancy related stress.

We hypothesized that maternal-fetal incompatibility at the Rh or ABO loci may contribute to the risk of autism. There are biologically plausible reasons to believe such effects may play a role, and two previous epidemiologic studies have provided suggestive evidence. To further test this hypothesis, we genotyped the Rh and ABO loci in a sample of 389 independent case-parent trios from the AGRE repository and analyzed the data using a modification of the log-linear model for case-parent trios in which the effects of maternal-fetal genotype incompatibility are modeled jointly with the effects of the affected child's or mother's genotypes. We did not find any evidence that incompatibility at the Rh or ABO loci increases the risk of autism. Furthermore, we did not find any evidence for the presence of a high-risk susceptibility allele at or near these two loci operating either through the mother or child.

The chromosome 10q region has recently received a great deal of attention in late-onset Alzheimer's disease (LOAD), given the growing evidence of linkage to LOAD, or to A-beta levels, reported by several groups. In a recent paper we reported evidence of linkage in this region in our subset of the NIMH AD genetics initiative pedigrees, approaching genome-wide significance (non-parametric LOD score = 3.27), when only families with maternal disease origin were analyzed [Bassett et al. (2002); Am J Med Genet 114:679-686]. We have now extended this work, using an independent subset of NIMH AD pedigrees from the University of Alabama at Birmingham (UAB), and show further evidence of linkage using parent-of-origin information. As in our Hopkins sample, maternal but not paternal pedigrees show significantly increased linkage in the chromosome 10q region compared to the unstratified sample. Combining data from our previous fine-mapping work on this region and five new markers genotyped in all pedigrees results in a non-parametric LOD score of 3.73 in the same region, a value that reaches genome wide significance for linkage, with an empirical P value = 0.003. These results support our earlier findings and narrow the region of interest. In combination with findings from other groups, these results provide further evidence that this chromosome 10 region harbors a gene implicated in LOAD, and our use of parent-of-origin information has been useful in further narrowing the region of interest., ((c) 2006 Wiley-Liss, Inc.)

Bipolar, schizophrenia, and schizoaffective disorders are common, highly heritable psychiatric disorders, for which familial coaggregation, as well as epidemiological and genetic evidence, suggests overlapping etiologies. No definitive susceptibility genes have yet been identified for any of these disorders. Genetic heterogeneity, combined with phenotypic imprecision and poor marker coverage, has contributed to the difficulty in defining risk variants. We focused on families of Ashkenazi Jewish descent, to reduce genetic heterogeneity, and, as a precursor to genomewide association studies, we undertook a single-nucleotide polymorphism (SNP) genotyping screen of 64 candidate genes (440 SNPs) chosen on the basis of previous linkage or of association and/or biological relevance. We genotyped an average of 6.9 SNPs per gene, with an average density of 1 SNP per 11.9 kb in 323 bipolar I disorder and 274 schizophrenia or schizoaffective Ashkenazi case-parent trios. Using single-SNP and haplotype-based transmission/disequilibrium tests, we ranked genes on the basis of strength of association (P<.01). Six genes (DAO, GRM3, GRM4, GRIN2B, IL2RB, and TUBA8) met this criterion for bipolar I disorder; only DAO has been previously associated with bipolar disorder. Six genes (RGS4, SCA1, GRM4, DPYSL2, NOS1, and GRID1) met this criterion for schizophrenia or schizoaffective disorder; five replicate previous associations, and one, GRID1, shows a novel association with schizophrenia. In addition, six genes (DPYSL2, DTNBP1, G30/G72, GRID1, GRM4, and NOS1) showed overlapping suggestive evidence of association in both disorders. These results may help to prioritize candidate genes for future study from among the many suspected/proposed for schizophrenia and bipolar disorders. They provide further support for shared genetic susceptibility between these two disorders that involve glutamate-signaling pathways.

Objective: It has been suggested that variation in catechol O-methyltransferase (COMT) activity associated with variation in COMT Val158Met genotypes may result in enhanced or reduced cognitive performance, depending on whether the phenotype requires cognitive stability or cognitive flexibility. The authors' goal was to determine whether, in confirmation of this prediction, performance on a measure of cognitive stability would be associated with Met loading., Method: COMT genotyping was investigated in relation to a measure of reaction time variability on the Continuous Performance Test, Identical Pairs Version, in a large and representative sample of 527 young men (mean age=21 years)., Results: Met loading was associated with reduced reaction time variability., Conclusions: Met genotype loading may confer enhanced "tuning" or greater stability in performance, possibly by stabilizing active neural representations in the prefrontal cortex during tasks involving working memory.

Cases of early onset AD have been attributed to three genes, PSEN1, PSEN2, and APP, while the only gene consistently associated with late onset AD (LOAD) is APOE. Several genome scans have now been performed for LOAD with inconsistent findings in several genomic regions, possibly reflecting the underlying genetic heterogeneity. Many lines of evidence suggest that the absence or presence of psychotic symptoms, common in AD, might delineate distinct etiologic disease subtypes. We have performed a genome scan of 148 AD pedigrees (ages of onset more than 50 years) including the presence or absence of delusions and hallucinations as covariates. This approach identified linkage to a locus on chromosome 14q24.3, close to the PSEN1 locus (LOD score 3.91; genome-wide empirical P = 0.052), derived from individuals that do not have co-morbid hallucinations. The finding appears stronger (LOD score 5.74; genome-wide empirical P = 0.048) in families that include younger affected members (AAO between 50 and 65 years), however it is not present without the inclusion of the covariate and we observe no correlation between the presence of hallucinations and the age of onset. A mutation screen of PSEN1 did not detect any coding region or splice site mutations. This linkage finding suggests the presence of a gene causing AD without co-morbid hallucinations and with an earlier (yet not early) age at onset (AAO) in the 14q24 region. This region requires further study to replicate the finding and identify the genetic variant responsible for the linkage., (Copyright 2004 Wiley-Liss, Inc.)

