Systematic exploration of a decade of publications on psychiatric genetics in Latin America.

Psychiatric disorders have a great impact in terms of mortality, morbidity, and disability across the lifespan. Considerable effort has been devoted to understanding their complex and heterogeneous genetic architecture, including diverse ancestry populations. Our aim was to review the psychiatric genetics research published with Latin American populations from 2010 to 2019, and classify it according to country of origin, type of analysis, source of funding, and other variables. We found that most publications came from Brazil, Mexico, and Colombia. Also, local funds are generally not large enough for genome-wide studies in Latin America, with the exception of Brazil and Mexico; larger studies are often done in collaboration with international partners, mostly funded by US agencies. In most of the larger studies, the participants are individuals of Latin American ancestry living in the United States, which limits the potential for exploring the complex gene-environment interaction. Family studies, traditionally strong in Latin America, represent about 30% of the total research publications. Scarce local resources for research in Latin America have probably been an important limitation for conducting bigger and more complex studies, contributing to the reduced representation of these populations in global psychiatric genetics studies. Increasing diversity must be a goal to improve generalizability and applicability in clinical settings.

Genome-wide mapping of brain phenotypes in extended pedigrees with strong genetic loading for bipolar disorder.

Bipolar disorder is a highly heritable illness, associated with alterations of brain structure. As such, identification of genes influencing inter-individual differences in brain morphology may help elucidate the underlying pathophysiology of bipolar disorder (BP). To identify quantitative trait loci (QTL) that contribute to phenotypic variance of brain structure, structural neuroimages were acquired from family members (n = 527) of extended pedigrees heavily loaded for bipolar disorder ascertained from genetically isolated populations in Latin America. Genome-wide linkage and association analysis were conducted on the subset of heritable brain traits that showed significant evidence of association with bipolar disorder (n = 24) to map QTL influencing regional measures of brain volume and cortical thickness. Two chromosomal regions showed significant evidence of linkage; a QTL on chromosome 1p influencing corpus callosum volume and a region on chromosome 7p linked to cortical volume. Association analysis within the two QTLs identified three SNPs correlated with the brain measures.

Genetic analysis of activity, brain and behavioral associations in extended families with heavy genetic loading for bipolar disorder.

BACKGROUND: Disturbed sleep and activity are prominent features of bipolar disorder type I (BP-I). However, the relationship of sleep and activity characteristics to brain structure and behavior in euthymic BP-I patients and their non-BP-I relatives is unknown. Additionally, underlying genetic relationships between these traits have not been investigated. METHODS: Relationships between sleep and activity phenotypes, assessed using actigraphy, with structural neuroimaging (brain) and cognitive and temperament (behavior) phenotypes were investigated in 558 euthymic individuals from multi-generational pedigrees including at least one member with BP-I. Genetic correlations between actigraphy-brain and actigraphy-behavior associations were assessed, and bivariate linkage analysis was conducted for trait pairs with evidence of shared genetic influences. RESULTS: More physical activity and longer awake time were significantly associated with increased brain volumes and cortical thickness, better performance on neurocognitive measures of long-term memory and executive function, and less extreme scores on measures of temperament (impulsivity, cyclothymia). These associations did not differ between BP-I patients and their non-BP-I relatives. For nine activity-brain or activity-behavior pairs there was evidence for shared genetic influence (genetic correlations); of these pairs, a suggestive bivariate quantitative trait locus on chromosome 7 for wake duration and verbal working memory was identified. CONCLUSIONS: Our findings indicate that increased physical activity and more adequate sleep are associated with increased brain size, better cognitive function and more stable temperament in BP-I patients and their non-BP-I relatives. Additionally, we found evidence for pleiotropy of several actigraphy-behavior and actigraphy-brain phenotypes, suggesting a shared genetic basis for these traits.

Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates.

Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica pedigrees ascertained for bipolar disorder 1 (BP1), the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 838 individuals and high-coverage whole-genome sequencing of 449 individuals. We compared polygenic risk scores (PRS), estimated using the latest BP1 genome-wide association study (GWAS) summary statistics, between BP1 individuals and related controls. We also evaluated whether BP1 individuals had a higher burden of rare deleterious single-nucleotide variants (SNVs) and rare copy number variants (CNVs) in a set of genes related to BP1. We found that compared with unaffected relatives, BP1 individuals had higher PRS estimated from BP1 GWAS statistics (P = 0.001 ~ 0.007) and displayed modest increase in burdens of rare deleterious SNVs (P = 0.047) and rare CNVs (P = 0.002 ~ 0.033) in genes related to BP1. We did not observe rare variants segregating in the pedigrees. These results suggest that small-to-moderate effect rare and common variants are more likely to contribute to BP1 risk in these extended pedigrees than a few large-effect rare variants.

Reproductive consequences of variation in flowering phenology in the dry forest tree Enterolobium cyclocarpum in Guanacaste, Costa Rica.

PREMISE OF THE STUDY: Flowering initiation, duration and magnitude, and degree of flowering synchrony within a population can affect the reproductive fitness of individuals. We examined the flowering phenology within a population of the tropical dry forest Guanacaste tree (Enterolobium cyclocarpum) to gauge the impact of phenological variation among trees on fruit production and progeny vigor. METHODS: We monitored the flowering phenology of 93 trees weekly during 2005, 2006, and 2007, using a scale based on the percentage of the crown with open flowers. We also monitored fruit production for each tree in 2005, 2006, 2007, and 2008. Finally, we evaluated the relationship between phenological variation and progeny performance. KEY RESULTS: Ten measures of flowering phenology and synchrony among flowering trees, based on the number of weeks when anthesis of the crown exceeded 50%, were used to develop four phenological profiles. These profiles were correlated with significant differences in fruit production and progeny vigor. Trees with flowers in >50% of their crown for at least 2 weeks produced more fruits and more vigorous progeny than trees with other profiles. Trees also tended to produce the same phenological profile among years than predicted by chance. CONCLUSIONS: Guanacaste trees vary significantly in the initiation of anthesis, duration and magnitude of flowering, and degree of synchrony among trees. Trees also tend to maintain the same flowering profile among years. Finally, the flowering behavior of E. cyclocarpum leads to significant differences in fruit and seed production, germination, and early progeny growth.

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.

Genetic contributions to circadian activity rhythm and sleep pattern phenotypes in pedigrees segregating for severe bipolar disorder.

Abnormalities in sleep and circadian rhythms are central features of bipolar disorder (BP), often persisting between episodes. We report here, to our knowledge, the first systematic analysis of circadian rhythm activity in pedigrees segregating severe BP (BP-I). By analyzing actigraphy data obtained from members of 26 Costa Rican and Colombian pedigrees [136 euthymic (i.e., interepisode) BP-I individuals and 422 non-BP-I relatives], we delineated 73 phenotypes, of which 49 demonstrated significant heritability and 13 showed significant trait-like association with BP-I. All BP-I-associated traits related to activity level, with BP-I individuals consistently demonstrating lower activity levels than their non-BP-I relatives. We analyzed all 49 heritable phenotypes using genetic linkage analysis, with special emphasis on phenotypes judged to have the strongest impact on the biology underlying BP. We identified a locus for interdaily stability of activity, at a threshold exceeding genome-wide significance, on chromosome 12pter, a region that also showed pleiotropic linkage to two additional activity phenotypes.

Brain structure-function associations in multi-generational families genetically enriched for bipolar disorder.

