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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.

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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.

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Most population isolates examined to date were founded from a single ancestral population. Consequently, there is limited knowledge about the demographic history of admixed population isolates. Here we investigate genomic diversity of recently admixed population isolates from Costa Rica and Colombia and compare their diversity to a benchmark population isolate, the Finnish. These Latin American isolates originated during the 16th century from admixture between a few hundred European males and Amerindian females, with a limited contribution from African founders. We examine whole-genome sequence data from 449 individuals, ascertained as families to build mutigenerational pedigrees, with a mean sequencing depth of coverage of approximately 36×. We find that Latin American isolates have increased genetic diversity relative to the Finnish. However, there is an increase in the amount of identity by descent (IBD) segments in the Latin American isolates relative to the Finnish. The increase in IBD segments is likely a consequence of a very recent and severe population bottleneck during the founding of the admixed population isolates. Furthermore, the proportion of the genome that falls within a long run of homozygosity (ROH) in Costa Rican and Colombian individuals is significantly greater than that in the Finnish, suggesting more recent consanguinity in the Latin American isolates relative to that seen in the Finnish. Lastly, we find that recent consanguinity increased the number of deleterious variants found in the homozygous state, which is relevant if deleterious variants are recessive. Our study suggests that there is no single genetic signature of a population isolate.

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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.

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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.

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We performed a whole genome microsatellite marker scan in six multiplex families with bipolar (BP) mood disorder ascertained in Antioquia, a historically isolated population from North West Colombia. These families were characterized clinically using the approach employed in independent ongoing studies of BP in the closely related population of the Central Valley of Costa Rica. The most consistent linkage results from parametric and non-parametric analyses of the Colombian scan involved markers on 5q31-33, a region implicated by the previous studies of BP in Costa Rica. Because of these concordant results, a follow-up study with additional markers was undertaken in an expanded set of Colombian and Costa Rican families; this provided a genome-wide significant evidence of linkage of BPI to a candidate region of approximately 10 cM in 5q31-33 (maximum non-parametric linkage score=4.395, P<0.00004). Interestingly, this region has been implicated in several previous genetic studies of schizophrenia and psychosis, including disease association with variants of the enthoprotin and gamma-aminobutyric acid receptor genes.

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We have ascertained in the Central Valley of Costa Rica a new kindred (CR201) segregating for severe bipolar disorder (BP-I). The family was identified by tracing genealogical connections among eight persons initially independently ascertained for a genome wide association study of BP-I. For the genome screen in CR201, we trimmed the family down to 168 persons (82 of whom are genotyped), containing 25 individuals with a best-estimate diagnosis of BP-I. A total of 4,690 SNP markers were genotyped. Analysis of the data was hampered by the size and complexity of the pedigree, which prohibited using exact multipoint methods on the entire kindred. Two-point parametric linkage analysis, using a conservative model of transmission, produced a maximum LOD score of 2.78 on chromosome 6, and a total of 39 loci with LOD scores >1.0. Multipoint parametric and non-parametric linkage analysis was performed separately on four sections of CR201, and interesting (nominal P-value from either analysis <0.01), although not statistically significant, regions were highlighted on chromosomes 1, 2, 3, 12, 16, 19, and 22, in at least one section of the pedigree, or when considering all sections together. The difficulties of analyzing genome wide SNP data for complex disorders in large, potentially informative, kindreds are discussed.

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