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.

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.

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.

Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases.

BACKGROUND: Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood. METHODS: Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis. RESULTS: CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10-5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden. CONCLUSIONS: CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.

Confirmation of MRI anatomical measurements as endophenotypic markers for bipolar disorder in a new sample from the NIMH Genetics of Bipolar Disorder in Latino Populations study.

The main objective of this study is to establish potential neuromorphometric differences which might act as markers of genetic risk for bipolar disorder and therefore serve as endophenotypes for discovery of genes that contribute to bipolar disorder. Magnetic resonance imaging (MRI) was used to assess structural brain volumes of 49 subjects. Volumetric analyses were first performed to test possible differences in the volume of brain structures between subjects with bipolar disorder type I (BPI) and control subjects in a new sample, based on regions previously reported in the literature as being either increased or decreased in size in bipolar patients. Subsequently, for those brain regions showing statistical difference between subjects with BPI and control subjects in our new sample, we tested whether unaffected first degree relatives (UFRs) of the BPI subjects also showed similar differences compared with controls. Four specific regions (right prefrontal, right middle prefrontal, right globus pallidus and left globus pallidus) met criteria for being possible endophenotypes for BPI in this sample.

Genome-wide methylome analyses reveal novel epigenetic regulation patterns in schizophrenia and bipolar disorder.

Schizophrenia (SZ) and bipolar disorder (BP) are complex genetic disorders. Their appearance is also likely informed by as yet only partially described epigenetic contributions. Using a sequencing-based method for genome-wide analysis, we quantitatively compared the blood DNA methylation landscapes in SZ and BP subjects to control, both in an understudied population, Hispanics along the US-Mexico border. Remarkably, we identified thousands of differentially methylated regions for SZ and BP preferentially located in promoters 3'-UTRs and 5'-UTRs of genes. Distinct patterns of aberrant methylation of promoter sequences were located surrounding transcription start sites. In these instances, aberrant methylation occurred in CpG islands (CGIs) as well as in flanking regions as well as in CGI sparse promoters. Pathway analysis of genes displaying these distinct aberrant promoter methylation patterns showed enhancement of epigenetic changes in numerous genes previously related to psychiatric disorders and neurodevelopment. Integration of gene expression data further suggests that in SZ aberrant promoter methylation is significantly associated with altered gene transcription. In particular, we found significant associations between (1) promoter CGIs hypermethylation with gene repression and (2) CGI 3'-shore hypomethylation with increased gene expression. Finally, we constructed a specific methylation analysis platform that facilitates viewing and comparing aberrant genome methylation in human neuropsychiatric disorders.

The DNA methylome and transcriptome of different brain regions in schizophrenia and bipolar disorder.

Extensive changes in DNA methylation have been observed in schizophrenia (SC) and bipolar disorder (BP), and may contribute to the pathogenesis of these disorders. Here, we performed genome-scale DNA methylation profiling using methylated DNA immunoprecipitation followed by sequencing (MeDIP-seq) on two brain regions (including frontal cortex and anterior cingulate) in 5 SC, 7 BP and 6 normal subjects. Comparing with normal controls, we identified substantial differentially methylated regions (DMRs) in these two brain regions of SC and BP. To our surprise, different brain regions show completely distinct distributions of DMRs across the genomes. In frontal cortex of both SC and BP subjects, we observed widespread hypomethylation as compared to normal controls, preferentially targeting the terminal ends of the chromosomes. In contrast, in anterior cingulate, both SC and BP subjects displayed extensive gain of methylation. Notably, in these two brain regions of SC and BP, only a few DMRs overlapped with promoters, whereas a greater proportion occurs in introns and intergenic regions. Functional enrichment analysis indicated that important psychiatric disorder-related biological processes such as neuron development, differentiation and projection may be altered by epigenetic changes located in the intronic regions. Transcriptome analysis revealed consistent dysfunctional processes with those determined by DMRs. Furthermore, DMRs in the same brain regions from SC and BP could successfully distinguish BP and/or SC from normal controls while differentially expressed genes could not. Overall, our results support a major role for brain-region-dependent aberrant DNA methylation in the pathogenesis of these two disorders.