Recent theories regarding the pathophysiology of bipolar disorder suggest contributions of both neurodevelopmental and neurodegenerative processes. While structural neuroimaging studies indicate disease-associated neuroanatomical alterations, the behavioural correlates of these alterations have not been well characterized. Here, we investigated multi-generational families genetically enriched for bipolar disorder to: (i) characterize neurobehavioural correlates of neuroanatomical measures implicated in the pathophysiology of bipolar disorder; (ii) identify brain-behaviour associations that differ between diagnostic groups; (iii) identify neurocognitive traits that show evidence of accelerated ageing specifically in subjects with bipolar disorder; and (iv) identify brain-behaviour correlations that differ across the age span. Structural neuroimages and multi-dimensional assessments of temperament and neurocognition were acquired from 527 (153 bipolar disorder and 374 non-bipolar disorder) adults aged 18-87 years in 26 families with heavy genetic loading for bipolar disorder. We used linear regression models to identify significant brain-behaviour associations and test whether brain-behaviour relationships differed: (i) between diagnostic groups; and (ii) as a function of age. We found that total cortical and ventricular volume had the greatest number of significant behavioural associations, and included correlations with measures from multiple cognitive domains, particularly declarative and working memory and executive function. Cortical thickness measures, in contrast, showed more specific associations with declarative memory, letter fluency and processing speed tasks. While the majority of brain-behaviour relationships were similar across diagnostic groups, increased cortical thickness in ventrolateral prefrontal and parietal cortical regions was associated with better declarative memory only in bipolar disorder subjects, and not in non-bipolar disorder family members. Additionally, while age had a relatively strong impact on all neurocognitive traits, the effects of age on cognition did not differ between diagnostic groups. Most brain-behaviour associations were also similar across the age range, with the exception of cortical and ventricular volume and lingual gyrus thickness, which showed weak correlations with verbal fluency and inhibitory control at younger ages that increased in magnitude in older subjects, regardless of diagnosis. Findings indicate that neuroanatomical traits potentially impacted by bipolar disorder are significantly associated with multiple neurobehavioural domains. Structure-function relationships are generally preserved across diagnostic groups, with the notable exception of ventrolateral prefrontal and parietal association cortex, volumetric increases in which may be associated with cognitive resilience specifically in individuals with bipolar disorder. Although age impacted all neurobehavioural traits, we did not find any evidence of accelerated cognitive decline specific to bipolar disorder subjects. Regardless of diagnosis, greater global brain volume may represent a protective factor for the effects of ageing on executive functioning.

Multisystem component phenotypes of bipolar disorder for genetic investigations of extended pedigrees.

IMPORTANCE: Genetic factors contribute to risk for bipolar disorder (BP), but its pathogenesis remains poorly understood. A focus on measuring multisystem quantitative traits that may be components of BP psychopathology may enable genetic dissection of this complex disorder, and investigation of extended pedigrees from genetically isolated populations may facilitate the detection of specific genetic variants that affect BP as well as its component phenotypes. OBJECTIVE: To identify quantitative neurocognitive, temperament-related, and neuroanatomical phenotypes that appear heritable and associated with severe BP (bipolar I disorder [BP-I]) and therefore suitable for genetic linkage and association studies aimed at identifying variants contributing to BP-I risk. DESIGN, SETTING, AND PARTICIPANTS: Multigenerational pedigree study in 2 closely related, genetically isolated populations: the Central Valley of Costa Rica and Antioquia, Colombia. A total of 738 individuals, all from Central Valley of Costa Rica and Antioquia pedigrees, participated; among them, 181 have BP-I. MAIN OUTCOMES AND MEASURES: Familial aggregation (heritability) and association with BP-I of 169 quantitative neurocognitive, temperament, magnetic resonance imaging, and diffusion tensor imaging phenotypes. RESULTS: Of 169 phenotypes investigated, 126 (75%) were significantly heritable and 53 (31%) were associated with BP-I. About one-quarter of the phenotypes, including measures from each phenotype domain, were both heritable and associated with BP-I. Neuroimaging phenotypes, particularly cortical thickness in prefrontal and temporal regions as well as volume and microstructural integrity of the corpus callosum, represented the most promising candidate traits for genetic mapping related to BP based on strong heritability and association with disease. Analyses of phenotypic and genetic covariation identified substantial correlations among the traits, at least some of which share a common underlying genetic architecture. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the most extensive investigation of BP-relevant component phenotypes to date. Our results identify brain and behavioral quantitative traits that appear to be genetically influenced and show a pattern of BP-I association within families that is consistent with expectations from case-control studies. Together, these phenotypes provide a basis for identifying loci contributing to BP-I risk and for genetic dissection of the disorder.

