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.

Identification of circadian gene variants in bipolar disorder in Latino populations.

BACKGROUND: Variations in circadian genes can impact biological rhythms. Given the rhythm disturbances that characterize bipolar disorder (BD), genes encoding components of molecular clocks are good candidate genes for the illness. METHODS: A family based association analysis of circadian gene single nucleotide polymorphisms (SNPs) and BD was conducted in Latino pedigrees. 884 individuals from 207 pedigrees (473BP phenotype and 411 unaffected family members) were genotyped. Family based single marker association testing was performed. Ancestral haplotypes (SNPs found to be in strong LD defined using confidence intervals) were also tested for association with BD. RESULTS: Multiple suggestive associations between circadian gene SNPs and BD were noted. These included CSNK1E (rs1534891, p=0.00689), ARNTL (rs3789327, p=0.021172), CSNK1D (rs4510078, p=0.022801), CLOCK (rs17777927, p=0.031664). Individually, none of the SNPs were significantly associated with BD after correction for multiple testing. However, a 4-locus CSNK1E haplotype encompassing the rs1534891 SNP (Z-score=2.685, permuted p=0.0076) and a 3-locus haplotype in ARNTL (Z-score=3.269, permuted p=0.0011) showed a significant association with BD. LIMITATIONS: Larger samples are required to confirm these findings and assess the relationship between circadian gene SNPs and BD in Latinos. CONCLUSIONS: The results suggest that ARNTL and CSKN1E variants may be associated with BD. Further studies are warranted to assess the relationships between these genes and BD in Latino populations.

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.

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.

Genetic structure of personality factors and bipolar disorder in families segregating bipolar disorder.

BACKGROUND: Bipolar disorder (BPD) has been associated with variations in personality dimensions, but the nature of this relationship has been unclear. In this study, the heritabilities of BPD and the Big Five personality factors and the genetic correlations between BPD and personality factors are reported. METHODS: The participants in this study were 1073 individuals from 172 families of Mexican or Central American ancestry. Heritabilities and genetic correlations were calculated under a polygenic model using the maximum-likelihood method of obtaining variance components implemented in the SOLAR software package. RESULTS: Heritabilities of 0.49, 0.43, and 0.43 were found for the narrowest phenotype (schizoaffective bipolar and bipolar I), the intermediate phenotype (schizoaffective bipolar, bipolar I, and bipolar II), and the broadest phenotype (schizoaffective bipolar, bipolar I, bipolar II, and recurrent depression), respectively. For the Big Five personality factors, heritabilities were 0.25 for agreeableness, 0.24 for conscientiousness, 0.24 for extraversion, 0.23 for neuroticism, and 0.32 for openness to experience. For the narrowest phenotype, a significant negative correlation (-0.32) with extraversion was found. For the broadest phenotype, negative correlations were found for agreeableness (-0.35), conscientiousness (-0.39), and extraversion (-0.44). A positive correlation (0.37) was found with neuroticism. LIMITATIONS: It is not possible to determine whether aspects of personality are factors in the development of bipolar disorder or vice versa. The short form of the NEO does not provide the ability to examine in detail which facets of extraversion are most closely related to bipolar disorder or to compare our results with studies that have used the long version of the scale. CONCLUSIONS: This study establishes a partial genetic basis for the Big Five personality factors in this set of families, while the environmental variances demonstrate that non-genetic factors are also important in their influence on bipolar and personality phenotypes. BPD may be most associated with decreased extraversion (less interaction with one's surroundings) because patients spend more time in depressive than manic states.

Substance use disorder comorbidity with schizophrenia in families of Mexican and Central American ancestry.

OBJECTIVES: The aims of this study were to estimate the frequency and course of substances use disorders in Latino patients with schizophrenia and to ascertain risk factors associated with substance use disorders in this population. METHOD: We studied 518 subjects with schizophrenia recruited for a genetic study from the Southwest United States, Mexico, and Central America (Costa Rica and Guatemala). Subjects were assessed using structured interviews and a best estimate consensus process. Logistic regression, chi(2), t test, Fisher's exact test, and Yates' correction, as appropriate, were performed to assess the sociodemographic variables associated with dual diagnosis. We defined substance use disorder as either alcohol or substance abuse or dependence. RESULTS: Out of 518 patients with schizophrenia, 121 (23.4%) had substance use disorders. Comorbid substance use disorders were associated with male gender, residence in the United States, immigration of Mexican men to the United States, history of depressive syndrome or episode, and being unemployed. The most frequent substance use disorder was alcohol abuse/dependence, followed by marijuana abuse/dependence, and solvent abuse/dependence. CONCLUSION: This study provides data suggesting that depressive episode or syndrome, unemployment, male gender, and immigration of Mexican men to the United States were factors associated with substance use disorder comorbidity in schizophrenia. Binary logistic regression showed that country of residence was associated with substance use disorder in schizophrenic patients. The percentage of subjects with comorbid substance use disorders was higher in the Latinos living in the United States compared with subjects living in Central America and Mexico.