Background: Increased catechol-O-methyltransferase activity associated with variation in catechol-O-methyltransferase valine158 methionine genotypes may result in reduced dopamine neurotransmission in the prefrontal cortex and thus contribute to the poor performance of frontally mediated cognitive tasks and the occurrence of associated negative symptoms observed in patients with schizophrenia; however, reported associations between catechol-O-methyltransferase valine158 methionine genotypes and measures of cognition have not been consistent., Methods: Catechol-O-methyltransferase genotyping, measures of schizotypy, cognitive measures of memory and attention, as well as the antisaccade eye movement task, a measure sensitive to prefrontal cortical function, were obtained in a sample of 543 young men representative for that age group (mean age 21 years)., Results: None of the cognitive measures was associated with catechol-O-methyltransferase valine158 methionine genotypes; however, there was an effect of high-activity allele loading on schizotypy, in particular the negative and disorganization dimensions., Conclusions: Previously reported inconsistencies in the relationship between catechol-O-methyltransferase valine158 methionine genotypes and cognition were not resolved; however, catechol-O-methyltransferase genotype may affect expression of negative schizotypy by direct or indirect effects on central dopamine neurotransmitter signaling.

Background: Rates of psychotic disorder and related attenuated psychotic experiences are higher in urban areas. We examined to what degree differences between urban and rural areas could be attributed to differences in cognitive development., Method: Scores on the nine subscales of the schizotypal personality questionnaire (SPQ) as well as IQ and specific neuropsychological functions of memory and attention were assessed in a representative sample of 943 young army conscripts from the 49 counties of Greece., Results: Young men from urban areas had higher scores on the SPQ subscale Odd beliefs/magical thinking (OR = 1.99, 95% CI: 1.42, 2.78), but lower scores on Excessive social anxiety (OR = 0.63, 95 % CI: 0.49, 0.81) and No close friends (OR = 0.42, 95% CI: 0.29, 0.62). Adjustment for demographic factors, IQ and specific neuropsychological functions did not change the results. When the lower scores on Excessive social anxiety and No close friends were taken into account, the differences on the Odd beliefs/magical thinking subscale became even more pronounced (OR = 2.33, 95% CI: 1.56, 3.49)., Conclusions: Young men from urban areas are socially more competent, but display higher levels of positive psychotic experiences, which are not mediated by lower IQ or higher levels of neuropsychological impairment.

A total of 940 young men performed a task in which they actively maintained fixation for 50 s in three conditions: a). on a visual target, b). on a visual target while distracting targets appeared briefly on the periphery and c). with no visual target present. The same individuals completed psychometric evaluation tests measuring IQ, schizotypy and current state-dependent psychopathology. The proportion of fixation time decreased and saccade frequency increased in condition b compared wih condition a, and sequentially in condition c compared with condition b. A trend towards a decrease in proportion of fixation time and increase in saccade frequency was found as the subjects maintained fixation during the task and this time-dependent deterioration of performance was again most pronounced in condition c, less so in condition b and absent in condition a. Psychometric test scores were significantly correlated with fixation performance in the population. Worse performance in all three fixation conditions was observed for individuals with lower IQ scores. A deterioration of fixation performance with time in condition b was correlated with disorganization characteristics of schizotypy, suggesting that these individuals had difficulty maintaining active fixation in the presence of increased inhibitory load. A connection of such a difficulty with the frontal lobes and their role in the control of voluntary inhibitory functions is discussed.

Our group first reported a linkage finding for bipolar (BP) disorder on chromosome 8q24 in a study of 50 multiplex pedigrees, with an HLOD score reaching 2.39. Recently, Cichon et al reported an LOD score of 3.62 in the same region using two-point parametric analysis. Subsequently, we published the results of a genome scan for linkage to BP disorder using a sample extended to 65 pedigrees in which chromosome 8q24 provided the best finding, an NPL score of 3.13, approaching the accepted score for suggestive linkage. We have now fine mapped this region of chromosome 8 in our 65 pedigrees by the addition of 19 microsatellite markers reaching a marker density of 0.8 cM and an information content of 0.84. After the addition of the new data, the original NPL score slightly increased to 3.25. Two-point parametric analysis using the model employed by Cichon et al obtained an LOD score of 3.32 for marker D8S256 at theta=0.14 exceeding the proposed threshold for genomewide significance. After adjusting the parameters in accordance with the 'common disease-common variant' hypothesis, multipoint parametric analysis resulted in an HLOD of 2.49 (alpha=0.78) between D8S529 and D8S256, and defined a 1-LOD interval corresponding to a 2.3 Mb region. No allelic association with the disease was observed for our set of microsatellite markers. Biologically, plausible candidate genes in this region include thyroglobulin, KCNQ3 coding for a voltage-gated potassium channel and the gene for brain adenyl-cyclase (ADCY8).

