Geospatial investigations in Colombia reveal variations in the distribution of mood and psychotic disorders.

BACKGROUND: Geographical variations in mood and psychotic disorders have been found in upper-income countries. We looked for geographic variation in these disorders in Colombia, a middle-income country. We analyzed electronic health records from the Clínica San Juan de Dios Manizales (CSJDM), which provides comprehensive mental healthcare for the one million inhabitants of Caldas. METHODS: We constructed a friction surface map of Caldas and used it to calculate the travel-time to the CSJDM for 16,295 patients who had received an initial diagnosis of mood or psychotic disorder. Using a zero-inflated negative binomial regression model, we determined the relationship between travel-time and incidence, stratified by disease severity. We employed spatial scan statistics to look for patient clusters. RESULTS: We show that travel-times (for driving) to the CSJDM are less than 1 h for ~50% of the population and more than 4 h for ~10%. We find a distance-decay relationship for outpatients, but not for inpatients: for every hour increase in travel-time, the number of expected outpatient cases decreases by 20% (RR = 0.80, 95% confidence interval [0.71, 0.89], p = 5.67E-05). We find nine clusters/hotspots of inpatients. CONCLUSIONS: Our results reveal inequities in access to healthcare: many individuals requiring only outpatient treatment may live too far from the CSJDM to access healthcare. Targeting of resources to comprehensively identify severely ill individuals living in the observed hotspots could further address treatment inequities and enable investigations to determine factors generating these hotspots.

The frequencies of mental disorders vary by geographic region. Investigating such variations may lead to more equitable access to mental healthcare and to scientific discoveries that reveal specific localized factors that contribute to the causes of mental illness. This study examined the frequency of three disorders with a major impact on public health ­ schizophrenia, bipolar disorder, and major depressive disorder ­ by analyzing electronic health records from a hospital providing comprehensive mental health care for a large region in Colombia. We show that individuals receiving outpatient care mainly live relatively near the facility. Those receiving inpatient care live throughout the region, but cluster in a few scattered locations. Future research could lead to strategies for more equitable provision of mental healthcare in Colombia and identify environmental or genetic factors that affect the likelihood that someone will develop one of these disorders.

Predicting diagnostic conversion from major depressive disorder to bipolar disorder: an EHR based study from Colombia.

Bipolar Disorder (BD) is a severe and chronic disorder characterized by recurrent episodes of depression, mania, and/or hypomania. Most BD patients initially present with depressive symptoms, resulting in a delayed diagnosis of BD and poor clinical outcomes. This study leverages electronic health record (EHR) data from the Clínica San Juan de Dios Manizales in Colombia to identify features predictive of the transition from Major Depressive Disorder (MDD) to BD. Analyzing EHR data from 13,607 patients diagnosed with MDD over 15 years, we identified 1,610 cases of conversion to BD. Using a multivariate Cox regression model, we identified severity of the initial MDD episode, the presence of psychosis and hospitalization at first episode, family history of mood or psychotic disorders, female gender to be predictive of the conversion to BD. Additionally, we observed associations with medication classes (prescriptions of mood stabilizers, antipsychotics, and antidepressants) and clinical features (delusions, suicide attempt, suicidal ideation, use of marijuana and alcohol use/abuse) derived from natural language processing (NLP) of clinical notes. Together, these risk factors predicted BD conversion within five years of the initial MDD diagnosis, with a recall of 72% and a precision of 38%. Our study confirms many previously identified risk factors identified through registry-based studies (such as female gender and psychotic depression at the index MDD episode), and identifies novel ones (specifically, suicidal ideation and suicide attempt extracted from clinical notes). These results simultaneously demonstrate the validity of using EHR data for predicting BD conversion as well as underscore its potential for the identification of novel risk factors and improving early diagnosis.

Diversity matters: opportunities in the study of the genetics of psychotic disorders in low- and middle-income countries in Latin America.