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.

Diagnosis of schizophrenia in latino populations: a comparison of direct interview and consensus based multi-source methods.

We determined the rates of agreement between diagnoses, using the Diagnostic Interview for Genetic Studies (DIGS) and diagnoses arrived at, using additional sources of information, to establish whether there are differences in agreement between direct interview diagnoses at US and non-US sites in comparison best estimate consensus process and to identify diagnoses that could increase diagnostic error when only the DIGS is used. DIGS diagnoses were compared with consensus diagnoses that used the same DIGS interview, plus Family Interview for Genetic Studies (FIGS) and review of medical records in 342 psychotic subjects. We found similar numbers of subjects diagnosed with schizophrenia (225 by direct interview, and 232 by consensus process). The majority of those "misdiagnosed" by direct interview had mood disorder by the consensus. Over 10% of the total subjects diagnosed by direct interview as not meeting criteria for schizophrenia had schizophrenia by consensus. There were no statistically significant differences between countries (US vs. non-US sites) in the agreement rate between direct interview diagnosis and consensus diagnosis. In conclusion, a final best-estimate process is essential to make diagnostic distinctions and to reduce diagnostic misclassifications for both research studies and in clinical practice.

A schizophrenia gene locus on chromosome 17q21 in a new set of families of Mexican and central american ancestry: evidence from the NIMH Genetics of schizophrenia in latino populations study.

OBJECTIVE: The present study investigated a new set of families of Latin American ancestry in order to detect the location of genes predisposing to schizophrenia and related psychotic disorders. METHOD: A genome-wide scan was performed for 175 newly recruited families with at least two siblings suffering from a psychotic disorder. Best-estimate consensus procedures were used to arrive at diagnoses, and nonparametric allele-sharing statistics were calculated to detect linkage. RESULTS: Genome-wide significant evidence for linkage for the phenotype of DSM-IV schizophrenia or schizoaffective disorder was found in a region on chromosome 17q21 (lod score, 3.33). A region on chromosome 15q22-23 showed suggestive evidence of linkage with this same phenotype (lod score, 2.11). Analyses using a broader model (any psychosis) yielded evidence of suggestive linkage for the 17q21 region only, and no region achieved genome-wide significance of linkage. CONCLUSIONS: The new set of 175 families of Mexican and Central American ancestry delineates two new loci likely to harbor predisposition genes for schizophrenia and schizoaffective disorder. The region with the strongest support for linkage in this sample, 17q21, has been implicated in meta-analyses of schizophrenia genome screens, but the authors found no previous reports of it as a locus for schizophrenia in specific population- or family-based studies, and it may represent the location of a schizophrenia predisposition gene (or genes) of special relevance in Mexican and Central American populations.

Methionine sulfoxide reductase: a novel schizophrenia candidate gene.

Methionine sulfoxide reductase (MSRA) is an antioxidant enzyme implicated in protection against oxidative stress and protein maintenance. We have previously reported the association of marker D8S542, located within the MSRA gene, with schizophrenia in the Central Valley of Costa Rica (CVCR). By performing fine mapping analysis, we have now identified a potential three-marker at risk haplotype within MSRA in the same CVCR sample, with a global P-value slightly above nominal significance (P = 0.0526). By sequencing the MSRA gene in individuals carrying this haplotype, we identified a novel 4-base pair deletion 1,792 bases upstream of the MSRA transcription start site. This deletion was significantly under-transmitted to schizophrenia patients in the CVCR sample (P = 0.0292) using FBAT, and this was replicated in a large independent sample of 321 schizophrenia families from the Hispanic population (P = 0.0367). These findings suggest a protective effect of the deletion against schizophrenia. Further, MSRA mRNA levels were significantly lower in lymphoblastoid cell lines of individuals homozygous for the deletion compared to carriers of the normal allele (P = 0.0135), although significance was only evident when genotypes were collapsed. This suggests that the deleted sequence may play a role in regulating MSRA expression. In conclusion, this work points towards MSRA as a novel schizophrenia candidate gene. Further studies into the mechanisms by which MSRA is involved in schizophrenia pathophysiology may shed light into the biological underpinnings of this disorder.

The epsin 4 gene is associated with psychotic disorders in families of Latin American origin.

This study attempted to replicate evidence for association of the Epsin 4 gene (which encodes enthoprotin, a protein involved in vesicular transport) to schizophrenia in a new sample of families segregating schizophrenia drawn from the Latin American population. 1,423 subjects (767 with a history of psychosis) from 337 Latino families were genotyped using three single nucleotide polymorphisms (SNPs) spanning the Epsin 4 gene. A family based association test was utilized to test for association of these SNPs to the phenotypes of psychosis and schizophrenia. Haplotypes defined by these three SNPs showed significant association to the phenotype of psychosis in this sample (global p value=0.014, bi-allelic p value=0.047). Variation in the Epsin 4 gene is significantly associated with psychotic disorder in this Latino population. This provides additional support for the involvement of enthoprotin in the pathogenesis of schizophrenia and other psychotic disorders.