The aim of this study within the Athens Study of Psychosis Proneness and Incidence of Schizophrenia (ASPIS) was the examination of the latent structure of schizotypal dimensions among a large population of young male conscripts in the Greek Air Force during their first week of military training. Confirmatory factor analysis (CFA) was conducted on 1,355 reliable responders to the self-rated Schizotypal Personality Questionnaire (SPQ), which covers all nine aspects of DSM-III-R schizotypal personality disorder (SPD). A four-factor model (cognitive/perceptual, paranoid, negative, and disorganization schizotypal dimensions) provided a better fit to the data than did other competing models (one-, two-, three-, four, and five-factor models). This result is in agreement with recent findings supporting the notion of a multidimensional construct of the schizotypy and related schizophrenia phenotype.

The co-segregation in one pedigree of bipolar affective disorder with Darier's disease whose gene is on chromosome 12q23-q24.1, and findings from linkage and association studies with the neighbouring gene of phospholipase A2 (PLA2) indicate that PLA2 may be considered as a candidate gene for affective disorders. All relevant genetic association studies, however, were conducted on bipolar patients. In the present study, the possible association between the PLA2 gene and unipolar affective disorder was examined on 321 unipolar patients and 604 controls (all personally interviewed), recruited from six countries (Belgium, Bulgaria, Croatia, Germany, Greece, and Italy) participating in the European Collaborative Project on Affective Disorders. After controlling for population group and gender, one of the eight alleles of the investigated marker (allele 7) was found to be more frequent among unipolar patients with more than three major depressive episodes than among controls (P<0.01); genotypic association was also observed, under the dominant model of genetic transmission (P<0.02). In addition, presence of allele 7 was correlated with a higher frequency of depressive episodes (P<0.02). These findings suggest that structural variations at the PLA2 gene or the chromosomal region around it may confer susceptibility for unipolar affective disorder.

Background: In 1989 the National Institute of Mental Health began a collaborative effort to identify genes for bipolar disorder. The first 97 pedigrees showed evidence of linkage to chromosomes 1, 6, 7, 10, 16, and 22 (Nurnberger et al 1997). An additional 56 bipolar families have been genotyped, and the combined sample of 153 pedigrees studied., Methods: Three hierarchical affection status models were analyzed with 513 simple sequence repeat markers; 298 were common across all pedigrees. The primary analysis was a nonparametric genome-wide scan. We performed conditional analyses based on epistasis or heterogeneity for five regions., Results: One region, on 16p13, was significant at the genome-wide p <.05 level. Four additional chromosomal regions (20p12, 11p15, 6q24, and 10p12) showed nominally significant linkage findings (p

A total of 1,273 conscripts of the Greek Air Force performed antisaccades and completed self-reporting questionnaires measuring schizotypy and current state-dependent psychopathology. Only 1.0% of variability in antisaccade performance indices was related to psychometric scores in the population and could be attributed more to current state-dependent symptoms such as anxiety rather than to schizotypy. In contrast, a specific increase of error rate and response latency variability and a high correlation of these 2 variables was observed in a group with very high schizotypy scores. This effect was independent of anxiety and depression, suggesting that a specific group of psychosis-prone individuals has a characteristic deviance in antisaccade performance that is not present in the general population.

A sample of 676 healthy young males performed visually guided saccades and antisaccades and completed the Porac-Coren questionnaire measuring lateral preferences. There was no difference in mean latency between rightward versus leftward saccades or for saccades executed in the left versus right hemispace. There was also no right/left asymmetry for individuals with left or right dominance as assessed by the lateral preferences questionnaire. The same results were observed for the latency of antisaccades and for the error rate in the antisaccade task. Finally, we did not confirm any substantial subpopulation of individuals with idiosyncratic left/right latency asymmetries that persisted both in the saccade and antisaccade task. These results suggest that neither latency nor antisaccade error rate are good indicators of lateral preferences in these tasks. Other oculomotor tasks might be more sensitive to hemifield differences, or cerebral hemispheric asymmetry is not present at the level of cortical organization of saccades and antisaccades.

Objective: Linkage studies of bipolar disorder and schizophrenia have found overlapping evidence for susceptibility genes in four chromosomal regions-10p12-14, 13q32, 18p11.2, and 22q12-13. The authors previously demonstrated familial clustering of psychotic symptoms-defined as hallucinations and/or delusions-in some bipolar disorder pedigrees. In this study they used stratified linkage analysis to test the hypothesis that those bipolar disorder pedigrees most enriched for psychotic symptoms would show greater evidence of linkage to the regions of previous bipolar disorder/schizophrenia linkage overlap., Method: Nonparametric linkage analyses using GENEHUNTER and ASPEX were performed on 65 bipolar disorder families. Family subsets were defined by the number of family members with psychotic mood disorder., Results: The 10 families in which three or more members had psychotic mood disorder showed suggestive evidence of linkage to 13q31 (nonparametric linkage score=3.56; LOD score=2.52) and 22q12 (nonparametric linkage score=3.32; LOD score=3.06). These results differed significantly from those for the entire study group of 65 families, which showed little or no linkage evidence in the two regions. The 10 families with three or more psychotic members did not show evidence of linkage to 10p12-14 or 18p11.2. The 95% confidence interval on 22q12 spanned 4.3 centimorgans (2.6 megabases) and was congruent with previous findings., Conclusions: Bipolar disorder families in which psychotic symptoms cluster may carry susceptibility genes on chromosomal regions 13q31 and 22q12. Replication should be attempted in similar families and perhaps in schizophrenia families in which mood symptoms cluster because these overlapping phenotypes may correlate most closely with the putative susceptibility genes. The localization of the 22q12 finding particularly encourages further study of this region.

Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (epsilon 4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) >/=1.9 and/or multipoint lod score (MLS) >/=2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.

Antisaccade performance was investigated in a sample of 2,006 young males as part of a large epidemiological study investigating psychosis proneness. This report summarizes the effects of task parameters on performance using a sample of 55,678 antisaccade trials collected from a subpopulation of 947 individuals. Neither the amplitude nor the latency of an error prosaccade in the antisaccade task was correlated with the latency of the ensuing corrective antisaccade that almost always followed an error. However, the latency of the corrective antisaccade decreased with increasing stimulus distance. Concerning the effects of specific task parameters, trials with stimuli closer to the central fixation point and trials preceded by shorter fixation intervals resulted in more errors and longer latencies for the antisaccades. Finally, there were learning and fatigue effects reflected mainly in the error rate, which was greater at the beginning and at the end of the 5-min task. We used a model to predict whether an error or a correct antisaccade would follow a particular trial. All task parameters were significant predictors of the trial outcome but their power was negligible. However, when modeled alone, response latency of the first movement predicted 40% of errors. In particular, the smaller this latency was, the higher the probability of an error. These findings are discussed in light of current hypotheses on antisaccade production mechanisms involving mainly the superior colliculus.

A population of 2,075 young men aged 18-25 years selected from the conscripts of the Greek Air Force performed an antisaccade task as part of a prospective study for the identification of risk factors in the development of psychoses. The aim of this study, which is ongoing, is to follow this population and investigate the possible predictive value of oculomotor, cognitive, and psychometric factors for the development of psychosis and other psychiatric conditions. In this report we present data concerning the antisaccade task in this population. We measured performance indices, including the percentage of errors (PE), the latencies of different eye movement responses (latency for correct antisaccades, errors, corrections), and performance in perseveration-prone trials. These indices were also evaluated with respect to IQ (measured by the Raven progressive matrices test) and educational level. Mean PE was 23%, with 17% variance. This large variance is of particular importance whenever the detection of a putative deviant behavior is explored. As mean latency of the first eye movement decreased, the PE increased, as did the latency variance. While the negative correlation between percentage of error and mean latency is well established, the relationship of the latency variability of the first response to error production has not been studied before. Thus, optimal performance appears to require both an intermediate mean latency and a small variability. Furthermore, performance seems to be affected by IQ (the higher the IQ score, the lower the percentage of errors). This report offers an analysis of the interindividual variation in the performance of the antisaccade task and discusses some of the sources of this variation.

Evidence for a parent of origin effect in Alzheimer disease was obtained from a sample of 148 sibships on which affection status of the parents was sought using family history interviews. The parent study recruited families with two or more affected sibs for late onset AD utilizing rigorous diagnostic criteria. In 74 families, there was evidence of an affected parent, 49 maternal and 25 paternal. Genome scan data were analyzed for the sample as a whole and for the maternal and paternal families separately, using Genehunter-ASM. Seven regions with Z(lr) scores >or=2 were identified, four in maternal families (chr. 10,12,19,20) and three in paternal families (chr. 1,7,13). With the exception of the chromosome 10 finding, analysis by parent of origin greatly increased evidence of linkage in areas showing no linkage in the overall analyses. For example, a chr. 12 region reached a LOD = 2.29 among maternal families whereas the same region showed a LOD = 0.3 when all families were analyzed together. The strongest findings among maternal families (chr. 10 and 12) were followed up with fine mapping that resulted in an increase in maximum LOD scores from 2.7-3.2 on chr. 10, and 2.29-2.42 on chr. 12. These analyses highlight the importance of parent of origin effects in late-onset AD families and identify several genomic regions that may include genes linked to late-onset AD specific to disease transmission from the mother and require further investigation., (Copyright 2002 Wiley-Liss, Inc.)

Background: The aims of the study were: first to examine, using clinical symptoms of patients as a template, whether the correlated but independent dimensions of positive, negative and depressive symptoms that have been identified in clinical psychosis, also have a distribution as non-clinical experiences in the general population; and second, to establish to what degree population variation in experience of positive and negative features of psychosis is actually independent of experience of depression., Method: In a representative population sample of 932 young men, we measured experiences of positive, negative and depressive features of psychosis, using a 40-item self-report instrument. Confirmatory factor analysis was used to compare the fit of hypothesized one-, two- and three-factor solutions., Results: A three-factor model of separate depressive, positive and negative dimensions provided a better fit to the data than either a two-factor or unidimensional model. All three dimensions were correlated with each other, but also showed good discriminant validity in relation to established scales, confirming their relative independence., Conclusion: The data suggest that the correlated dimensions of clinical psychosis also have a distribution in the general population, and that depressive symptoms may form an integral part of psychosis-like experiences in the general population.

