De novo variation in bipolar disorder.

Bipolar disorder (BD) is a common, highly heritable disorder that affects 1-2% of the world's population. To date, most genetic studies of BD have focused on common gene variation, and while robustly associated loci have been identified, a substantial proportion of the heritability remains missing and could be partially attributable to rare variation. In this study, we apply a de novo paradigm in BD to identify newly arisen variants that have yet to undergo natural selection and may represent highly pathogenic variants. We performed whole genome sequencing of 97 trios of Ashkenazi Jewish descent, selecting "simplex" families with no family history of BD and an early age of onset. We found a total of 6882 de novo variants (an average of 70.9 ± 12.9 S.D. variants per trio), including 107 variants within protein-coding genes. We combined our exonic variations with the results of 79 previously published BD trios, identifying 20 loss-of-function (LoF) and 77 missense damaging de novo variants in BD. These variants showed significant enrichment for constrained genes and for genes located to the postsynaptic density (PSD) (all Bonferroni corrected p < 0.05). Pathway analyses showed enrichment in several pathways, including "Phosphoinositides (PI) and their downstream targets" (Bonferroni p = 4.2 × 10-6), a pathway prominently featured in lithium's hypothesized mechanism of action. In addition, while we found overall evidence for transmission of common variant polygenic risk of BD in our full sample (pTDT p = 2.21 × 10-4), specific trios with LoF variants showed no evidence of polygenic transmission. In sum, our findings support the de novo paradigm as a contributor to the genetic architecture of BD and provide evidence that constrained genes, as well as genes within the PSD and PI pathway harbor rare variation associated with BD.

Improving the understanding of the link between cognition and functional capacity in schizophrenia and bipolar disorder.

OBJECTIVE: Deficits in cognitive functioning are related to functional disability in people with serious mental illness. Measures of functional capacity are commonly used as a proxy for functional disabilities for cognitive remediation programs, and robust linear relationships between functional capacity and cognitive deficits are frequently observed. This study aimed to determine whether a curvilinear relationship better approximates the association between cognitive functioning and functional capacity. METHOD: Two independent samples were studied. Study 1: participants with schizophrenia (n=435) and bipolar disorder (n=390) aged 18-83 completed a neuropsychological battery and a performance-based measure of functional capacity. Study 2: 205 participants with schizophrenia (age range=39-72) completed a brief neuropsychological screening battery and a performance-based measure of functional capacity. For both studies, linear and quadratic curve estimations were conducted with cognitive performance predicting functional capacity scores. RESULTS: Significant linear and quadratic trends were observed for both studies. Study 1: in both the schizophrenia and bipolar participants, when cognitive composite z-scores were >0 (indicating normal to above normal performance), cognition was not related to functional capacity. Study 2: when neuropsychological screening battery z-scores were >-1 (indicating low average to average performance), cognition was not related to functional capacity. CONCLUSIONS: These results illustrate that in cognitively normal adults with serious mental illness, the relationship between cognitive function and functional capacity is relatively weak. These findings may aid clinicians and researchers determine who may optimally benefit from cognitive remediation programs, with greater benefits possibly being achieved for individuals with cognitive deficits relative to individuals with normal cognition.

Genome-wide association study of schizophrenia in Ashkenazi Jews.

Schizophrenia is a common, clinically heterogeneous disorder associated with lifelong morbidity and early mortality. Several genetic variants associated with schizophrenia have been identified, but the majority of the heritability remains unknown. In this study, we report on a case-control sample of Ashkenazi Jews (AJ), a founder population that may provide additional insights into genetic etiology of schizophrenia. We performed a genome-wide association analysis (GWAS) of 592 cases and 505 controls of AJ ancestry ascertained in the US. Subsequently, we performed a meta-analysis with an Israeli AJ sample of 913 cases and 1640 controls, followed by a meta-analysis and polygenic risk scoring using summary results from Psychiatric GWAS Consortium 2 schizophrenia study. The U.S. AJ sample showed strong evidence of polygenic inheritance (pseudo-R(2) ∼9.7%) and a SNP-heritability estimate of 0.39 (P = 0.00046). We found no genome-wide significant associations in the U.S. sample or in the combined US/Israeli AJ meta-analysis of 1505 cases and 2145 controls. The strongest AJ specific associations (P-values in 10(-6) -10(-7) range) were in the 22q 11.2 deletion region and included the genes TBX1, GLN1, and COMT. Supportive evidence (meta P < 1 × 10(-4) ) was also found for several previously identified genome-wide significant findings, including the HLA region, CNTN4, IMMP2L, and GRIN2A. The meta-analysis of the U.S. sample with the PGC2 results provided initial genome-wide significant evidence for six new loci. Among the novel potential susceptibility genes is PEPD, a gene involved in proline metabolism, which is associated with a Mendelian disorder characterized by developmental delay and cognitive deficits.

Infection and inflammation in schizophrenia and bipolar disorder: a genome wide study for interactions with genetic variation.

