Reciprocal duplication of the Williams-Beuren syndrome deletion on chromosome 7q11.23 is associated with schizophrenia.

BACKGROUND: Several copy number variants (CNVs) have been implicated as susceptibility factors for schizophrenia (SZ). Some of these same CNVs also increase risk for autism spectrum disorders, suggesting an etiologic overlap between these conditions. Recently, de novo duplications of a region on chromosome 7q11.23 were associated with autism spectrum disorders. The reciprocal deletion of this region causes Williams-Beuren syndrome. METHODS: We assayed an Ashkenazi Jewish cohort of 554 SZ cases and 1014 controls for genome-wide CNV. An excess of large rare and de novo CNVs were observed, including a 1.4 Mb duplication on chromosome 7q11.23 identified in two unrelated patients. To test whether this 7q11.23 duplication is also associated with SZ, we obtained data for 14,387 SZ cases and 28,139 controls from seven additional studies with high-resolution genome-wide CNV detection. We performed a meta-analysis, correcting for study population of origin, to assess whether the duplication is associated with SZ. RESULTS: We found duplications at 7q11.23 in 11 of 14,387 SZ cases with only 1 in 28,139 control subjects (unadjusted odds ratio 21.52, 95% confidence interval: 3.13-922.6, p value 5.5 × 10(-5); adjusted odds ratio 10.8, 95% confidence interval: 1.46-79.62, p value .007). Of three SZ duplication carriers with detailed retrospective data, all showed social anxiety and language delay premorbid to SZ onset, consistent with both human studies and animal models of the 7q11.23 duplication. CONCLUSIONS: We have identified a new CNV associated with SZ. Reciprocal duplication of the Williams-Beuren syndrome deletion at chromosome 7q11.23 confers an approximately tenfold increase in risk for SZ.

Sensitivity and specificity of the UCSD Performance-based Skills Assessment (UPSA-B) for identifying functional milestones in schizophrenia.

Schizophrenia is a highly debilitating illness that often results in disruption to independent living and employment. However, "gold standard" methods of assessing functional abilities to achieve these milestones are still lacking. In a sample of 367 individuals with schizophrenia, we examined the sensitivity and specificity of the Brief UCSD Performance-based Skills Assessment (UPSA-B) to predict both residential and employment status. Of all individuals residing independently, 75.9% scored 78 or above on the UPSA-B, and of all individuals not residing independently, 59% scored below 78 on the UPSA-B. Of individuals who were employed, 73.9% scored above 82 on the UPSA-B, and of those not employed, 57.8% scored below 82. These results expand upon both the population base and functional milestones with which the UPSA-B is validated, although future work should examine whether the UPSA-B can be used as a decision aid in the likelihood of success in a longitudinal study, such as at critical transitions (post-hospitalization, cessation of supported housing).

Linkage analysis of plasma dopamine ß-hydroxylase activity in families of patients with schizophrenia.

Dopamine ß-hydroxylase (DßH) catalyzes the conversion of dopamine to norepinephrine. DßH enters the plasma after vesicular release from sympathetic neurons and the adrenal medulla. Plasma DßH activity (pDßH) varies widely among individuals, and genetic inheritance regulates that variation. Linkage studies suggested strong linkage of pDßH to ABO on 9q34, and positive evidence for linkage to the complement fixation locus on 19p13.2-13.3. Subsequent association studies strongly supported DBH, which maps adjacent to ABO, as the locus regulating a large proportion of the heritable variation in pDßH. Prior studies have suggested that variation in pDßH, or genetic variants at DßH, associate with differences in expression of psychotic symptoms in patients with schizophrenia and other idiopathic or drug-induced brain disorders, suggesting that DBH might be a genetic modifier of psychotic symptoms. As a first step toward investigating that hypothesis, we performed linkage analysis on pDßH in patients with schizophrenia and their relatives. The results strongly confirm linkage of markers at DBH to pDßH under several models (maximum multipoint LOD score, 6.33), but find no evidence to support linkage anywhere on chromosome 19. Accounting for the contributions to the linkage signal of three SNPs at DBH, rs1611115, rs1611122, and rs6271 reduced but did not eliminate the linkage peak, whereas accounting for all SNPs near DBH eliminated the signal entirely. Analysis of markers genome-wide uncovered positive evidence for linkage between markers at chromosome 20p12 (multi-point LOD = 3.1 at 27.2 cM). The present results provide the first direct evidence for linkage between DBH and pDßH, suggest that rs1611115, rs1611122, rs6271 and additional unidentified variants at or near DBH contribute to the genetic regulation of pDßH, and suggest that a locus near 20p12 also influences pDßH.