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.

Genetic association analysis of ITGB3 polymorphisms with age at onset of schizophrenia.

Schizophrenia (SCZ) is a debilitating disorder with a prevalence of approximately 1 % worldwide. SCZ is known to have a high degree of genetic and clinical heterogeneity and is a major health problem worldwide. The integrin-ß 3 subunit gene (ITGB3) gene at 17q21.32 has been implicated in psychiatric disorders. We therefore hypothesized that ITGB3 gene polymorphisms might also play a role in SCZ and age at onset (AAO) of SCZ. We investigated the genetic associations of 23 single-nucleotide polymorphisms (SNPs) of the ITGB3 gene with AAO in SCZ in two Caucasian samples (2,166 cases and 2,525 controls) using linear regression analysis and meta-analysis. We observed four ITGB3-SNPs associated with AAO in SCZ in a non-Genetic Association Information Network (GAIN) sample (p < 10(-3)). Three of these four SNPs were replicated in the GAIN sample. The SNP rs16941771 was most significantly associated with AAO (p = 7.47 × 10(-5)). Meta-analysis showed that 6 of 23 SNPs were associated with AAO. The haplotype analysis also supports the association of ITGB3 with AAO. Three disease-associated SNPs were located at species-conserved regions, indicating functional importance. This is the first report which shows that ITGB3 variants are associated with AAO in SCZ, providing direct evidence of the use of AAO as an intermediate phenotype to dissect the complex genetics of SCZ.

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.

BCL9 and C9orf5 are associated with negative symptoms in schizophrenia: meta-analysis of two genome-wide association studies.

Schizophrenia is a chronic and debilitating psychiatric condition affecting slightly more than 1% of the population worldwide and it is a multifactorial disorder with a high degree of heritability (80%) based on family and twin studies. Increasing lines of evidence suggest intermediate phenotypes/endophenotypes are more associated with causes of the disease and are less genetically complex than the broader disease spectrum. Negative symptoms in schizophrenia are attractive intermediate phenotypes based on their clinical and treatment response features. Therefore, our objective was to identify genetic variants underlying the negative symptoms of schizophrenia by analyzing two genome-wide association (GWA) data sets consisting of a total of 1,774 European-American patients and 2,726 controls. Logistic regression analysis of negative symptoms as a binary trait (adjusted for age and sex) was performed using PLINK. For meta-analysis of two datasets, the fixed-effect model in PLINK was applied. Through meta-analysis we identified 25 single nucleotide polymorphisms (SNPs) associated with negative symptoms with p<5×10(-5). Especially we detected five SNPs in the first two genes/loci strongly associated with negative symptoms of schizophrenia (P(meta-analysis)<6.22×10(-6)), which included three SNPs in the BCL9 gene: rs583583 showed the strongest association at a P(meta-analysis) of 6.00×10(-7) and two SNPs in the C9orf5 (the top SNP is rs643410 with a p = 1.29 ×10(-6)). Through meta-analysis, we identified several additional negative symptoms associated genes (ST3GAL1, RNF144, CTNNA3 and ZNF385D). This is the first report of the common variants influencing negative symptoms of schizophrenia. These results provide direct evidence of using of negative symptoms as an intermediate phenotype to dissect the complex genetics of schizophrenia. However, additional studies are warranted to examine the underlying mechanisms of these disease-associated SNPs in these genes.

Polymorphisms in seizure 6-like gene are associated with bipolar disorder I: evidence of gene × gender interaction.