The impact of local extinction on genetic structure of wild populations of lima beans (Phaseolus lunatus) in the Central Valley of Costa Rica: consequences for the conservation of plant genetic resources

Plant populations may experience local extinction and at the same time new populations may appear in nearby suitable locations. Species may also colonize the same site on multiple occasions. Here, we examined the impact of local extinction and recolonization on the genetic structure of wild populations of lima beans (Phaseolus lunatus) in the Central valley of Costa Rica. We compared genetic diversity from the samples taken from the populations before and after extinction at 13 locations using microsatellite markers. Locations were classified according to the occurrence of extinction episodes during the previous five years into three groups: 1) populations that experienced extinction for more than one year, and were later recolonized (recolonized), 2) populations that did not experience local extinction (control), and 3) populations that did not experience local extinction during the study, but were cut to experimentally simulate extinction (experimental). Our data did not show a clear tendency in variation in allele frequencies, expected heterozygosity, and effective number of alleles within and between groups of populations. However, we found that the level of genetic differentiation between samples collected at different times at the same location was different in the three groups of populations. Recolonized locations showed the highest level of genetic differentiation (mean Fst= 0.2769), followed by control locations (mean Fst= 0.0576) and experimental locations (mean Fst= 0.0189). Similar findings were observed for Nei’s genetic distance between samples (di,j= 0.1786, 0.0400, and 0.0037, respectively). Our results indicate that genetic change in lima beans depends on the duration and frequency of local extinction episodes. These findings also showed that control populations are not in equilibrium. Implications of these results for the establishment of conservation strategies of genetic resources of lima beans are discussed. Rev. Biol. Trop. 56 (3): 1023-1041. Epub 2008 September 30.

Las poblaciones de plantas pueden experimentar extinción local, y al mismo tiempo, pueden surgir a sus alrededores nuevas poblaciones. Algunas especies pueden colonizar el mismo sitio en múltiples ocasiones. Aquí examinamos el impacto de la extinción local y recolonización en la estructura genética de poblaciones silvestres del frijol lima (Phaseolus lunatus) en el valle Central de Costa Rica. Comparamos la diversidad genética de muestras tomadas en poblaciones, antes y después de la extinción, en 13 sitios, usando marcadores de microsatélite. Según los episodios de extinción durante los cinco años previos, clasificamos los sitios así: 1) poblaciones que han experimentado extinción por más de un año, y después han recolonizado (recolonizado), 2) poblaciones que no han experimentado extinción local (control), y 3) poblaciones que no han experimentado extinción local durante el estudio, pero fueron cortadas experimentalmente, simulando una extinción (experimental). Nuestros datos no mostraron una clara tendencia en la variación de las frecuencias alélicas, heterozigosidad, o número efectivo de alelos en y entre grupos de poblaciones. Los niveles de diferenciación genética entre muestras recolectadas en diferentes momentos en el mismo sitio fueron diferentes en los tres grupos de poblaciones. Los sitios recolonizados mostraron el mayor nivel de diferenciación genética (Fst = 0.2769), seguidos de los sitios control (Fst= 0.0576) y sitios experimentales (Fst= 0.0189). Obtuvimos resultados similares en la distancia genética Neis entre muestras (d i,j = 0.1786, 0.0400, y 0.0037, respectivamente). Los cambios genéticos en los frijoles lima dependen de la duración y frecuencia de los episodios de extinción local. Las poblaciones "control" no están en equilibrio. Las implicaciones de estos resultados para el establecimiento de estrategias de conservación de los recursos genéticos de habas se encuentran en discusión.