Genetic structure analysis of three Hispanic populations from Costa Rica, Mexico, and the southwestern United States using Y-chromosome STR markers and mtDNA sequences.

Two hundred seventeen male subjects from Costa Rica, Mexico, and the Hispanic population of the southwestern United States were studied. Twelve Y-chromosome STRs and the HVSI sequence of the mtDNA were analyzed to describe their genetic structure and to compare maternal and paternal lineages. All subjects are part of two NIMH-funded studies to localize schizophrenia susceptibility genes in Hispanic populations of Mexican and Central American ancestry. We showed that these three populations are similar in their internal genetic characteristics, as revealed by analyses of mtDNA and Y-chromosome STR diversity. These populations are related through their maternal lineage in a stronger way than through their paternal lineage, because a higher number of shared haplotypes and polymorphisms are seen in the mtDNA (compared to Y-chromosome STRs). These results provide evidence of previous contact between the three populations and shared histories. An analysis of molecular variance revealed no genetic differentiation for the mtDNA for the three populations, but differentiation was detected in the Y-chromosome STRs. Genetic distance analysis showed that the three populations are closely related, probably as a result of migration between close neighbors, as indicated by shared haplotypes and their demographic histories. This relationship could be an important common feature for genetic studies in Latin American and Hispanic populations.

Psicofarmacología de la fobia social / Psychopharmacology of social phobia

La fobia social es un trastorno de ansiedad crónico y debilitante, caracterizado por la presencia de síntomas de severa ansiedad ante ciertas situaciones sociales. Este trastorno se complica frecuentemente con abuso o adicción al alcohol y las drogas. El empleo de psicofármacos en el tratamiento de la fobia sociales, ha despertado interés recientemente. Se han observado resultados favorables en tres clases de medicamentos: beta-bloqueadores, inhibidores de la monoamino-oxidasa (IMAO) y benzodiacepinas potentes. En este artículo realizamos una revisión de la literatura existente sobre el uso de fármacos en la fobia social, con recomendaciones sobre su tratamiento

Epidemiologia de la enfermedad de Chagas en una poblacion de Oaxaca, México / Epidemiologic study of Chagas' disease in a town in Oaxaca, México

A survey was made of residents and hospital patients in Miahuatlan, Oaxaca, México, for cases of Chagas'disease. This survey focused primarily upon 85 patients attending the local hospital who had clinical pictures suggesting the disease, 14 with possible acute cases and 71 with possible chronic cases. In addition, sera from 14 Miahuatlan blood donors were examined; seroepidemiologic testing was performed with 52 sera from schoolchildren at another community nearby, and triatomine bugs were collected from Miahuatlan residences. Each of the 85 patients provided a complete clinical history and blood specimen, and each was given an ECG and a series of heart X-rays or chest teleradiography. In some cases biopsy or necropsy speciments were obtained. A variety of parasitologic and serologic test performed with these specimens indicated chagasic infections in four of the 14 subjects with possible acute cases and eight of the 71 subjects with possible chronic cases. One of these latter subjects had the first case of Chagas'disease involving a megasigmoid that had ever been reported in México. A high proportion (78 percent of the sera from Miahuatlan blood donors tested positive for Trypanosoma cruzi antibodies by complement fixation, as did 88 percent of the sera from the 52 schoolchildren. A total of 57 triatomid vector insects were captured alive and tested for T. cruzi. Most (92 percent) were

Epidemiología de la enfermedad de Chagas en una población de Oaxaca, México / Epidemiologic study of Chagas'disease in a town in Oaxaca, Mexico

A survey was made of residents and hospital patients in Miahuatlan, Oaxaca, Mexico, for cases of Chagas'disease. This survey focused primarily upon 85 patients attending the local hospital who had clinical pictures suggesting the disease, 14 with possible acute cases and 71 with possible chronic cases. In addition, sera from 14 Miahuatlan blood donors were examined; seroepidemiologic testing was performed with 52 sera from schoolchildren at another community nearby, and triatomine bugs were collected from Miahuatlan residences. Each of the 85 patients provided a complete cllinical history and blood specimen, and each was given an ECG and a series of heart X-rays or chest teleradiography. In some cases biopsy or necropsy speciments were obtained. A variety of parasitologic and serologic test performed with these specimens indicated chagasic infections in four of the 14 subjects with possible acute cases and eight of the 71 subjects with possible chronic cases. One of these latter subjects had the first case of Chagas'disease involving a megasigmoid that had ever been reported in Mexico. A high proportion (78 percent of the sera from Miahuatlan blood donors tested positive for Trypanosoma cruzi antibodies by complement fixation, as did 88 percent of the sera from the 52 schoolchildren. A total of 57 triatomid vector insects were captured alive and tested for T. cruzi. Most (92 percent) were