The gene for COMT is located on chromosome 22q11, an area that has been implicated in the pathogenesis of schizophrenia through linkage studies and through the detection of deletions in schizophrenics and velocardiofacial syndrome patients that often present psychotic symptomatology. Additionally catechol-O-methyl transferase activity has been found increased in schizophrenia and a functional polymorphism in the COMT gene itself has been associated with the disease, as well as with aggression in patients. We tested the hypothesis that COMT genotype for the functional Val158Met might contribute to the variance of self reported schizotypy and aggression scores in the normal population. We genotyped 379 healthy 18- to 24-year-old male individuals who had completed the PAS, SPQ and AQ questionnaires. Our results showed that self-reported schizotypy scores in both questionnaires were significantly related to COMT genotype (P = 0.028 for the PAS and P = 0.015 for the SPQ) with individuals homozygous for the high activity allele showing the highest scores. No significant differences were detected for AQ scores. We conclude that the COMT genotype for the functional Val158Met polymorphism is correlated to self-reported schizotypy in healthy males. This finding is in the same direction as reported findings on schizophrenia and it adds to the list of evidence that COMT or a nearby gene in linkage disequilibrium is involved in the pathogenesis of the disease.

There is accumulated evidence that the genes coding for the receptor of gamma aminobutyric acid (GABA), the most important inhibitory neurotransmitter in the CNS, may be involved in the pathogenesis of affective disorders. In a previous study, we have found a genetic association between the GABA-A receptor alpha5 subunit gene locus (GABRA5) on chromosome 15q11-of 13 and bipolar affective disorder. The aim of the present study was to examine the same subjects to see if there exists a genetic association between bipolar affective disorder and the GABA receptor beta3 subunit gene (GABRB3), which is located within 100 kb from GABRA5. The sample consisted of 48 bipolar patients compared to 44 controls (blood donors). All subjects were Greek, unrelated, and personally interviewed. Diagnosis was based on DSM-IV and ICD-10 criteria. The marker used was a dinucleotide (CA) repeat polymorphism with 12 alleles 179 to 201 bp long; genotyping was successful in all patients and 43 controls. The distribution of GABRB3 genotypes among the controls did not deviate significantly from the Hardy-Weinberg equilibrium. No differences in allelic frequencies between bipolar patients and controls were found for GABRB3, while this locus and GABRA5 did not seem to be in significant linkage disequilibrium. In conclusion, the GABRB3 CA-repeat polymorphism we investigated does not present the observed association between bipolar affective illness and GABRA5. This could be due to higher mutation rate in the GABRB3 CA-repeat polymorphism, but it might also signify that GABRA5 is the gene actually associated with the disease., (Copyright 2001 Wiley-Liss, Inc.)

Heritability is considered to be a major etiologic factor for schizophrenia. Among the genes considered as candidates for the disease, are those related to GABAergic neurotransmission. Our aim was to test for a genetic association between GABA-A receptor alpha 5 subunit gene locus (GABRA(5)) and schizophrenia. Genotyping of the GABRA(5) locus was performed by the use of a dinucleotide (CA) repeat marker in 46 schizophrenic patients and 50 healthy individuals, all unrelated Greeks. Eight alleles were identified, 276-290 bp long. A nonsignificant excess of the 282-bp allele, which was found in a previous study in a Greek population to be associated with bipolar affective disorder, was observed in schizophrenic patients (33.8 vs. 23.9% in the controls). The frequency of this allele was 43.3% among patients with a later age of onset (over 25 years), differing at a statistically significant level from the controls (p < 0.05). These results suggest that common pathophysiological mechanisms may possibly underlie affective disorders and schizophrenia, at least in a subgroup of patients., (Copyright 2001 S. Karger AG, Basel)

Several lines of evidence suggest a shared genetic susceptibility to Down syndrome (DS) and Alzheimer disease (AD). Rare forms of autosomal-dominant AD are caused by mutations in the APP and presenilin genes (PS-1 and PS-2). The presenilin proteins have been localized to the nuclear membrane, kinetochores, and centrosomes, suggesting a function in chromosome segregation. A genetic association between a polymorphism in intron 8 of the PS-1 gene and AD has been described in some series, and an increased risk of AD has been reported in mothers of DS probands. We therefore studied 168 probands with free trisomy 21 of known parental and meiotic origin and their parents from a population-based material, by analyzing the intron 8 polymorphism in the PS-1 gene. An increased frequency of allele 1 in mothers with a meiosis II error (70.8%) was found compared with mothers with a meiosis I error (52.7%, P < 0.01), with an excess of the 11 genotype in the meiosis II mothers. The frequency of allele 1 in mothers carrying apolipoprotein E (APOE) epsilon4 allele (68.0%) was higher than in mothers without epsilon4 (52.2%, P < 0.01). We hypothesize that the PS-1 intronic polymorphism might be involved in chromosomal nondisjunction through an influence on the expression level of PS-1 or due to linkage disequilibrium with biologically relevant polymorphisms in or outside the PS-1 gene., (Copyright 2000 Wiley-Liss, Inc.)

