Rare coding variants in ten genes confer substantial risk for schizophrenia.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analysing the whole exomes of 24,248 schizophrenia cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in 10 genes as conferring substantial risk for schizophrenia (odds ratios of 3-50, P < 2.14 × 10-6) and 32 genes at a false discovery rate of <5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure and function of the synapse. The associations of the NMDA (N-methyl-D-aspartate) receptor subunit GRIN2A and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor subunit GRIA3 provide support for dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk among schizophrenia, autism spectrum disorders1, epilepsy and severe neurodevelopmental disorders2, although different mutation types are implicated in some shared genes. Most genes described here, however, are not implicated in neurodevelopment. We demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors converge at least partially on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, which indicates that more risk genes await discovery using this approach.

Genetic substrates of bipolar disorder risk in Latino families.

Genetic studies of bipolar disorder (BP) have been conducted in the Latin American population, to date, in several countries, including Mexico, the United States, Costa Rica, Colombia, and, to a lesser extent, Brazil. These studies focused primarily on linkage-based designs utilizing families with multiplex cases of BP. Significant BP loci were identified on Chromosomes 18, 5 and 8, and fine mapping suggested several genes of interest underlying these linkage peaks. More recently, studies in these same pedigrees yielded significant linkage loci for BP endophenotypes, including measures of activity, sleep cycles, and personality traits. Building from findings in other populations, candidate gene association analyses in Latinos from Mexican and Central American ancestry confirmed the role of several genes (including CACNA1C and ANK3) in conferring BP risk. Although GWAS, methylation, and deep sequencing studies have only begun in these populations, there is evidence that CNVs and rare SNPs both play a role in BP risk of these populations. Large segments of the Latino populations in the Americas remain largely unstudied regarding BP genetics, but evidence to date has shown that this type of research can be successfully conducted in these populations and that the genetic underpinnings of BP in these cohorts share at least some characteristics with risk genes identified in European and other populations.

Contributions of common genetic variants to risk of schizophrenia among individuals of African and Latino ancestry.

Schizophrenia is a common, chronic and debilitating neuropsychiatric syndrome affecting tens of millions of individuals worldwide. While rare genetic variants play a role in the etiology of schizophrenia, most of the currently explained liability is within common variation, suggesting that variation predating the human diaspora out of Africa harbors a large fraction of the common variant attributable heritability. However, common variant association studies in schizophrenia have concentrated mainly on cohorts of European descent. We describe genome-wide association studies of 6152 cases and 3918 controls of admixed African ancestry, and of 1234 cases and 3090 controls of Latino ancestry, representing the largest such study in these populations to date. Combining results from the samples with African ancestry with summary statistics from the Psychiatric Genomics Consortium (PGC) study of schizophrenia yielded seven newly genome-wide significant loci, and we identified an additional eight loci by incorporating the results from samples with Latino ancestry. Leveraging population differences in patterns of linkage disequilibrium, we achieve improved fine-mapping resolution at 22 previously reported and 4 newly significant loci. Polygenic risk score profiling revealed improved prediction based on trans-ancestry meta-analysis results for admixed African (Nagelkerke's R2 = 0.032; liability R2 = 0.017; P < 10-52), Latino (Nagelkerke's R2 = 0.089; liability R2 = 0.021; P < 10-58), and European individuals (Nagelkerke's R2 = 0.089; liability R2 = 0.037; P < 10-113), further highlighting the advantages of incorporating data from diverse human populations.

EXPLORATORY ANALYSIS OF POLYGENIC RISK SCORES FOR PSYCHIATRIC DISORDERS: APPLIED TO DUAL DIAGNOSIS.

BACKGROUND: Concurrence of substance use disorders (SUDs) is high in individuals with psychiatric illnesses; more importantly, individuals with both disorders (dual diagnosis) have more severe symptoms. Psychiatric disorders have been proposed to share a genetic susceptibility with SUDs. To explore this shared genetic susceptibility, we analyzed whether any of the polygenic risk scores (PRSs) for psychiatric disorders could be associated to dual diagnosis in patients with schizophrenia (SCZ) or bipolar disorder (BD). METHODS: We included 192 individuals of Mexican ancestry: 72 with SCZ, 53 with BD, and 67 unrelated controls without psychiatric disorders. We derived calculations of PRS for autism spectrum disorders, attention-deficit/hyperactive disorder, BD, major depression, and SCZ using summary genome-wide association statistics previously published. RESULTS: We found that dual diagnosis had a shared genetic susceptibility with major depressive disorder (MDD) and SCZ; furthermore, in individuals with BD, dual diagnosis could be predicted by PRS for MDD. CONCLUSIONS: Our results reinforce the notion that individuals with dual diagnosis have a higher genetic susceptibility to develop both disorders. However, analyses of larger sample sizes are required to further clarify how to predict risks through PRS within different populations.