Lack of diversity regarding genetic and environmental backgrounds weakens the generalization and clinical applicability of research findings on psychotic disorders. Notably, Latin Americans have been generally neglected in genetic studies, comprising less than 2% of genome-wide association study samples. But Latin American populations represent a unique opportunity for research, given the exceptionally high ethnic admixture of this group. Increasing genetic diversity is essential to improve the fine mapping of known regions associated with psychotic disorders, discover novel genetic associations, and replicate studies. Additionally, Latin America is characterized by massive social, political, and economic inequalities, all known risk factors for mental health issues, including psychotic disorders. This article aims to 1) discuss the challenges and advantages of studying Latin America's particular genetic makeup and environmental context; 2) review previous studies conducted in the region; and 3) describe three Latin American research initiatives in progress: the Neuropsychiatric Genetics of Psychosis in Mexican Populations (NeuroMEX), the Paisa, and the Latin American Network for the Study of Early Psychosis (ANDES) studies.

Distinct and shared contributions of diagnosis and symptom domains to cognitive performance in severe mental illness in the Paisa population: a case-control study.

BACKGROUND: Severe mental illness diagnoses have overlapping symptomatology and shared genetic risk, motivating cross-diagnostic investigations of disease-relevant quantitative measures. We analysed relationships between neurocognitive performance, symptom domains, and diagnoses in a large sample of people with severe mental illness not ascertained for a specific diagnosis (cases), and people without mental illness (controls) from a single, homogeneous population. METHODS: In this case-control study, cases with severe mental illness were ascertained through electronic medical records at Clínica San Juan de Dios de Manizales (Manizales, Caldas, Colombia) and the Hospital Universitario San Vicente Fundación (Medellín, Antioquía, Colombia). Participants were assessed for speed and accuracy using the Penn Computerized Neurocognitive Battery (CNB). Cases had structured interview-based diagnoses of schizophrenia, bipolar 1, bipolar 2, or major depressive disorder. Linear mixed models, using CNB tests as repeated measures, modelled neurocognition as a function of diagnosis, sex, and all interactions. Follow-up analyses in cases included symptom factor scores obtained from exploratory factor analysis of symptom data as main effects. FINDINGS: Between Oct 1, 2017, and Nov 1, 2019, 2406 participants (1689 cases [schizophrenia n=160; bipolar 1 disorder n=519; bipolar 2 disorder n=204; and major depressive disorder n=806] and 717 controls; mean age 39 years (SD 14); and 1533 female) were assessed. Participants with bipolar 1 disorder and schizophrenia had similar impairments in accuracy and speed across cognitive domains. Participants with bipolar 2 disorder and major depressive disorder performed similarly to controls, with subtle deficits in executive and social cognition. A three-factor model (psychosis, mania, and depression) best represented symptom data. Controlling for diagnosis, premorbid IQ, and disease severity, high lifetime psychosis scores were associated with reduced accuracy and speed across cognitive domains, whereas high depression scores were associated with increased social cognition accuracy. INTERPRETATION: Cross-diagnostic investigations showed that neurocognitive function in severe mental illness is characterised by two distinct profiles (bipolar 1 disorder and schizophrenia, and bipolar 2 disorder and major depressive disorder), and is associated with specific symptom domains. These results suggest the utility of this design for elucidating severe mental illness causes and trajectories. FUNDING: US National Institute of Mental Health.

Molecular Population Genetics of the Northern Elephant Seal Mirounga angustirostris.

The northern elephant seal, Mirounga angustirostris, was heavily hunted and declared extinct in the 19th century. However, a colony remained on remote Guadalupe Island, Mexico and the species has since repopulated most of its historical distribution. Here, we present a comprehensive evaluation of genetic variation in the species. First, we assess the effect of the demographic bottleneck on microsatellite variability and compare it with that found in other pinnipeds, demonstrating levels of variation similar to that in species that continue to be threatened with extinction. Next, we use sequence data from these markers to demonstrate that some of the limited polymorphism predates the bottleneck. However, most contemporary variation appears to have arisen recently and persisted due to exponential growth. We also describe how we use the range in allele size of microsatellites to estimate ancestral effective population size before the bottleneck, demonstrating a large reduction in effective size. We then employ a classical method for bacteria to estimate the microsatellite mutation rate in the species, deriving an estimate that is extremely similar to that estimated for a similar set of loci in humans, indicating consistency of microsatellite mutation rates in mammals. Finally, we find slight significant structure between some geographically separated colonies, although its biological significance is unclear. This work demonstrates that genetic analysis can be useful for evaluating the population biology of the northern elephant seal, in spite of the bottleneck that removed most genetic variation from the species.

