Maria Lopez

An association study of bipolar mood disorder (type I) with the 5-HTTLPR serotonin transporter polymorphism in a human population isolate from Colombia.

The short variant of a functional length polymorphism in the promoter region of the serotonin transporter has been associated with several behavioural and psychiatric traits, including bipolar mood disorder. The same short allele has also been implicated as a modifier of the bipolar phenotype. Here we evaluate the etiologic/modifier role of this polymorphism in a case (N=103) / control (N=112) sample for bipolar mood disorder (type I) collected from an isolated South American population. We did not detect an association between bipolar disorder and the 5-HTT promoter polymorphism in this sample. However, an excess of the short allele was seen in younger cases and in cases with psychotic symptoms. When combined with data from the literature, the increased frequency of the short allele in patients with psychotic symptoms was statistically significant.

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.

Identification of Suicide Risk Factors in Medellín, Colombia: A Case-Control Study of Psychological Autopsy in a Developing Country

The incidence, methods and risk factors for suicide may vary among the different cultures, which makes necessary to study the risk factors for suicide in specific settings in order to design adequate intervention strategies. This study aims to determine the risk factors for suicide in Medellín (Colombia). It is a case-control study conducted among 108 individuals who committed suicide and 108 deceased in accidents, matched for age and gender. Both cases and controls were examined by means of psychological autopsy. Conditional logistic regression analysis identified the following factors: Adverse life events in the last six months (OR = 11.81, 95% CI: 4.29–32.52), family history of suicide (OR = 10.82, 95% CI: 2.23–52.47), major depressive episode (OR = 4.58, 95% CI: 1.53–13.67) and expression of a wish to die (OR = 3.54, 95% CI: 1.25–10.06). These findings may suggest that risk factors for suicide are similar across cultures.

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

Significance Characterizing the abnormalities in sleep and activity that are associated with bipolar disorder (BP) and identifying their causation are key milestones in unraveling the biological underpinnings of this severe and highly prevalent disorder. We have conducted the first systematic evaluation of sleep and activity phenotypes in pedigrees that include multiple BP-affected members. By delineating specific sleep and activity measures that are significantly heritable in these families, and those whose variation correlated with the BP status of their members, and by determining the chromosomal position of loci contributing to many of these traits, we have taken the first step toward discovery of causative genetic variants. These variants, in turn, could provide clues to new approaches for both preventing and treating BP. 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.

Hijos de pacientes con trastorno afectivo bipolar tipo I de una población paisa: perfil psicopatológico y neuropsicológico

Resumen Objetivo Caracterizar los principales hallazgos psicopatologicos y los perfiles neuropsicologicos de un grupo de hijos de pacientes adultos con TAB de ascendencia antioquena. Metodos 20 sujetos hijos de pacientes con TAB tipo I se evaluaron por medio de la entrevista diagnostica K-SADS-LP para establecer sus diagnosticos segun criterios del DSM-IV-TR. Tambien se les aplicaron varias subpruebas de la Evaluacion Neuropsicologica Infantil (ENI) y una version abreviada de la Escala de Inteligencia para ninos WISC III. Los padres bipolares y los copadres biologicos fueron evaluados con la Entrevista Diagnostica para Estudios Geneticos (DIGS). Resultados Los trastornos psiquiatricos mas frecuentes fueron los de ansiedad de separacion (35%), fobia simple (20%), trastorno por deficit de atencion con hiperactividad (50%) y trastorno oposicionista y desafiante (20%). Como un hallazgo psicopatologico frecuente, este grupo presento, ademas, sintomas subsindromaticos de ansiedad y trastorno por deficit de atencion con hiperactividad. Ninguno de los hijos evaluados presento TAB y solo dos casos presentaron trastorno depresivo mayor; sin embargo, se encontraron sintomas subsindromaticos para mania en una cuarta parte de la muestra. Los hallazgos neuropsicologicos principales en los HPB fueron dificultades de memoria de evocacion, memoria diferida y almacenamiento de informacion. Conclusiones Este grupo de ninos y adolescentes hijos de padres con TAB tipo I del aislado genetico antioqueno, presenta diagnosticos segun el DSM-IV-TR de trastorno de ansiedad y TDAH y, ademas, sintomas subsindromicos de diversos trastornos psiquiatricos, incluido el TAB. Algunas medidas neuropsicologicas muestran un menor rendimiento en pruebas de memoria y atencion.

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 evaluate this hypothesis, we conducted genetic analyses in 26 Colombian (CO) and Costa Rican (CR) pedigrees ascertained for BP1, the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 856 individuals and high-coverage whole-genome sequencing of 454 individuals. Compared to their unaffected relatives, BP1 individuals had higher polygenic risk scores estimated from SNPs associated with BP discovered in independent genome-wide association studies, and also displayed a higher burden of rare deleterious single nucleotide variants (SNVs) and rare copy number variants (CNVs) in genes likely to be relevant to BP1. Parametric and non-parametric linkage analyses identified 15 BP1 linkage peaks, encompassing about 100 genes, although we observed no significant segregation pattern for any particular rare SNVs and CNVs. These results suggest that even in extended pedigrees, genetic risk for BP appears to derive mainly from small to moderate effect rare and common variants.

Understanding the Hidden Complexity of Latin American Population Isolates

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.