Fine-mapping scan of bipolar disorder susceptibility loci in Latino pedigrees.

We previously identified bipolar disorder (BD) susceptibility loci on 8q24, 14q32, and 2q12-14 in a genome-wide nonparametric linkage screen in a Latino cohort. We now perform a fine mapping analysis using a dense map of additional SNPs to identify BD susceptibility genes within these regions. One thousand nine hundred and thirty-eight individuals with Latino ancestry (880 individuals with BD Type I or Schizoaffective, Bipolar Type) from 416 Latino pedigrees from the United States, Mexico, Costa Rica, and Guatemala were genotyped with 3,074 SNPs to provide dense coverage of the 8q24 (11.5 cM), 14q32 (7.5 cM), and 2q12-14 (6.5 cM) chromosomal loci. Single-marker association tests in the presence of linkage were performed using the LAMP software. The top linkage peak (rs7834818; LOD = 5.08, p = 3.30E - 5) and associated single marker (rs2280915, p = 2.70E - 12) were located within FBXO32 on 8q24. On chromosome 2, the top linkage peak (rs6750326; LOD = 5.06, p = 3.50E - 5) and associated single marker (rs11887088, p = 2.90E - 6) were located in intragenic regions near ACTR3 and DPP10. None of the additional markers in the region around chromosome 14q32 met significance levels for linkage or association. We identified six SNPs on 2q12-q14 and one SNP in FBXO32 on 8q24 that were significantly associated with BD in this Latino cohort.

A genome-wide quantitative trait locus (QTL) linkage scan of NEO personality factors in Latino families segregating bipolar disorder.

Personality traits have been suggested as potential endophenotypes for Bipolar Disorder (BP), as they can be quantitatively measured and show correlations with BP. The present study utilized data from 2,745 individuals from 686 extended pedigrees originally ascertained for having multiplex cases of BP (963 cases of BPI or schizoaffective BP). Subjects were assessed with the NEO Personality Inventory, Revised (NEO PI-R) and genotyped using the Illumina HumanLinkage-24 Bead Chip, with an average genetic coverage of 0.67 cM. Two point linkage scores were calculated for each trait as a quantitative variable using SOLAR (Sequential Oligogenic Linkage Analysis Routines). Suggestive evidence for linkage was found for neuroticism at 1q32.1 (LOD = 2.52), 6q23.3 (2.32), 16p12 (2.79), extraversion at 4p15.3 (2.33), agreeableness at 4q31.1 (2.37), 5q34 (2.80), 7q31.1 (2.56), 16q22 (2.52), and conscientiousness at 4q31.1 (2.50). Each of the above traits have been shown to be correlated with the broad BP phenotype in this same sample. In addition, for the trait of openness, we found significant evidence of linkage to chromosome 3p24.3 (rs336610, LOD = 4.75) and suggestive evidence at 1q43 (2.74), 5q35.1 (3.03), 11q14.3 (2.61), 11q21 (2.30), and 19q13.1 (2.52). These findings support previous linkage findings of the openness trait to chromosome 19q13 and the agreeableness trait to 4q31 and identify a number of new loci for personality endophenotypes related to bipolar disorder.

Replication of genome-wide association study (GWAS) susceptibility loci in a Latino bipolar disorder cohort.