Characterization of Expression Quantitative Trait Loci in Pedigrees from Colombia and Costa Rica Ascertained for Bipolar Disorder.

The observation that variants regulating gene expression (expression quantitative trait loci, eQTL) are at a high frequency among SNPs associated with complex traits has made the genome-wide characterization of gene expression an important tool in genetic mapping studies of such traits. As part of a study to identify genetic loci contributing to bipolar disorder and other quantitative traits in members of 26 pedigrees from Costa Rica and Colombia, we measured gene expression in lymphoblastoid cell lines derived from 786 pedigree members. The study design enabled us to comprehensively reconstruct the genetic regulatory network in these families, provide estimates of heritability, identify eQTL, evaluate missing heritability for the eQTL, and quantify the number of different alleles contributing to any given locus. In the eQTL analysis, we utilize a recently proposed hierarchical multiple testing strategy which controls error rates regarding the discovery of functional variants. Our results elucidate the heritability and regulation of gene expression in this unique Latin American study population and identify a set of regulatory SNPs which may be relevant in future investigations of complex disease in this population. Since our subjects belong to extended families, we are able to compare traditional kinship-based estimates with those from more recent methods that depend only on genotype information.

Prevalence and clinical correlates of explosive outbursts in Tourette syndrome.

The aim of this study was to examine the prevalence and clinical correlates of explosive outbursts in two large samples of individuals with Tourette syndrome (TS), including one collected primarily from non-clinical sources. Participants included 218 TS-affected individuals who were part of a genetic study (N=104 from Costa Rica (CR) and N=114 from the US). The relationships between explosive outbursts and comorbid attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), tic severity, and prenatal and perinatal complications were examined using regression analyses. Twenty percent of participants had explosive outbursts, with no significant differences in prevalence between the CR (non-clinical) and the US (primarily clinical) samples. In the overall sample, ADHD, greater tic severity, and lower age of tic onset were strongly associated with explosive outbursts. ADHD, prenatal exposure to tobacco, and male gender were significantly associated with explosive outbursts in the US sample. Lower age of onset and greater severity of tics were significantly associated with explosive outbursts in the CR sample. This study confirms previous studies that suggest that clinically significant explosive outbursts are common in TS and associated with ADHD and tic severity. An additional potential risk factor, prenatal exposure to tobacco, was also identified.

Sex-stratified linkage analysis identifies a female-specific locus for IgE to cockroach in Costa Ricans.

RATIONALE: The basis for gender influences on allergen-specific IgEs is unclear. OBJECTIVES: To perform regular and sex-stratified genomewide linkage analyses of IgE to each of three allergens (Ascaris lumbricoides, Blatella germanica [German cockroach]), and Dermatophagoides pteronyssinus [dust mite]) and to conduct an association study of a candidate gene in a linked genomic region. METHODS: Genomewide linkage analyses of allergen-specific IgEs were conducted in 653 members of eight large families of Costa Rican children with asthma. An analysis of the association between single-nucleotide polymorphisms in thymic stromal lymphopoietin (TSLP) and IgE measurements was conducted in 417 parent-child trios in Costa Rica. Significant results were replicated in 470 families of white children in the Childhood Asthma Management Program (CAMP). MEASUREMENTS AND MAIN RESULTS: Among all subjects, there was suggestive evidence of linkage (LOD >/= 2.72) to IgE to Ascaris (on chromosome 7q) and IgE to dust mite (on chromosomes 7p and 12q). In a sex-stratified analysis, there was significant evidence of linkage to IgE to cockroach on chromosome 5q23 (peak LOD, 4.14 at 127 cM) in female subjects. TSLP is located within the 1.5 LOD-unit support interval for this linkage peak and has female-specific effects on lung disease in mice. In a sex-stratified analysis, the T allele of single-nucleotide polymorphism rs2289276 in TSLP was associated with reductions in IgE to cockroach (in Costa Rican girls) and total IgE (in girls in Costa Rica and in CAMP; P value for sex-by-genotype interaction, <0.01 in both studies). CONCLUSIONS: Consistent with findings in murine models, a variant in TSLP may have female-specific effects on allergic phenotypes.