Linkage and association on 8p21.2-p21.1 in schizophrenia.

In the past decade, we and others have consistently reported linkage to a schizophrenia (SZ) susceptibility region on chromosome 8p21. Most recently, in the largest SZ linkage sample to date, a multi-site international collaboration performed a SNP-based linkage scan (~6,000 SNPs; 831 pedigrees; 121 from Johns Hopkins (JHU)), that showed the strongest evidence for linkage in a 1 Mb region of chr 8p21 from rs1561817 to rs9797 (Z(max) = 3.22, P = 0.0004) [Holmans et al. 2009. Mol Psychiatry]. We have investigated this 8p21 peak region further in two ways: first by linkage and family-based association in 106 8p-linked European-Caucasian (EUC) JHU pedigrees using 1,402 SNPs across a 4.4 Mb region surrounding the peak; second, by an independent case-control association study in the genetically more homogeneous Ashkenazim (AJ) (709 cases, 1,547 controls) using 970 SNPs in a further narrowed 2.8 Mb region. Family-based association analyses in EUC pedigrees and case-control analyses in AJ samples reveal significant associations for SNPs in and around DPYSL2 and ADRA1A, candidate genes previously associated with SZ in our work and others. Further, several independent gene expression studies have shown that DPYSL2 is differentially expressed in SZ brains [Beasley et al. 2006. Proteomics 6(11):3414­3425; Edgar et al. 2000. Mol Psychiatry 5(1):85­90; Johnston-Wilson et al. 2000. Mol Psychiatry 5(2):142­149] or in response to psychosis-inducing pharmaceuticals [Iwazaki et al. 2007. Proteomics 7(7):1131­1139; Paulson et al. 2004. Proteomics 4(3):819­825]. Taken together, this work further supports DPYSL2 and the surrounding genomic region as a susceptibility locus for SZ.

Social competence and observer-rated social functioning in bipolar disorder.

OBJECTIVE: Impairment in social functioning appears to be common in bipolar disorder, although estimates have been derived largely from self-report measures. We examined performance-based and observer-based ratings of social competence and functioning and assessed the contribution of symptoms and neurocognitive ability to social functioning in bipolar disorder. METHODS: In this cross-sectional study, 164 subjects with bipolar disorder were administered the performance-based Social Skills Performance Assessment (SSPA), rated by an informant on the Specific Level of Functioning (SLOF)-Interpersonal subscale, received clinical ratings of depression and manic symptoms, and performed neurocognitive tests. We assessed the proportion of patients exhibiting social deficits and examined the associations between composite measures of neurocognitive ability, depression and manic symptoms, and SSPA scores with informant-rated, real-world social functioning. RESULTS: Mean age of the sample was 47.6 years (SD = 14.1). Subjects were experiencing, on average, mild levels of depression and minimal manic symptoms. A total of 29% exhibited norm-referenced impairment on the SSPA, and 64% registered at least one impairment on SLOF items; unemployed subjects had lower SSPA and SLOF ratings. Neurocognitive performance correlated with both performance-based and observer-rated social functioning, whereas depressive and manic symptoms correlated only with observer-rated social impairments. In multivariate models, depression was the most potent association with social functioning, and impairment in social competence (i.e., capacity) increased the strength of the relationships between depression and neurocognitive impairment and social functioning (i.e., real-world functioning). CONCLUSIONS: Our study confirmed the negative relationship of bipolar depression with social functioning. A subgroup of outpatients with bipolar disorder has impaired social competence, which, when present, worsened the impact of depression and cognitive impairment on social functioning.