OBJECTIVES: Recent genome-wide association studies (GWASs) have identified numerous putative genetic polymorphisms associated with bipolar disorder (BD) and/or schizophrenia (SC). We hypothesized that a portion of these polymorphisms would also be associated with BD in the Latino American population. To identify such regions, we tested previously identified genetic variants associated with BD and/or SC and ancestral haploblocks containing these single nucleotide polymorphisms (SNPs) in a sample of Latino subjects with BD. METHODS: A total of 2254 Latino individuals were genotyped for 91 SNPs identified in previous BD and/or SC GWASs, along with selected SNPs in strong linkage disequilibrium with these markers. Family-based single marker and haplotype association testing was performed using the PBAT software package. Empirical P-values were derived from 10 000 permutations. RESULTS: Associations of eight a priori GWAS SNPs with BD were replicated with nominal (P≤.05) levels of significance. These included SNPs within nuclear factor I A (NFIA), serologically defined colon cancer antigen 8 (SDCCAG8), lysosomal associated membrane protein 3 (LAMP3), nuclear factor kappa B subunit 1 (NFKB1), major histocompatibility complex, class I, B (HLA-B) and 5'-nucleotidase, cytosolic II (NT5C2) and SNPs within intragenic regions microRNA 6828 (MIR6828)-solute carrier family 7 member 14 (SLC7A14) and sonic hedgehog (SHH)-long intergenic non-protein coding RNA 1006 (LINC01006). Of the 76 ancestral haploblocks that were tested for associations with BD, our top associated haploblock was located in LAMP3; however, the association did not meet statistical thresholds of significance following Bonferroni correction. CONCLUSIONS: These results indicate that some of the gene variants found to be associated with BD or SC in other populations are also associated with BD risk in Latinos. Variants in six genes and two intragenic regions were associated with BD in our Latino sample and provide additional evidence for overlap in genetic risk between SC and BD.

Global signaling effects of a schizophrenia-associated missense mutation in neuregulin 1: an exploratory study using whole genome and novel kinome approaches.

Aberrant neuregulin 1-ErbB4 signaling has been implicated in schizophrenia. We previously identified a novel schizophrenia-associated missense mutation (valine to leucine) in the NRG1 transmembrane domain. This variant inhibits formation of the NRG1 intracellular domain (ICD) and causes decreases in dendrite formation. To assess the global effects of this mutation, we used lymphoblastoid cell lines from unaffected heterozygous carriers (Val/Leu) and non-carriers (Val/Val). Transcriptome data showed 367 genes differentially expressed between the two groups (Val/Val N = 6, Val/Leu N = 5, T test, FDR (1 %), α = 0.05, -log10 p value >1.5). Ingenuity pathway (IPA) analyses showed inflammation and NRG1 signaling as the top pathways altered. Within NRG1 signaling, protein kinase C (PKC)-eta (PRKCH) and non-receptor tyrosine kinase (SRC) were down-regulated in heterozygous carriers. Novel kinome profiling (serine/threonine) was performed after stimulating cells (V/V N = 6, V/L N = 6) with ErbB4, to induce release of the NRG1 ICD, and revealed significant effects of treatment on the phosphorylation of 35 peptides. IPA showed neurite outgrowth (six peptides) as the top annotated function. Phosphorylation of these peptides was significantly decreased in ErbB4-treated Val/Val but not in Val/Leu cells. These results show that perturbing NRG1 ICD formation has major effects on cell signaling, including inflammatory and neurite formation pathways, and may contribute significantly to schizophrenia pathophysiology.

NRG3 gene is associated with the risk and age at onset of Alzheimer disease.

The Neuregulin 3 (NRG3) gene at 10q22-q24 has been implicated in multiple psychiatric traits such as cognitive impairment. We therefore hypothesized that NRG3 gene polymorphisms may play a role in Alzheimer disease (AD). This present study explored the association of NRG3 with the age at onset (AAO) of AD and the risk of developing AD. Secondary data analysis of 257 single-nucleotide polymorphisms (SNPs) in NRG3 gene was performed in 806 Alzheimer's disease patients and 782 controls using logistic regression and linear regression analyses. Eight SNPs were associated with the risk of AD (p < 0.05), while linear regression analysis showed 33 SNPs associated with the AAO of AD (p < 0.05). Two-SNP haplotype analyses based on UNPHASED revealed that the G-C haplotype from rs17685233 and rs17101017 was significantly associated with AD (p = 0.0031) and the A-G haplotype from rs504522 and rs474018 as well as the A-G haplotype from rs504522 and rs2483295 were more significantly associated with the AAO of AD (p = 6.72 × 10(-5)). Using an independent family-based sample, we found one SNP rs11192423 associated with AAO both in the case-control sample (p = 0.0155) and in the family sample (p = 0.0166). In addition, we observed nominally significant associations with AD and AAO for several flanking SNPs (p < 0.05). This is the first study demonstrating that genetic variants in the NRG3 gene play a role in AD. Our results also revealed that SNPs in the NRG3 genes were more strongly associated with AAO of AD.