Tic symptom profiles in subjects with Tourette Syndrome from two genetically isolated populations.

BACKGROUND: Tourette Syndrome (TS) has a complex etiology and wide variability in phenotypic expression. Identifying underlying symptom patterns may be useful for etiological and outcome studies of TS. METHODS: Lifetime tic and related symptom data were collected between 1996 and 2001 in 121 TS subjects from the Central Valley of Costa Rica and 133 TS subjects from the Ashkenazi Jewish (AS) population in the US. Subjects were grouped by tic symptoms using an agglomerative hierarchical cluster analysis. Cluster membership was tested for association with available ancillary information (age of onset, tic severity, comorbid disorders, medication treatment and family history). RESULTS: Cluster analysis identified two distinct groups in each sample, those with predominantly simple tics (cluster 1), and those with multiple complex tics (cluster 2). Membership in cluster 2 was correlated with increased tic severity, global impairment, medication treatment, and presence of comorbid obsessive-compulsive symptoms in both samples, and with family history of tics, lower verbal IQ, earlier age of onset, and comorbid obsessive-compulsive disorder and attention-deficit/hyperactivity disorder in the AS sample. CONCLUSIONS: This study provides evidence for consistent and reproducible symptom profiles in two independent TS study samples. These findings have implications for etiological studies of TS.

Significant linkage to airway responsiveness on chromosome 12q24 in families of children with asthma in Costa Rica.

Although asthma is a major public health problem in certain Hispanic subgroups in the United States and Latin America, only one genome scan for asthma has included Hispanic individuals. Because of small sample size, that study had limited statistical power to detect linkage to asthma and its intermediate phenotypes in Hispanic participants. To identify genomic regions that contain susceptibility genes for asthma and airway responsiveness in an isolated Hispanic population living in the Central Valley of Costa Rica, we conducted a genome-wide linkage analysis of asthma (n = 638) and airway responsiveness (n = 488) in members of eight large pedigrees of Costa Rican children with asthma. Nonparametric multipoint linkage analysis of asthma was conducted by the NPL-PAIR allele-sharing statistic, and variance component models were used for the multipoint linkage analysis of airway responsiveness as a quantitative phenotype. All linkage analyses were repeated after exclusion of the phenotypic data of former and current smokers. Chromosome 12q showed some evidence of linkage to asthma, particularly in nonsmokers (P < 0.01). Among nonsmokers, there was suggestive evidence of linkage to airway responsiveness on chromosome 12q24.31 (LOD = 2.33 at 146 cM). After genotyping 18 additional short-tandem repeat markers on chromosome 12q, there was significant evidence of linkage to airway responsiveness on chromosome 12q24.31 (LOD = 3.79 at 144 cM), with a relatively narrow 1.5-LOD unit support interval for the observed linkage peak (142-147 cM). Our results suggest that chromosome 12q24.31 contains a locus (or loci) that influence a critical intermediate phenotype of asthma (airway responsiveness) in Costa Ricans.

Genome-wide linkage analysis of pulmonary function in families of children with asthma in Costa Rica.