Microdeletions of 3q29 confer high risk for schizophrenia.

Schizophrenia (SZ) is a severe psychiatric illness that affects approximately 1% of the population and has a strong genetic underpinning. Recently, genome-wide analysis of copy-number variation (CNV) has implicated rare and de novo events as important in SZ. Here, we report a genome-wide analysis of 245 SZ cases and 490 controls, all of Ashkenazi Jewish descent. Because many studies have found an excess burden of large, rare deletions in cases, we limited our analysis to deletions over 500 kb in size. We observed seven large, rare deletions in cases, with 57% of these being de novo. We focused on one 836 kb de novo deletion at chromosome 3q29 that falls within a 1.3-1.6 Mb deletion previously identified in children with intellectual disability (ID) and autism, because increasing evidence suggests an overlap of specific rare copy-number variants (CNVs) between autism and SZ. By combining our data with prior CNV studies of SZ and analysis of the data of the Genetic Association Information Network (GAIN), we identified six 3q29 deletions among 7545 schizophrenic subjects and one among 39,748 controls, resulting in a statistically significant association with SZ (p = 0.02) and an odds ratio estimate of 17 (95% confidence interval: 1.36-1198.4). Moreover, this 3q29 deletion region contains two linkage peaks from prior SZ family studies, and the minimal deletion interval implicates 20 annotated genes, including PAK2 and DLG1, both paralogous to X-linked ID genes and now strong candidates for SZ susceptibility.

Detection of SNP-SNP interactions in trios of parents with schizophrenic children.

Schizophrenia (SZ) is a heritable and complex psychiatric disorder with an estimated worldwide prevalence of about 1%. Research on the risk factors for SZ has thus far yielded few clues to causes, but has pointed to a heterogeneous etiology that likely involves multiple genes and gene-environment interactions. In this manuscript, we apply a novel method (trio logic regression, Li et al., 2009) to case-parent trio data from a SZ candidate gene study conducted on families of Ashkenazi Jewish descent, and demonstrate the method's ability to detect multi-gene models for SZ risk in the family-based design. In particular, we demonstrate how this method revealed a genotype-phenotype association that includes an allele without marginal effect.

Relationship of the Brief UCSD Performance-based Skills Assessment (UPSA-B) to multiple indicators of functioning in people with schizophrenia and bipolar disorder.

OBJECTIVE: This study assessed the relationship between multiple indicators of 'real-world' functioning and scores on a brief performance-based measure of functional capacity known as the Brief University of California San Diego (UCSD) Performance-based Skills Assessment (UPSA-B) in a sample of 205 patients with either serious bipolar disorder (n = 89) or schizophrenia (n = 116). METHODS: Participants were administered the UPSA-B and assessed on the following functional domains: (i) independent living status (e.g., residing independently as head of household, living in residential care facility); (ii) informant reports of functioning (e.g., work skills, daily living skills); (iii) educational attainment and estimated premorbid IQ as measured by years of education and Wide Range Achievement Test reading scores, respectively; and (iv) employment. RESULTS: Better scores on the UPSA-B were associated with greater residential independence after controlling for age, diagnosis, and symptoms of psychopathology. Among both bipolar disorder and schizophrenia patients, higher UPSA-B scores were significantly related to better informant reports of functioning in daily living skills and work skills domains. Greater estimated premorbid IQ was associated with higher scores on the UPSA-B for both schizophrenia and bipolar disorder participants. Participants who were employed scored higher on the UPSA-B when controlling for age and diagnosis, but not when controlling for symptoms of psychopathology. CONCLUSIONS: These data suggest the UPSA-B may be useful for assessing capacity for functioning in a number of domains in both people diagnosed with schizophrenia and bipolar disorder.