A genome-wide linkage scan of bipolar disorder in Latino families identifies susceptibility loci at 8q24 and 14q32.

A genome-wide nonparametric linkage screen was performed to localize Bipolar Disorder (BP) susceptibility loci in a sample of 3757 individuals of Latino ancestry. The sample included 963 individuals with BP phenotype (704 relative pairs) from 686 families recruited from the US, Mexico, Costa Rica, and Guatemala. Non-parametric analyses were performed over a 5 cM grid with an average genetic coverage of 0.67 cM. Multipoint analyses were conducted across the genome using non-parametric Kong & Cox LOD scores along with Sall statistics for all relative pairs. Suggestive and significant genome-wide thresholds were calculated based on 1000 simulations. Single-marker association tests in the presence of linkage were performed assuming a multiplicative model with a population prevalence of 2%. We identified two genome-wide significant susceptibly loci for BP at 8q24 and 14q32, and a third suggestive locus at 2q13-q14. Within these three linkage regions, the top associated single marker (rs1847694, P = 2.40 × 10(-5)) is located 195 Kb upstream of DPP10 in Chromosome 2. DPP10 is prominently expressed in brain neuronal populations, where it has been shown to bind and regulate Kv4-mediated A-type potassium channels. Taken together, these results provide additional evidence that 8q24, 14q32, and 2q13-q14 are susceptibly loci for BP and these regions may be involved in the pathogenesis of BP in the Latino population.

Suggestive evidence for association between L-type voltage-gated calcium channel (CACNA1C) gene haplotypes and bipolar disorder in Latinos: a family-based association study.

OBJECTIVES: Through recent genome-wide association studies (GWASs), several groups have reported significant association between variants in the calcium channel, voltage-dependent, L-type, alpha 1C subunit (CACNA1C) and bipolar disorder (BP) in European and European-American cohorts. We performed a family-based association study to determine whether CACNA1C is associated with BP in the Latino population. METHODS: This study included 913 individuals from 215 Latino pedigrees recruited from the USA, Mexico, Guatemala, and Costa Rica. The Illumina GoldenGate Genotyping Assay was used to genotype 58 single-nucleotide polymorphisms (SNPs) that spanned a 602.9-kb region encompassing the CACNA1C gene including two SNPs (rs7297582 and rs1006737) previously shown to associate with BP. Individual SNP and haplotype association analyses were performed using Family-Based Association Test (version 2.0.3) and Haploview (version 4.2) software. RESULTS: An eight-locus haplotype block that included these two markers showed significant association with BP (global marker permuted p = 0.0018) in the Latino population. For individual SNPs, this sample had insufficient power (10%) to detect associations with SNPs with minor effect (odds ratio = 1.15). CONCLUSIONS: Although we were not able to replicate findings of association between individual CACNA1C SNPs rs7297582 and rs1006737 and BP, we were able to replicate the GWAS signal reported for CACNA1C through a haplotype analysis that encompassed these previously reported significant SNPs. These results provide additional evidence that CACNA1C is associated with BP and provides the first evidence that variations in this gene might play a role in the pathogenesis of this disorder in the Latino population.

The genomic psychiatry cohort: partners in discovery.

The Genomic Psychiatry Cohort (GPC) is a longitudinal resource designed to provide the necessary population-based sample for large-scale genomic studies, studies focusing on Research Domain Criteria (RDoC) and/or other alternate phenotype constructs, clinical and interventional studies, nested case-control studies, long-term disease course studies, and genomic variant-to-phenotype studies. We provide and will continue to encourage access to the GPC as an international resource. DNA and other biological samples and diagnostic data are available through the National Institute of Mental Health (NIMH) Repository. After appropriate review and approval by an advisory board, investigators are able to collaborate in, propose, and co-lead studies involving cohort participants.

Substance use disorder and schizophrenia: prevalence and sociodemographic characteristics in the Latin American population.