The impact of local extinction on genetic structure of wild populations of lima beans (Phaseolus lunatus) in the Central Valley of Costa Rica: consequences for the conservation of plant genetic resources.

Plant populations may experience local extinction and at the same time new populations may appear in nearby suitable locations. Species may also colonize the same site on multiple occasions. Here, we examined the impact of local extinction and recolonization on the genetic structure of wild populations of lima beans (Phaseolus lunatus) in the Central Valley of Costa Rica. We compared genetic diversity from the samples taken from the populations before and after extinction at 13 locations using microsatellite markers. Locations were classified according to the occurrence of extinction episodes during the previous five years into three groups: 1) populations that experienced extinction for more than one year, and were later recolonized (recolonized), 2) populations that did not experience local extinction (control), and 3) populations that did not experience local extinction during the study, but were cut to experimentally simulate extinction (experimental). Our data did not show a clear tendency in variation in allele frequencies, expected heterozygosity, and effective number of alleles within and between groups of populations. However, we found that the level of genetic differentiation between samples collected at different times at the same location was different in the three groups of populations. Recolonized locations showed the highest level of genetic differentiation (mean F(st) = 0.2769), followed by control locations (mean F(st) = 0.0576) and experimental locations (mean F(st) = 0.0189). Similar findings were observed for Neis genetic distance between samples (d(ij) = 0.1786, 0.0400, and 0.0037, respectively). Our results indicate that genetic change in lima beans depends on the duration and frequency of local extinction episodes. These findings also showed that control populations are not in equilibrium. Implications of these results for the establishment of conservation strategies of genetic resources of lima beans are discussed.

Convergent linkage evidence from two Latin-American population isolates supports the presence of a susceptibility locus for bipolar disorder in 5q31-34.

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.

Results of a SNP genome screen in a large Costa Rican pedigree segregating for severe bipolar disorder.

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.

Variación del tamaño de frutos y semillas en 38 poblaciones silvestres de Phaseolus lunatus (Fabaceae) del Valle Central de Costa Rica / Variation in fruit and seed size from 38 wild populations of Phaseoulus lunatus (Fabaceae) from Central Valley, Costa Rica

We studied the morfological diversity in fruits and seeds in 38 wild populations of Phaseolus lunatus var. lunatus (lima beans) in the central valley of Costa Rica. In order to do so, measured the length and width of the fruits and the length, width and thickness of seeds. We also calculated the ratio between these traits and determined the weight of 100 seeds. In general, we found significant variation between populations for all variables. When we grouped the 38 populations into eight geographical regions within the study area, we found significant differences between regions. However, the levels of variation between populations within geographical regions was larger than that found between geographical regions. These findings suggested that there is no clear relationship between these variables and the geographical grouping established in this study. The implications of these findings for the establishment of strategies for in situ conservation of wild populations of lima beans are discussed.

[Variation in fruit and seed size from 38 wild populations of Phaseolus lunatus (Fabaceae) from Central Valley, Costa Rica]. / Variación del tamaño de frutos y semillas en 38 poblaciones silvestres de Phaseolus lunatus (Fabaceae) del Valle Central de Costa Rica.

We studied the morfological diversity in fruits and seeds in 38 wild populations of Phaseolus lunatus var. lunatus (lima beans) in the central valley of Costa Rica. In order to do so, measured the length and width of the fruits and the length, width and thickness of seeds. We also calculated the ratio between these traits and determined the weight of 100 seeds. In general, we found significant variation between populations for all variables. When we grouped the 38 populations into eight geographical regions within the study area, we found significant differences between regions. However, the levels of variation between populations within geographical regions was larger than that found between geographical regions. These findings suggested that there is no clear relationship between these variables and the geographical grouping established in this study. The implications of these findings for the establishment of strategies for in situ conservation of wild populations of lima beans are discussed.