Huntington's disease (HD) is an autosomal dominant degenerative disease of the central nervous system manifested by involuntary movements (chorea), psychiatric manifestations, and cognitive impairment with a variable age at onset. This variability is mainly attributed to genetic factors. The so-called aging genes [e.g., those for apolipoprotein E (APOE) and presenilin-1 (PS-1) have been implicated in determining the age at onset of Alzheimer's disease, a disease sharing common clinical features with HD. In 60 unrelated patients suffering from HD (mean age at onset 40.1 years, range 20-65) we determined number of CAG repeats and the distribution of the APOE alleles (epsilon2, epsilon3, epsilon4) and PS-1 alleles. The results showed that: (a) The age at onset was higher in the group of patients with the epsilon4 allele (51.6 vs. 38.0 P<0.002), (b) The correlation between the age at onset and the number of CAG repeats was strong in patients with the epsilon3/epsilon3 genotype while it was not detected in patients with epsilon3/epsilon4 genotype. (c) No correlation was found between age at onset and PS-1 alleles. In conclusion, APOE seems to be a significant factor influencing the age at onset of Huntington's disease.

Charcot-Marie-Tooth (CMT) disease type CMTX has been linked with mutations in GJB1, a gene on chromosome X coding for a gap junction protein, Connexin 32. We screened the GJB1 gene for mutations by SSCP analysis and sequencing of candidate regions, in five unrelated CMT affected individuals, members of families presenting a mode of transmission and clinical findings compatible with CMTX. Mutations were detected in all five patients. Three not previously reported mutations were identified: C164T, G491A and T359A. Two patients shared the same mutation (C164T) while one had a reported mutation (C43T). Restriction enzyme digestion confirmed the sequencing results, as well as the co-segregation of the mutation with the disease. The same method was used to screen 150 control X chromosomes and the variations were not detected.

Causes of chromosomal nondisjunction is one of the remaining unanswered questions in human genetics. In order to increase our understanding of the mechanisms underlying nondisjunction we have performed a molecular study on trisomy 8 and trisomy 8 mosaicism. We report the results on analyses of 26 probands (and parents) using 19 microsatellite DNA markers mapping along the length of chromosome 8. The 26 cases represented 20 live births, four spontaneous abortions, and two prenatal diagnoses (CVS). The results of the nondisjunction studies show that 20 cases (13 maternal, 7 paternal) were probably due to mitotic (postzygotic) duplication as reduction to homozygosity of all informative markers was observed and as no third allele was ever detected. Only two cases from spontaneous abortions were due to maternal meiotic nondisjunction. In four cases we were not able to detect the extra chromosome due to a low level of mosaicism. These results are in contrast to the common autosomal trisomies (including mosaics), where the majority of cases are due to errors in maternal meiosis.

Paternal non-disjunction of chromosome 21 accounts for 5-10% of Down syndrome cases, therefore, relative to the maternally derived cases, little is known about paternally derived trisomy 21. We present the first analysis of recombination and non-disjunction for a large paternally derived population of free trisomy 21 conceptuses ( n = 67). Unlike maternal cases where the ratio of meiosis I (MI) to meiosis II (MII) errors is 3:1, a near 1:1 ratio exists among paternal cases, with a slight excess of MII errors. We found no paternal age effect for the overall population nor when classifying cases according to stage of non-disjunction error. Among 22 MI cases, only five had an observable recombinant event. This differs significantly from the 11 expected events ( P < 0.02, Fisher's exact), suggesting reduced recombination along the non-disjoined chromosomes 21 involved in paternal MI non-disjunction. No difference in recombination was detected among 27 paternal MII cases as compared with controls. However, cases exhibited a slight increase in the frequency of proximal and medial exchange when compared with controls (0.37 versus 0.28, respectively). Lastly, this study confirmed previous reports of excess male probands among paternally derived trisomy 21 cases. However, we report evidence suggesting an MII stage-specific sex ratio disturbance where 2.5 male probands were found for each female proband. Classification of MII cases based on the position of the exchange event suggested that the proband sex ratio disturbance was restricted to non-telomeric exchange cases. Based on these findings, we propose new models to explain the association between paternally derived trisomy 21 and excessive male probands.

Genetic factors seem to play an important role in the pathogenesis of affective disorder. The candidate gene strategies are being used, among others, to identify the genes conferring vulnerability to the disease. The genes coding for the receptors of gamma-aminobutyric acid (GABA) have been proposed as candidates for affective disorder, since the GABA neurotransmitter system has been implicated in the pathogenesis of the illness. We examined the possible genetic association between the GABA(A) receptor alpha5 subunit gene locus (GABRA5) on chromosome 15 and affective disorder, in 48 bipolar patients (BP), 40 unipolar patients (UP), and 50 healthy individuals, age- and sex-matched to the patients. All patients and controls were unrelated Greeks. Diagnoses were made after direct interviews according to the DSM-IV and ICD-10 criteria. For the genotyping, a dinucleotide (CA) repeat marker was used. The polymerase chain reaction (PCR) products found were nine alleles with lengths between 272 and 290 base pairs (bp). The distribution of allelic frequencies of the GABRA5 locus differed significantly between BP patients and controls with the 282-bp allele found to be associated with BP affective disorder, while no such difference was observed between the groups of UP patients and controls nor between the two patient groups. The presence or absence of the 282-bp allele in the genotype of BP patients was not shown to influence the age of onset and the overall clinical severity, but was found to be associated with a preponderance of manic over depressive episodes in the course of the illness.