Inflammation and maternal or fetal infections have been suggested as risk factors for schizophrenia (SZ) and bipolar disorder (BP). It is likely that such environmental effects are contingent on genetic background. Here, in a genome-wide approach, we test the hypothesis that such exposures increase the risk for SZ and BP and that the increase is dependent on genetic variants. We use genome-wide genotype data, plasma IgG antibody measurements against Toxoplasma gondii, Herpes simplex virus type 1, Cytomegalovirus, Human Herpes Virus 6 and the food antigen gliadin as well as measurements of C-reactive protein (CRP), a peripheral marker of inflammation. The subjects are SZ cases, BP cases, parents of cases and screened controls. We look for higher levels of our immunity/infection variables and interactions between them and common genetic variation genome-wide. We find many of the antibody measurements higher in both disorders. While individual tests do not withstand correction for multiple comparisons, the number of nominally significant tests and the comparisons showing the expected direction are in significant excess (permutation p=0.019 and 0.004 respectively). We also find CRP levels highly elevated in SZ, BP and the mothers of BP cases, in agreement with existing literature, but possibly confounded by our inability to correct for smoking or body mass index. In our genome-wide interaction analysis no signal reached genome-wide significance, yet many plausible candidate genes emerged. In a hypothesis driven test, we found multiple interactions among SZ-associated SNPs in the HLA region on chromosome 6 and replicated an interaction between CMV infection and genotypes near the CTNNA3 gene reported by a recent GWAS. Our results support that inflammatory processes and infection may modify the risk for psychosis and suggest that the genotype at SZ-associated HLA loci modifies the effect of these variables on the risk to develop SZ.

Functional variants in DPYSL2 sequence increase risk of schizophrenia and suggest a link to mTOR signaling.

Numerous linkage and association studies by our group and others have implicated DPYSL2 at 8p21.2 in schizophrenia. Here we explore DPYSL2 for functional variation that underlies these associations. We sequenced all 14 exons of DPYSL2 as well as 27 conserved noncoding regions at the locus in 137 cases and 151 controls. We identified 120 variants, eight of which we genotyped in an additional 729 cases and 1542 controls. Several were significantly associated with schizophrenia, including a three single-nucleotide polymorphism (SNP) haplotype in the proximal promoter, two SNPs in intron 1, and a polymorphic dinucleotide repeat in the 5'-untranslated region that alters sequences predicted to be involved in translational regulation by mammalian target of rapamycin signaling. The 3-SNP promoter haplotype and the sequence surrounding one of the intron 1 SNPs direct tissue-specific expression in the nervous systems of Zebrafish in a pattern consistent with the two endogenous dpysl2 paralogs. In addition, two SNP haplotypes over the coding exons and 3' end of DPYSL2 showed association with opposing sex-specific risks. These data suggest that these polymorphic, schizophrenia-associated sequences function as regulatory elements for DPYSL2 expression. In transient transfection assays, the high risk allele of the polymorphic dinucleotide repeat diminished reporter expression by 3- to 4-fold. Both the high- and low-risk alleles respond to allosteric mTOR inhibition by rapamycin until, at high drug levels, allelic differences are eliminated. Our results suggest that reduced transcription and mTOR-regulated translation of certain DPYSL2 isoforms increase the risk for schizophrenia.

Association of obesity and treated hypertension and diabetes with cognitive ability in bipolar disorder and schizophrenia.

OBJECTIVES: People with bipolar disorder or schizophrenia are at greater risk for obesity and other cardio-metabolic risk factors, and several prior studies have linked these risk factors to poorer cognitive ability. In a large ethnically homogenous outpatient sample, we examined associations among variables related to obesity, treated hypertension and/or diabetes and cognitive abilities in these two patient populations. METHODS: In a study cohort of outpatients with either bipolar disorder (n = 341) or schizophrenia (n = 417), we investigated the association of self-reported body mass index and current use of medications for hypertension or diabetes with performance on a comprehensive neurocognitive battery. We examined sociodemographic and clinical factors as potential covariates. RESULTS: Patients with bipolar disorder were less likely to be overweight or obese than patients with schizophrenia, and also less likely to be prescribed medication for hypertension or diabetes. However, obesity and treated hypertension were associated with worse global cognitive ability in bipolar disorder (as well as with poorer performance on individual tests of processing speed, reasoning/problem-solving, and sustained attention), with no such relationships observed in schizophrenia. Obesity was not associated with symptom severity in either group. CONCLUSIONS: Although less prevalent in bipolar disorder compared to schizophrenia, obesity was associated with substantially worse cognitive performance in bipolar disorder. This association was independent of symptom severity and not present in schizophrenia. Better understanding of the mechanisms and management of obesity may aid in efforts to preserve cognitive health in bipolar disorder.

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.

Determinants of occupational and residential functioning in bipolar disorder.