Interest in understanding the comorbidity of schizophrenia and substance use disorder has been increasing due to the increase of this diagnosis, to the negative effects observed in the subject and to the health service costs. This dual disorder can have dramatic effects on the clinical course of the psychiatric disorder, this being, for example increased relapses, re-hospitalizations, more severe symptoms, noncompliance with antipsychotic medication, marked mood changes, increased rates of hostility and suicidal ideation as well as in other areas of functioning, including interpersonal violence and victimization, homelessness, and legal problems. Literature from the United States and Europe in particular suggests that the prevalence rates for this dual diagnosis may range from 10 to 70%. In this study, we have reviewed the prevalence of the dual diagnosis of schizophrenia and substance use disorder as well as the sociodemographic characteristics in the literature on Latin-American populations. Notwithstanding that the dual disorder is a widely accepted diagnosis, relatively little is known about its prevalence in Latin American populations or about the environmental factors that may influence it, as well as about the demographic, clinical, and other characteristics of these individuals. A better understanding of this diagnosis might improve the methods for the detection and assessment of substance use disorder in persons with severe mental illness such as schizophrenia.

Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans.

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world's population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. METHODS: We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. RESULTS: Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10-30) and African American (P < .0005) participants in CSP #572. CONCLUSIONS: We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations.

Assessment of genetic ancestry and population substructure in Costa Rica by analysis of individuals with a familial history of mental disorder.

The population of Costa Rica has been considered valuable for locating susceptibility genes of complex disorders because of historical events and a gradual admixture process. We present an assessment of 426 unrelated individuals with a familial history of mental disorder and with ancestors born in the Central Valley, genotyped at 730 microsatellites to evaluate genetic diversity, ancestry, and substructure at the general and regional population levels using quantitative methods. Low population substructure was found. Estimated mean ancestry proportions were 54%, 32%, and 13% for European, Amerindian, and African components, respectively, with some regional variation. The F(ST) values obtained confirm the largest genetic similarity to Europeans. Subdivision of the Amerindians into individual populations revealed strong similarity to Chibchan groups. Analysis of the African ancestry showed high similarity to West and Central African populations. Gene ancestries from other African areas were also detected, probably resulting from ancestral admixture within Africa prior to colonial times. Our analyses show, in an ethnohistorical-genetic context, that gene flow and admixture are important components of Costa Rican population history. The results confirm the need to consider the particular regional genetic structure, the effects of genetic drift and the ancestry when designing and interpreting investigations of genetic traits in this population.

Association of serotonin transporter promoter gene polymorphism (5-HTTLPR) with depression in Costa Rican schizophrenic patients.

Depression and suicidal behavior are frequently observed in patients with schizophrenia. The serotonin transporter protein regulates serotonergic signaling at synapses and is encoded by a single gene (SLC6A4; Locus Link ID: 6532), located at 17q11.1-q12 with two polymorphic variants (the short and the long allele). The short allele of serotonin transporter gene has been associated with depression and suicidality in individuals who suffered negative life events and with depression in individuals with chronic psychosis.. Subjects were recruited from a genetic study of schizophrenia conducted in Costa Rica. The authors replicated their previous research, using a more narrow phenotype (only schizophrenic subjects) and a more ethnically homogenous sample (only Costa Rican schizophrenic individuals who were not included in the previous study). The authors hypothesized that subjects with at least one copy of the serotonin transporter promoter gene polymorphism (5-HTTLPR) "s" allele would have a greater history of lifetime depression and suicidability rate than those who had an "l/l" genotype. The authors analyzed 155 subjects with a DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) diagnosis of schizophrenia (73% male, age at interview 38.3, SD = 11.23). The genotype distribution was "ss" 58 (37%), "sl" 69 (45%), and "ll" 28 (18%). In the secondary analysis, the authors explored association of the "s" allele with lifetime history of suicide behavior in 173 subjects (18 more subjects than primary analysis because schizophrenic individuals were included regardless of history of depression). The authors found that subjects carrying at least one short allele had a significant increased lifetime risk for depressive syndromes (chi(2) = 5.4, df = 1, P = 0.02; odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.15-6.3). No association was found for suicidal behavior in the same sample (chi(2) = 0.928, P = 0.629). In conclusion, the genotype at the 5-HTTLPR promoter polymorphic locus increases the risk of developing major depression but not suicidal behavior during the course of the schizophrenia in these patients. Due to the small sample size, these results should be followed by definitive replication.

The role of complex emotions in inconsistent diagnoses of schizophrenia.