BACKGROUND: Previous reports have suggested that there may be gene × gender interaction for bipolar disorder (BD)-associated genes/loci at 22q11-13. This study aimed to investigate the associations of SEZ6L genetic variants with bipolar disorder I (BD-I) and to examine gender-specific genetic associations. METHODS: 605 BD-I Caucasian cases and 1034 controls were selected from the publicly available data of the Whole Genome Association Study of BD. To increase power, an additional 362 Caucasian controls were added to this study from the Genome-Wide Association Study of Schizophrenia. In total, 605 BD-I cases and 1396 controls (934 males and 1067 females) were available for genetic association analysis of 118 SNPs within the SEZ6L gene using PLINK software. RESULTS: 16 SNPs showed significant gene x gender interactions influencing BD-I (P<0.01). In addition, significant differences in the distribution of the alleles for these 16 SNPs were observed between the female BD-I patients and healthy controls (P<0.015) but no significant associations were found for the male sample (P>0.05). The SNP rs4822691 showed the strongest association with BD-I in the female sample (P=2.18 × 10(-4)) and the strongest gene × gender interaction in influencing BD-I (P=9.16 × 10(-5)). LIMITATIONS: The findings of this study need to be replicated in independent samples. CONCLUSIONS: This is the first demonstration that genetic variants in the SEZ6L gene are associated with BD-I in female patients and provides additional compelling evidence for genetic variation at 22q11-13 that influences BD-I risk. The present findings highlight the gene x gender interactions modifying BD-I susceptibility.

Health-related conditions and depression in elderly mexican american and non-Hispanic white residents of a United States-Mexico border county: moderating effects of educational attainment.

We investigated the prevalence of "high" levels of depressive symptomatology and 13 health-related medical conditions in elderly Mexican American (MA) and non-Hispanic white (NHW) residents of El Paso County, Texas. We analyzed the extent to which depressive symptoms in this population are associated with these conditions. Elderly MA residents possessed a higher prevalence of current depression, a relatively unique health-related condition profile, and were more likely to experience a set of conditions that impede participation in daily life-conditions that we found to be strongly associated with high depressive symptomatology in the elderly. After adjusting for educational attainment, using multiple regression analyses, depression was not associated with ethnicity and only six of the health related conditions showed significant differences between MA and NHW subjects. We believe these results provide an important insight into the mechanism of health-related conditions and depressive symptomatology in a large sample of elderly MAs; and how conditions typically attributed to MA ethnicity may in actuality be an artifact of socioeconomic status variables such as educational-attainment.

Clozapine treatment causes oxidation of proteins involved in energy metabolism in lymphoblastoid cells: a possible mechanism for antipsychotic-induced metabolic alterations.

There is increasing concern about the serious metabolic side effects and neurotoxicity caused by atypical (second-generation) antipsychotics. In a previous study by our group (Walss-Bass et al. Int J Neuropsychopharmacol 2008;11:1097-104), using a novel proteomic approach, we showed that clozapine treatment in SKNSH cells induces oxidation of proteins involved in energy metabolism, leading us to hypothesize that protein oxidation could be a mechanism by which atypical antipsychotics increase the risk for metabolic alterations. In this study, the same proteomic approach was used to identify specific proteins oxidized after clozapine treatment in lymphoblastoid cell lines from patients with schizophrenia and normal controls. Cells were treated with 0 and 20 µM clozapine for 24 hours and protein extracts were labeled with 6-iodoacetamide fluorescein (6-IAF). The lack of incorporation of 6-IAF into the thiol group of cysteine residues is an indicator of protein oxidation. Labeled proteins were exposed to two dimensional electrophoresis, and differential protein labeling was assessed. Increased oxidation after clozapine treatment was observed in 9 protein spots (P<0.05). The following 7 proteins were identified by high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) in those 9 spots: enolase, triosephosphate isomerase (TPI), glyceraldehyde-3-phosphate dehydrogenase (GAPD), Rho GDP dissociation inhibitor (GDI), cofilin, uridine monophosphate/ cytidine monophosphate (UMP-CMP) kinase, and translation elongation factor. Several of these proteins play important roles in energy metabolism and mitochondrial function. These results further support the hypothesis that oxidative stress may be a mechanism by which antipsychotics increase the risk of metabolic syndrome and diabetes.

In vivo and in vitro genetic evidence of involvement of neuregulin 1 in immune system dysregulation.