BACKGROUND: Bipolar disorder is associated with reduced rates of employment and residential independence. The influence of cognitive impairment and affective symptoms on these functional attainments has received little previous attention and is the focus of this study. METHOD: A total of 229 adult outpatients with bipolar disorder without active substance use disorders and with an average of mild severity of affective symptoms were included in the analyses. After adjusting for sociodemographic and illness history covariates, univariate and multivariate analyses were used to evaluate the independent and interactive associations of neurocognitive ability, performance-based functional capacity, and affective symptom severity with residential independence, occupational status and number of hours worked. RESULTS: A total of 30% of the sample was unemployed and 18% was not independently residing. Neurocognitive ability was the strongest predictor of any employment, but depressive symptom severity was the only variable significantly related to hours worked. The strongest predictor of residential independence was performance-based functional capacity. Affective symptoms and neurocognitive ability were independent (non-interactive) predictors of occupational and residential status. LIMITATIONS: This is a cross-sectional study and thus causal direction among variables is unknown. The sample was ethnically homogeneous and thus the results may not generalize to ethnically diverse samples. CONCLUSIONS: This study confirmed elevated rates of unemployment and residential non-independence in adults with bipolar disorder. Interventions targeting cognitive deficits and functional capacity may increase the likelihood of any employment or residential independence, respectively. Interventions targeting depressive symptoms may be most influential on work outcomes among those already employed.

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.

Replication of an association of a common variant in the Reelin gene (RELN) with schizophrenia in Ashkenazi Jewish women.

A single nucleotide polymorphism (rs7341475) in RELN has recently been shown to be associated with schizophrenia (SZ) in an Ashkenazi Jewish (AJ) case--control study specifically in women by Shifman et al. We have replicated this association in women in another large independent Ashkenazi Jewish collection (721 cases, 259 female; 1455 controls, 834 female) and confirmed that it applies to both SZ and schizoaffective disorder. Furthermore, we explore the effects of this polymorphism through quantitative trait loci analysis of nine SZ related factors providing information on sex-specific genotype--phenotype correlations.

Prediction of real-world functional disability in chronic mental disorders: a comparison of schizophrenia and bipolar disorder.

OBJECTIVE: Schizophrenia and bipolar disorder are associated with multidimensional disability. This study examined differential predictors of functional deficits in the two disorders. METHOD: Community-dwelling individuals with schizophrenia (N=161) or bipolar disorder (N=130) were assessed with neuropsychological tests, symptom measures, and performance-based social and adaptive (i.e., everyday living skills) functional competence measures as well as three domains of real-world functioning: community and household activities; work skills; and interpersonal relationships. The authors used confirmatory path analysis to find the best-fitting models to examine the direct and indirect (as mediated by competence) prediction of the three domains of real-world functioning. RESULTS: In all models for both groups, neurocognition's relationship with outcomes was largely mediated by competence. Symptoms were negatively associated with outcomes but unassociated with competence, with the exception of depression, which was a direct and mediated (through social competence) predictor in bipolar disorder. In both groups, neurocognition was related to activities directly and through a mediated relationship with adaptive competence. Work skills were directly and indirectly (through mediation with social competence) predicted by neurocognition in schizophrenia and entirely mediated by adaptive and social competence in bipolar disorder. Neurocognition was associated with interpersonal relationships directly in the schizophrenia group and mediated by social competence in both groups. CONCLUSIONS: Although there was greater disability in schizophrenia, neurocognition predicted worse functioning in all outcome domains in both disorders. These results support the shared role of neurocognition in bipolar disorder and schizophrenia in producing disability, with predictive differences between disorders in domain-specific effects of symptoms and social and adaptive competence.

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.

Fine mapping on chromosome 10q22-q23 implicates Neuregulin 3 in schizophrenia.

Linkage studies have implicated 10q22-q23 as a schizophrenia (SZ) susceptibility locus in Ashkenazi Jewish (AJ) and Han Chinese from Taiwan populations. To further explore our previous linkage signal in the AJ population (NPL score: 4.27, empirical p = 2 x 10(-5)), we performed a peakwide association fine mapping study by using 1414 SNPs across approximately 12.5 Mb in 10q22-q23. We genotyped 1515 AJ individuals, including 285 parent-child trios, 173 unrelated cases, and 487 unrelated controls. We analyzed the binary diagnostic phenotype of SZ and 9 heritable quantitative traits derived from a principal components factor analysis of 73 items from our consensus diagnostic ratings and direct assessment interviews. Although no marker withstood multiple test correction for association with the binary SZ phenotype, we found strong evidence of association by using the "delusion" factor as the quantitative trait at three SNPs (rs10883866, rs10748842, and rs6584400) located in a 13 kb interval in intron 1 of Neuregulin 3 (NRG3). Our best p value from family-based association analysis was 7.26 x 10(-7). We replicated this association in the collection of 173 unrelated AJ cases (p = 1.55 x 10(-2)), with a combined p value of 2.30 x 10(-7). After performing 10,000 permutations of each of the phenotypes, we estimated the empirical study-wide significance across all 9 factors (90,000 permutations) to be p = 2.7 x 10(-3). NRG3 is primarily expressed in the central nervous system and is one of three paralogs of NRG1, a gene strongly implicated in SZ. These biological properties together with our linkage and association results strongly support NRG3 as a gene involved in SZ.

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.