BACKGROUND: Although asthma is highly prevalent among certain Hispanic subgroups, genetic determinants of asthma and asthma-related traits have not been conclusively identified in Hispanic populations. A study was undertaken to identify genomic regions containing susceptibility loci for pulmonary function and bronchodilator responsiveness (BDR) in Costa Ricans. METHODS: Eight extended pedigrees were ascertained through schoolchildren with asthma in the Central Valley of Costa Rica. Short tandem repeat (STR) markers were genotyped throughout the genome at an average spacing of 8.2 cM. Multipoint variance component linkage analyses of forced expiratory volume in 1 second (FEV(1)) and FEV(1)/ forced vital capacity (FVC; both pre-bronchodilator and post-bronchodilator) and BDR were performed in these eight families (pre-bronchodilator spirometry, n = 640; post-bronchodilator spirometry and BDR, n = 624). Nine additional STR markers were genotyped on chromosome 7. Secondary analyses were repeated after stratification by cigarette smoking. RESULTS: Among all subjects, the highest logarithm of the odds of linkage (LOD) score for FEV(1) (post-bronchodilator) was found on chromosome 7q34-35 (LOD = 2.45, including the additional markers). The highest LOD scores for FEV(1)/FVC (pre-bronchodilator) and BDR were found on chromosomes 2q (LOD = 1.53) and 9p (LOD = 1.53), respectively. Among former and current smokers there was near-significant evidence of linkage to FEV(1)/FVC (post-bronchodilator) on chromosome 5p (LOD = 3.27) and suggestive evidence of linkage to FEV(1) on chromosomes 3q (pre-bronchodilator, LOD = 2.74) and 4q (post-bronchodilator, LOD = 2.66). CONCLUSIONS: In eight families of children with asthma in Costa Rica, there is suggestive evidence of linkage to FEV(1) on chromosome 7q34-35. In these families, FEV(1)/FVC may be influenced by an interaction between cigarette smoking and a locus (loci) on chromosome 5p.

Sex-specific linkage to total serum immunoglobulin E in families of children with asthma in Costa Rica.

Serum total immunoglobulin E (IgE) is a critical intermediate phenotype of allergic diseases. Although total IgE exhibits sexual dimorphism in humans (with males demonstrating higher IgE than females), the molecular basis of this difference is unknown. A genome-wide scan of 380 short-tandem repeat (STR) markers was performed in eight extended pedigrees of asthmatic children (n=655) from the Central Valley of Costa Rica. Genome-wide linkage analysis of total IgE was performed by variance component models. Among all subjects, only one genomic region (chromosome 7p15) showed modest evidence of linkage to total IgE (LOD=1.60). In contrast, a sex-stratified analysis revealed distinct genetic architectures of total IgE in males and females and identified significant linkage to total IgE on a novel male-specific locus on chromosome 20p12 (LOD=3.63 at 36 cM). Genotyping of additional STRs on chromosome 20 resulted in improved evidence for linkage (LOD=3.75 at 33 cM) and a 1.5 LOD-unit support interval for the linkage peak between 26 and 38 cM. Three polymorphisms in two genes on chromosome 20p12 (JAG1 and ANKRD5) were then found to be associated with total IgE in 420 nuclear families of Costa Rican children with asthma. Two of these polymorphisms (in JAG1) were significantly associated with total IgE in families of boys (n=264) but not in families of girls (n=156) with asthma. JAG1 is a hematopoetic cell growth factor that may regulate normal B-cell development. This is the first demonstration of a possible genetic basis for differences in total IgE between sexes.

Overrepresentation of rare variants in a specific ethnic group may confuse interpretation of association analyses.

Rare sequence variants may be important in understanding the biology of common diseases, but clearly establishing their association with disease is often difficult. Association studies of such variants are becoming increasingly common as large-scale sequence analysis of candidate genes has become feasible. A recent report suggested SLITRK1 (Slit and Trk-like 1) as a candidate gene for Tourette Syndrome (TS). The statistical evidence for this suggestion came from association analyses of a rare 3'-UTR variant, var321, which was observed in two patients but not observed in more than 2000 controls. We genotyped 307 Costa Rican and 515 Ashkenazi individuals (TS probands and their parents) and observed var321 in five independent Ashkenazi parents, two of whom did not transmit this variant to their affected child. Furthermore, we identified var321 in one subject from an Ashkenazi control sample. Our findings do not support the previously reported association and suggest that var321 is overrepresented among Ashkenazi Jews compared with other populations of European origin. The results further suggest that overrepresentation of rare variants in a specific ethnic group may complicate the interpretation of association analyses of such variants, highlighting the particular importance of precisely matching case and control populations for association analyses of rare variants.

Genetic studies of neuropsychiatric disorders in Costa Rica: a model for the use of isolated populations.