We describe a 17-month-old infant with clinical features of Down syndrome and a normal karyotype by standard chromosomal analysis, her two uncles aged 28 and 30 years, respectively, with reduced intelligence and unusual appearance but not apparent Down syndrome, and a severely retarded 6-year-old girl with dysmorphy and epilepsy from the same family. Cytogenetic studies of patients and normal intervening relatives had been carried out at different institutions with normal results. Fluorescence in situ hybridization using whole chromosome painting and unique-copy probes (cosmids) and high-resolution banding revealed a familial subtelomeric translocation of chromosomes 18 and 21, resulting in partial trisomy 21 in the infant and her two uncles, and partial monosomy 21 in the 6-year-old girl. Cytogenetic breakpoints were located in bands 18q23 and 21q22.1, respectively. The molecular breakpoint on chromosome 21 was located between D21S211 (proximal) and D21S1283 (distal) and thus maps within the Down syndrome critical region.

The APOE gene is located on chromosome 19, and the three common alleles are designated epsilon2, epsilon3, and epsilon4. The epsilon4 allele is associated with increased plasma cholesterol, atherosclerosis and cardiovascular disease, Alzheimer's disease, and decreased longevity. The objective of the present study was to estimate the distribution of APOE alleles in the Greek population by DNA analysis. The material consisted of 216 voluntary, healthy Greek blood donors (146 males/70 females). The APOE allele frequencies were epsilon2: 5.3%, epsilon3: 88.2%, epsilon4: 6.5%. The epsilon4 allele frequency of 6.5% in the Greek population is, together with the frequency in the Chinese population, among the lowest in the world.

Recent studies of trisomy 21 have shown that altered levels of recombination are associated with maternal non-disjunction occurring at both meiosis I (MI) and meiosis II (MII). To comprehend better the association of recombination with nondisjunction, an understanding of the pattern of meiotic exchange, i.e. the exchange of genetic material at the four-strand stage during prophase, is required. We examined this underlying exchange pattern to determine if specific meiotic configurations are associated with a higher risk of non-disjunction than others. We examined the crossover frequencies of chromosome 21 for three populations: (i) normal female meiotic events; (ii) meiotic events leading to MI non-disjunction; and (iii) those leading to MII non-disjunction. From these crossover frequencies, we estimated the array of meiotic tetrads that produced the observed crossovers. Using this approach, we found that nearly one-half of MI errors were estimated to be achiasmate. The majority of the remaining MI bivalents had exchanges that clustered at the telomere. In contrast, exchanges occurring among MII cases clustered at the pericentromeric region of the chromosome. Unlike the single exchange distributions, double exchanges from the non-disjoined populations seemed to approximate the distribution in the normal population. These data suggest that the location of certain exchanges makes a tetrad susceptible to non-disjunction. Specifically, this susceptibility is associated with the distance between the centromere and closest exchange. This result challenges the widely held concept that events occurring at MII are largely independent of events occurring at MI, and suggests that all non-disjunction events may be initiated during MI and simply resolved at either of the two meiotic stages.

We describe a case of apparent trisomy 21 that does not fulfill the criteria for the clinical diagnosis of Down's syndrome (DS). Our patient was subjected to karyotype analysis and found to have full, non-mosaic trisomy 21 in both blood lymphocytes and skin fibroblasts, while examination of the term placenta, which was performed earlier in the course of a different study, had shown mosaicism (73%) for trisomy 21. FISH analysis showed no obvious rearrangement of the DS chromosomal region in any of the chromosomes 21. Molecular analysis using polymorphic markers on chromosome 21 verified the existence of trisomy for the entire long arm of the chromosome and showed that the origin of the extra chromosome was maternal and was probably the result of a mitotic error. In contrast with the above, the clinical evaluation using the Jackson checklist of 25 signs failed to establish the diagnosis of DS. We believe that our patient might present mosaicism in other tissues that are not available for analysis and can be regarded as an extreme example in the continuous spectrum of karyotype phenotype associations in mosaic cases.

The cause of non-disjunction of chromosome 21 remains largely unknown. Advanced maternal age is associated with both maternal meiosis I (MI) and meiosis II (MII) non-disjunction events. While reduced genetic recombination has been demonstrated in maternal MI errors, the basis for MII errors remains uncertain. We studied 133 trisomy 21 cases with maternal MII errors to test the hypothesis that segregation at MII may also be influenced by genetic recombination. Our data support a highly significant association: MII non-disjunction involves increased recombination that is largely restricted to proximal 21q. Thus, while absence of a proximal recombination appears to predispose to non-disjunction in MI, the presence of a proximal exchange predisposes to non-disjunction in MII. These findings profoundly affect our understanding of trisomy 21 as they suggest that virtually all maternal non-disjunction results from events occurring in meiosis I.

We have used eight PCR-based DNA polymorphisms to determine the parental origin and mechanisms of formation in 9 patients with de novo nonmosaic tetrasomy 18p. The 9 patients, 4 girls and 5 boys, had clinical features characteristic of i(18p) syndrome. The supernumerary marker chromosome was identified by fluorescence in situ hybridization (FISH) analysis using centromeric probes and a flow-sorted 18p-specific library. The isochromosome was of maternal origin in all 9 cases. The formation of tetrasomy 18p cannot be explained by a single model. In 6 cases, meiosis II nondisjunction, followed by subsequent postzygotic misdivsion, and in 1 case postzygotic nondisjunction and postzygotic misdivision were the most likely mechanisms of formation. Alternative mechanisms are suggested in the remaining 2 cases.