Familiality of novel factorial dimensions of schizophrenia.

CONTEXT: Factor analysis of the signs and symptoms of schizophrenia yields dimensional phenotypes that may relate to underlying genetic variation. Examination of familiality of factor scores can demonstrate whether they are likely to be of use in genetic research. OBJECTIVE: To produce a broader set of factorial phenotypes that are tested for familiality including core symptoms of schizophrenia and additional indicators of social, work, and educational dysfunction. DESIGN: The study used psychiatric assessment data collected from several large samples of individuals with schizophrenia who have participated in family or case-control genetic studies (1988-2006) in the Epidemiology-Genetics Program in Psychiatry, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Seventy-three signs and symptoms were selected from direct assessment interviews and consensus diagnostic ratings (integrating interview data, medical records, and informant reports). SETTING: Study participants were recruited from across the United States, and a few additional participants were recruited from Canada, Greece, Italy, Poland, and Israel. Assessments generally were performed in the individuals' homes. PARTICIPANTS: Forty-three percent of 1199 volunteers had largely white European backgrounds. The remaining individuals were recruited for family and case-control studies with focus on Ashkenazi Jews. All individuals had a consensus diagnosis of schizophrenia (including schizoaffective disorder) using DSM-III or DSM-IV criteria. MAIN OUTCOME MEASURES: The 73 indicators were subjected to principal components factor analysis, and factor scores representing 9 dimensions were analyzed for familiality. RESULTS: The 9 factors include the often-reported delusions, hallucinations, disorganization, negative, and affective factors; novel factors included child/adolescent sociability, scholastic performance, disability/impairment, and prodromal factors. All 9 factors demonstrated significant familiality (measured by a heritability statistic), with the highest scores for disability/impairment (0.61), disorganization (0.60), and scholastic performance (0.51). CONCLUSIONS: The factor scores show varying degrees of familiality and may prove useful as quantitative traits and covariates in linkage and association studies.

Stage II follow-up on a linkage scan for bipolar disorder in the Ashkenazim provides suggestive evidence for chromosome 12p and the GRIN2B gene.

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.

Bipolar I disorder and schizophrenia: a 440-single-nucleotide polymorphism screen of 64 candidate genes among Ashkenazi Jewish case-parent trios.

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.

Genomewide linkage scan for bipolar-disorder susceptibility loci among Ashkenazi Jewish families.

The relatively short history of linkage studies in bipolar disorders (BPs) has produced inconsistent findings. Implicated regions have been large, with reduced levels of significance and modest effect sizes. Both phenotypic and genetic heterogeneity may have contributed to the failure to define risk loci. BP is part of a spectrum of apparently familial affective disorders, which have been organized by severity. Heterogeneity may arise because of insufficient data to define the spectrum boundaries, and, in general, the less-severe disorders are more difficult to diagnose reliably. To address the inherent complexities in detecting BP susceptibility loci, we have used restricted diagnostic classifications and a genetically more homogeneous (Ashkenazi Jewish) family collection to perform a 9-cM autosomal genomewide linkage scan. Although they are genetically more homogeneous, there are no data to suggest that the rate of illness in the Ashkenazim differs from that in other populations. In a genome scan of 41 Ashkenazi pedigrees with a proband affected with bipolar I disorder (BPI) and at least one other member affected with BPI or bipolar II disorder (BPII), we identified four regions suggestive of linkage on chromosomes 1, 3, 11, and 18. Follow-up genotyping showed that the regions on chromosomes 1, 3, and 18 are also suggestive of linkage in a subset of pedigrees limited to relative pairs affected with BPI. Furthermore, our chromosome 18q22 signal (D18S541 and D18S477) overlaps with previous BP findings. This research is being conducted in parallel with our companion study of schizophrenia, in which, by use of an identical approach, we recently reported significant evidence for a schizophrenia susceptibility locus in the Ashkenazim on chromosome 10q22.