The importance of genetics in understanding the etiology of mental illness has become increasingly clear in recent years, as more evidence has mounted that almost all neuropsychiatric disorders have a genetic component. It has also become clear, however, that these disorders are etiologically complex, and multiple genetic and environmental factors contribute to their makeup. So far, traditional linkage mapping studies have not definitively identified specific disease genes for neuropsychiatric disorders, although some potential candidates have been identified via these methods (e.g. the dysbindin gene in schizophrenia; Straub et al., 2002; Schwab et al., 2003). For this reason, alternative approaches are being attempted, including studies in genetically isolated populations. Because isolated populations have a high degree of genetic homogeneity, their use may simplify the process of identifying disease genes in disorders where multiple genes may play a role. Several areas of Latin America contain genetically isolated populations that are well suited for the study of neuropsychiatric disorders. Genetic studies of several major psychiatric illnesses, including bipolar disorder, major depression, schizophrenia, Tourette Syndrome, alcohol dependence, attention deficit hyperactivity disorder, and obsessive-compulsive disorder, are currently underway in these regions. In this paper we highlight the studies currently being conducted by our groups in the Central Valley of Costa Rica to illustrate the potential advantages of this population for genetic studies.

Genetic mapping using haplotype and model-free linkage analysis supports previous evidence for a locus predisposing to severe bipolar disorder at 5q31-33.

We report further evidence for our previous suggestion [Garner et al., 2001: Am J Hum Genet 68:1061-1064] of a locus on 5q predisposing to bipolar I disorder (BP-I) in an extended Costa Rican pedigree. We genotyped additional microsatellite markers in this region and applied a multi-point non-parametric linkage analysis (SimWalk2). Significant identity-by-descent allele sharing among affected relatives was observed for all of the 20 markers tested in a segment of approximately 15 cM. Most affected individuals shared a single haplotype over this region; breaks within this haplotype may suggest a more restricted candidate location for a BP-I gene. These results support the suggestion that a locus at 5q31-33, together with a previously reported locus at 18q22-23, may provide the major genetic risk for BP-I in this family.

Comorbidity of bipolar disorder and substance abuse in Costa Rica: pedigree- and population-based studies.

BACKGROUND: The purpose of this study was to determine the prevalence of substance use disorders (substance abuse or substance dependence: SA/SD) in a large sample of Bipolar Type I (BPI) patients drawn from the Costa Rican population and to describe the effects of SA/SD on the course of their bipolar disorder. METHOD: 110 subjects from two high-risk (for BPI) Costa Rican pedigrees and 205 unrelated Costa Rican BPI subjects were assessed using structured interviews and a best estimate process. Chi(2) and survival analyses were performed to assess the effect of gender on comorbidity risk, and the effect of comorbidity on the clinical course of BPI. RESULTS: SA/SD (primarily alcohol dependence) occurred in 17% of the BPI patients from the population sample and 35% of the BPI patients from the pedigree sample. Comorbid SA/SD was strongly associated with gender chi(2) = 16.84, P = 0.00004). In comorbid subjects, alcohol dependence tended to predate the first manic episode (chi(2) = 6.54, P < 0.025). History of SA/SD did not significantly alter the prevalence of psychosis or age of onset of mania in BPI subjects. CONCLUSIONS: These results suggest that SA/SD comorbidity rates are lower in this type of population than in BPI patient populations in the US. Gender is a strong predictor of comorbidity prevalence in BPI patients from this population. Although SA/SD may be a risk factor for precipitating BPI in those at risk, in this population comorbid BPI subjects do not have a different onset or course of BPI in comparison to BPI patients without comorbidity.

Genomewide linkage disequilibrium mapping of severe bipolar disorder in a population isolate.

Genomewide association studies may offer the best promise for genetic mapping of complex traits. Such studies in outbred populations require very densely spaced single-nucleotide polymorphisms. In recently founded population isolates, however, extensive linkage disequilibrium (LD) may make these studies feasible with currently available sets of short tandem repeat markers, spaced at intervals as large as a few centimorgans. We report the results of a genomewide association study of severe bipolar disorder (BP-I), using patients from the isolated population of the central valley of Costa Rica. We observed LD with BP-I on several chromosomes; the most striking results were in proximal 8p, a region that has previously shown linkage to schizophrenia. This region could be important for severe psychiatric disorders, rather than for a specific phenotype.