Six novel polymorphic short sequence repeats were identified and localized on the linkage map of human chromosome 21 by genotyping the CEPH reference pedigrees. One of these markers, the tetrameric (AAAG)n repeat D21S1245, was found to be hypermutable. In the DNAs from lymphoblastoid cell lines of members of the 40 CEPH families a total of 18 new alleles were detected. These new alleles, sometimes appearing in mosaic forms, arose equally in paternal and maternal DNAs, and could be equally larger or smaller than the alleles from which they were derived. The larger alleles of D21S1245 are more prone to be converted to new alleles. None of the new alleles with mosaicism were present in the corresponding genomic blood DNA, and therefore originated during or after the establishment of the lymphoblastoid cell lines; half of the new alleles without mosaicism were also found in genomic blood DNA of the appropriate CEPH individuals. The range of germline mutation rate observed in the 716 meioses examined was 0.56-1.4 x 10(-2); the range of somatic mutations observed in the 405 cell lines examined was 1.96-3.46 x 10(-2). This is one of the most hypermutable microsatellite repeat polymorphism in the human genome detected to date. D21S1245, is highly polymorphic (heterozygosity of 0.96) and maps between D21S231 and D21S198.

In order to investigate the mechanism(s) underlying mosaicism for trisomy 21, we genotyped 17 families with mosaic trisomy 21 probands, using 28 PCR-detectable DNA polymorphic markers that map in the pericentromeric region and long arm of chromosome 21. The percentage of cells with trisomy 21 in the probands' blood lymphocytes was 6%-94%. There were two classes of autoradiographic results: In class I, a "third allele" of lower intensity was detected in the proband's DNA for at least two chromosome 21 markers. The interpretation of this result was that the proband had inherited three chromosomes 21 after meiotic nondisjunction (NDJ) (trisomy 21 zygote) and subsequently lost one because of mitotic (somatic) error, the lost chromosome 21 being that with the lowest-intensity polymorphic allele. The parental origin and the meiotic stage of NDJ could also be determined. In class II, a "third allele" was never detected. In these cases, the mosaicism probably occurred either by a postzygotic, mitotic error in a normal zygote that followed a normal meiosis (class IIA mechanism); by premeiotic, mitotic NDJ yielding an aneusomic zygote after meiosis, and subsequent mitotic loss (class IIB mechanism); or by a meiosis II error with lack of crossover in the preceding meiosis I, followed by mitotic loss after fertilization (class IIC mechanism). Among class II mechanisms, the most likely is mechanism IIA, while IIC is the least likely. There were 10 cases of class I and 7 cases of class II results.(ABSTRACT TRUNCATED AT 250 WORDS)

We report the isolation and characterization of a polymorphic pentanucleotide repeat (TAAAA)n, which was mapped to human chromosomes X and Y (loci DXYS156X and DXYS156Y) by PCR amplification of DNA from a monochromosomal somatic cell hybrid panel (NIGMS panel 2). The (TAAAA)n repeat of loci DXYS156 occurs within a human LINE element at a position where the consensus sequence contains a single TAAAA motif. In 72 unrelated CEPH individuals seven alleles were detected which ranged in size from 125 to 165 bp in 5 bp intervals. The two largest alleles (160 and 165 bp) were observed only in males, which suggests that they were amplified from the Y chromosome DXYS156Y locus. The other 5 alleles were present in two copies in females and in a single copy in males, which suggests that they were amplified from the X chromosome DXYS156X locus. Locus DXYS156X was polymorphic in CEPH families with an observed heterozygosity in females of 46% (27 of 59). Linkage analysis with DNA markers on the X chromosome revealed significant lod scores for a location of DXYS156X close to markers DXS1002 (theta = 0.000; zeta = 8.43), DXYS1X (theta = 0.015; zeta = 17.3), DXS3, and PGK1 in the region of chromosome Xq13. The sequence of DXYS156Y derived from the 165 bp allele has been deposited in Genbank with accession number X71600.

Uniparental disomy (UPD) involving several different chromosomes has been described in several cases of human pathologies. In order to investigate whether UPD for chromosome 21 is associated with abnormal phenotypes, we analyzed DNA polymorphisms in DNA from a family with de novo Robertsonian translocation t(21q;21q). The proband was a healthy male with 45 dup(21q) who was ascertained through his trisomy 21 offspring. No phenotypic abnormalities were noted in the physical exam, and his past medical history was unremarkable. We obtained genotypes for the proband and his parents' leukocyte DNAs from 17 highly informative short sequence repeat polymorphisms that map in the pericentromeric region and along the entire length of 21q. The order of the markers has been previously determined through the linkage and physical maps of this chromosome. For the nine informative markers there was no maternal allele contribution to the genotype of the proband; in addition, there was always reduction to homozygosity of a paternal allele. These data indicated that there was paternal uniparental isodisomy for chromosome 21 (pUPiD21). We conclude that pUPiD21 is not associated with abnormal phenotypes and that there are probably no imprinted genes on chromosome 21.