In the case of large-scale epidemiological studies, there is evidence of substantial disagreement when lay diagnoses of schizophrenia based on structured interviews are compared with expert diagnoses of the same patients. Reasons for this level of disagreement are investigated in the current study, which made use of advances in text-mining techniques and associated structural representations of language expressions. Specifically, the current study examined whether content analyses of transcribed diagnostic interviews obtained from 150 persons with serious psychiatric disorders yielded any discernable patterns that correlated with diagnostic inconsistencies of schizophrenia. In summary, it was found that the patterning or structure of spontaneous self-reports of emotion states in the diagnostic interview was associated with diagnostic inconsistencies of schizophrenia, irrespective of confounders; i.e., age of patient, gender, or ethnicity. In particular, complex emotion patterns were associated with greater disagreement between experts and trained lay interviewers than were simpler patterns.

Social and clinical comparison between schizophrenia and bipolar disorder type I with psychosis in Costa Rica.

INTRODUCTION: Schizophrenia (SC) and bipolar disorder (BP) are two of the most severe and incapacitating mental disorders. It has been questioned whether these two conditions designate distinct illnesses with different etiologies or whether they represent different ends of a clinical spectrum with a common etiology. MATERIALS AND METHODS: This study compares social and clinical characteristics of 84 SC and 84 BP subjects from the Costa Rican Central Valley (CRCV) using information from the DIGS, FIGS and psychiatric records. Each of these subjects had a best estimate lifetime consensus diagnosis of either bipolar type I or SC. RESULTS: Subjects with SC differed from subjects with BP in social adjustment measures like marital and employment status, and number of children. Both groups were very similar in years of education, age of onset of their illness, history of other psychiatric co-morbidities, and treatment received. DISCUSSION: The high percentage of psychosis in the BP group (97.6%) may largely explain the similarities found between groups in their clinical characteristics. CONCLUSION: The differences in social and functional decline support the original dichotomy described by Kraepelin based on chronicity and periodicity between these two psychotic disorders.

Psychiatric syndromes in individuals with chromosome 18 abnormalities.

Chromosome 18 abnormalities are associated with a range of physical abnormalities such as short stature and hearing impairments. Psychiatric manifestations have also been observed. This study focuses on the presentations of psychiatric syndromes as they relate to specific chromosomal abnormalities of chromosome 18. Twenty-five subjects (13 with an 18q deletion, 9 with 18p tetrasomy, and 3 with an 18p deletion), were interviewed by psychiatrists (blind to specific chromosomal abnormality) using the DIGS (subjects 18 and older) or KSADS-PL (subjects under 18). A consensus best estimation diagnostic process was employed to determine psychiatric syndromes. Oligonucleotide Array Comparative Genomic Hybridization (Agilent Technologies) was utilized to define specific regions of chromosome 18 that were deleted or duplicated. These data were further analyzed to determine critical regions of the chromosome as they relate to phenotypic manifestations in these subjects. 58.3% of the chromosome 18q- deletion subjects had depressive symptoms, 58.3% had anxiety symptoms, 25% had manic symptoms, and 25% had psychotic symptoms. 66.6% of the chromosome 18p- deletion subjects had anxiety symptoms, and none had depressive, manic, or psychotic symptoms. Fifty percent of the chromosome 18p tetrasomy subjects had anxiety symptoms, 12.5% had psychotic symptoms, and 12.5% had a mood disorder. All three chromosomal disorders were associated with high anxiety rates. Psychotic, manic and depressive disorders were seen mostly in 18q- subjects and this may be helpful in narrowing regions for candidate genes for these psychiatric conditions.

Heritability of age of onset of psychosis in schizophrenia.

Schizophrenia is a genetically complex illness with heterogeneous clinical presentation, including variable age of onset. In this study, the heritability, or proportion of variation in age of onset of psychotic symptoms due to genetic factors, was estimated using a maximum likelihood method. The subjects were 717 members of families with more than one member affected with schizophrenia from Mexican and Central American populations. Age of onset of psychosis was determined by best-estimate consensus diagnosis based on the Diagnostic Interview for Genetic Studies, Family Interview for Genetic Studies, and each subject's medical records. Mean age of onset was 21.44 years (SD 8.07); 20.55 years for males (SD 6.90), and 22.67 for females (SD 9.34). Variance components were estimated using a polygenic model in the SOLAR software package. The sex of the participant was a significant covariate (P = 0.010) accounting for 0.02 of the total variance in age of onset. The heritability of age of onset of psychosis was 0.33 (SE = 0.09; P = 0.00004). These findings suggest that genetic factors significantly contribute to the age of onset of psychotic symptoms in individuals with schizophrenia and that sex influences this trait as well.