Neuregulin 1 (NRG1) has been implicated in several disorders including breast cancer, multiple sclerosis, and schizophrenia. Also, recent evidence suggests that NRG1 may play a role in regulation of inflammation and immune system response. We therefore hypothesized that a schizophrenia-associated missense mutation (valine to leucine) we identified within the transmembrane region of NRG1 would also be linked to immune dysregulation. We used plasma samples from families carrying the mutation to measure levels of antibodies to 41 autoimmune markers and six cytokines (IL-1b, IL-6, IL-10, IL-8, IL-12p70, and TNF-α) and used these levels as quantitative traits to evaluate association with the NRG1 mutation, using FBAT. Next, we used Epstein-Barr virus-transformed B cells from heterozygous mutation carriers and wild-type individuals to evaluate protein and mRNA cytokine expression in vitro using quantitative PCR and ELISA assays. In vivo, increased levels of 25 autoimmune markers as well as elevated levels of cytokines were significantly associated with the NRG1 mutation. In vitro, we observed a significant increase in protein secretion levels of IL-6, TNF-α, and IL-8 in mutation carriers compared with controls. At the mRNA level, we observed a significant increase in IL-6 expression, while IL-4 levels appeared to be down-regulated in heterozygous individuals compared with wild-type controls. This is the first report of association of a NRG1 mutation with immune dysregulation. This study could contribute towards understanding the role of NRG1 in the pathogenesis of schizophrenia and other disorders in which inflammation plays an important role.

Neurocognitive endophenotypes for bipolar disorder identified in multiplex multigenerational families.

CONTEXT: Although genetic influences on bipolar disorder are well established, localization of genes that predispose to the illness has proven difficult. Given that genes predisposing to bipolar disorder may be transmitted without expression of the categorical clinical phenotype, a strategy for identifying risk genes is to identify and map quantitative intermediate phenotypes or endophenotypes. OBJECTIVE: To adjudicate neurocognitive endophenotypes for bipolar disorder. DESIGN: All participants underwent diagnostic interviews and comprehensive neurocognitive evaluations. Neurocognitive measures found to be heritable were entered into analyses designed to determine which test results are impaired in affected individuals, are sensitive to the genetic liability for the illness, and are genetically correlated with affection status. SETTING: Central valley of Costa Rica; Mexico City, Mexico; and San Antonio, Texas. PARTICIPANTS: Seven hundred nine Latino individuals participated in the study. Of these, 660 were members of extended pedigrees with at least 2 siblings diagnosed as having bipolar disorder (n = 230). The remaining subjects were community control subjects drawn from each site who did not have a personal or family history of bipolar disorder or schizophrenia. MAIN OUTCOME MEASURE: Neurocognitive test performance. RESULTS: Two of the 22 neurocognitive variables were not significantly heritable and were excluded from subsequent analyses. Patients with bipolar disorder were impaired on 6 cognitive measures compared with nonrelated healthy controls. Nonbipolar first-degree relatives were impaired on 5 of these, and the following 3 tests were genetically correlated with affection status: Digit Symbol Coding Task, Object Delayed Response Task, and immediate facial memory. CONCLUSION: This large-scale extended pedigree study of cognitive functioning in bipolar disorder identifies measures of processing speed, working memory, and declarative (facial) memory as candidate endophenotypes for bipolar disorder.

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.

Linkage disequilibrium mapping of the chromosome 6q21-22.31 bipolar I disorder susceptibility locus.

We previously reported genome-wide significant evidence for linkage between chromosome 6q and bipolar I disorder (BPI) by performing a meta-analysis of original genotype data from 11 genome scan linkage studies. We now present follow-up linkage disequilibrium mapping of the linked region utilizing 3,047 single nucleotide polymorphism (SNP) markers in a case-control sample (N = 530 cases, 534 controls) and family-based sample (N = 256 nuclear families, 1,301 individuals). The strongest single SNP result (rs6938431, P = 6.72 x 10(-5)) was observed in the case-control sample, near the solute carrier family 22, member 16 gene (SLC22A16). In a replication study, we genotyped 151 SNPs in an independent sample (N = 622 cases, 1,181 controls) and observed further evidence of association between variants at SLC22A16 and BPI. Although consistent evidence of association with any single variant was not seen across samples, SNP-wise and gene-based test results in the three samples provided convergent evidence for association with SLC22A16, a carnitine transporter, implicating this gene as a novel candidate for BPI risk. Further studies in larger samples are warranted to clarify which, if any, genes in the 6q region confer risk for bipolar disorder.

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.