An indirect test of the new mutation hypothesis associating advanced paternal age with the etiology of schizophrenia.

Two studies by Malaspina et al. [2001: Arch Gen Psychiatr 58:361-367]; [2002: Am J Med Genet 114:299-303] have put forward the hypothesis that advanced paternal age with concomitant mutations in the male germ line is associated with sporadic schizophrenia in offspring. The hypothesis was supported by an observation of a monotonic increase in the risk for schizophrenia with increased paternal age, and a second observation in a separate sample of greater paternal mean age at birth among cases of apparent sporadic schizophrenia. The present study did not test the association of the risk of schizophrenia with advanced paternal age, but repeated the test of paternal age at birth among sporadic versus familial schizophrenic probands. We also examined the risk of schizophrenia, psychosis, and broad psychosis among paternal 1st and 2nd degree relatives of schizophrenic probands as a function of paternal age at birth of the proband, reasoning that if probands born to older fathers are more likely to be sporadic cases, the risk of schizophrenia (or psychosis) should be lower on the paternal side of the family. Results indicate a lack of support for the previous finding that sporadic probands tend to have older fathers at birth than familial probands. Results also failed to support the related hypothesis that increased paternal age is associated with the lower risk of schizophrenia (or psychosis) in the relatives of schizophrenic probands. The failure to support the paternal age hypothesis may be a function of heterogeneous samples, but calls for further research in the context of family studies.

Five latent factors underlying schizophrenia: analysis and relationship to illnesses in relatives.

Clinical signs and symptoms in a sample of 1,043 individuals with schizophrenia or schizoaffective disorder were subjected to latent class factor analysis. Positive, negative, disorganized, and affective factors were similar in content to factors described in a number of other studies, while a fifth factor representing early onset/developmental signs provided a new area for investigation. The five sets of factor scores were logistically regressed on psychiatric illness indicators in first and second degree relatives. Relatives of probands with higher positive or negative symptom factor scores had a lower risk of depressive illness. Higher affective factor scores in probands predicted more mania and depression in relatives. Both the disorganized and the early onset/developmental factors were related to increased risk of psychiatric hospitalization in relatives, as well as increased risk of psychosis (marginally so for the disorganization factor). Increased early onset/developmental signs in the proband were also associated with increased risk for depression in relatives. These findings suggest a possible endophenotypic role for the factor scores in future studies.

Genomewide linkage scan for schizophrenia susceptibility loci among Ashkenazi Jewish families shows evidence of linkage on chromosome 10q22.

Previous linkage studies in schizophrenia have been discouraging due to inconsistent findings and weak signals. Genetic heterogeneity has been cited as one of the primary culprits for such inconsistencies. We have performed a 10-cM autosomal genomewide linkage scan for schizophrenia susceptibility regions, using 29 multiplex families of Ashkenazi Jewish descent. Although there is no evidence that the rate of schizophrenia among the Ashkenazim differs from that in other populations, we have focused on this population in hopes of reducing genetic heterogeneity among families and increasing the detectable effects of any particular locus. We pursued both allele-sharing and parametric linkage analyses as implemented in Genehunter, version 2.0. Our strongest signal was achieved at chromosome 10q22.3 (D10S1686), with a nonparametric linkage score (NPL) of 3.35 (genomewide empirical P=.035) and a dominant heterogeneity LOD score (HLOD) of 3.14. Six other regions gave NPL scores >2.00 (on chromosomes 1p32.2, 4q34.3, 6p21.31, 7p15.2, 15q11.2, and 21q21.2). Upon follow-up with an additional 23 markers in the chromosome 10q region, our peak NPL score increased to 4.27 (D10S1774; empirical P=.00002), with a 95% confidence interval of 12.2 Mb for the location of the trait locus (D10S1677 to D10S1753). We find these results encouraging for the study of schizophrenia among Ashkenazi families and suggest further linkage and association studies in this chromosome 10q region.