Jorge Ospina-Duque

Strong Amerind/White sex bias and a possible sephardic contribution among the founders of a population in Northwest Colombia

Historical and genetic evidences suggest that the recently founded population of Antioquia (Colombia) is potentially useful for the genetic mapping of complex traits. This population was established in the 16th-17th centuries through the admixture of Amerinds, Europeans, and Africans and grew in relative isolation until the late 19th century. To examine the origin of the founders of Antioquia, we typed 11 markers on the nonrecombining portion of the Y chromosome and four markers on mtDNA in a sample of individuals with confirmed Antioquian ancestry. The polymorphisms on the Y chromosome (five biallelic markers and six microsatellites) allow an approximation to the origin of founder men, and those on mtDNA identify the four major founder Native American lineages. These data indicate that approximately 94% of the Y chromosomes are European, 5% are African, and 1% are Amerind. Y-chromosome data are consistent with an origin of founders predominantly in southern Spain but also suggest that a fraction came from northern Iberia and that some possibly had a Sephardic origin. In stark contrast with the Y-chromosome, approximately 90% of the mtDNA gene pool of Antioquia is Amerind, with the frequency of the four Amerind founder lineages being closest to Native Americans currently living in the area. These results indicate a highly asymmetric pattern of mating in early Antioquia, involving mostly immigrant men and local native women. The discordance of our data with blood-group estimates of admixture suggests that the number of founder men was larger than that of women.

Effects of recurrence on the cognitive performance of patients with bipolar I disorder: implications for relapse prevention and treatment adherence

OBJECTIVE To determine if the repeated occurrence of manic episodes in bipolar I disorder (BD-I) patients is associated with reduced cognitive performance, which could in turn imply a worsening in the disorders evolution. METHOD Cognitive performance in euthymic patients was assessed using attention, memory, and executive function tests on 24 BD-I patients who had experienced only 1 manic episode, on 27 BD-I patients with 2 manic episodes, on 47 BD-I patients with 3 or more manic episodes, and on 66 healthy control subjects. RESULTS In BD-I patients, number of manic episodes was positively associated with poorer performance on neurocognitive tests, an association that was not accounted for by depression, disease chronicity, onset, or medication. Significant differences in attention and executive function were found between patients and controls and in those patients who had had just 1 manic episode compared to those who had 3 or more. CONCLUSION The number of manic episodes predicted poor cognitive performance, suggesting that the recurrence of mania may have a long-term neuropsychological impact. Prospective follow-up studies need to be completed to explore this effect further as better treatment adherence may have a protective effect on neurocognitive function.

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.

Lithium treatment effects on the neuropsychological functioning of patients with bipolar I disorder.

OBJECTIVE To determine if medication plays a major role in cognitive impairment in bipolar disorder and if regular treatment with lithium influences the cognitive performance of a group of euthymic patients with bipolar I disorder. METHOD Cognitive performance was assessed using neuropsychological tests of attention, memory, and executive function on 60 subjects: 20 euthymic bipolar I patients with no medication intake, 20 euthymic bipolar I patients who were following regular treatment with lithium carbonate monotherapy, and a third group of 20 control healthy subjects. The subjects were evaluated from January 2005 to October 2006. Patients were diagnosed using DSM-IV criteria for bipolar disorder. RESULTS Compared to the healthy group, bipolar I patients had significantly lower performance on episodic verbal and visual-verbal memory regardless of their medication status. No significant cognitive performance differences were found between the two groups of patients with bipolar disorder, suggesting that lithium therapy had no deleterious effects on cognition. CONCLUSION Patients with bipolar I disorder have verbal memory deficits that are not explained by medication or by lithium monotherapy, but by the condition itself.

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.

Evidence for a role of the NOS1AP (CAPON) gene in schizophrenia and its clinical dimensions: an association study in a South American population isolate.

Background/Aims: Recent studies have implicated a region on chromosome 1q21-23, including the NOS1AP gene, in susceptibility to schizophrenia. However, replication studies have been inconsistent, a fact that could partly relate to the marked psychopathological heterogeneity of schizophrenia. The aim of this study is to evaluate association of polymorphisms in the NOS1AP gene region to schizophrenia, in patients from a South American population isolate, and to assess if these variants are associated with specific clinical dimensions of the disorder. Methods: We genotyped 24 densely spaced SNPs in the NOS1AP gene region in a schizophrenia trio sample. The transmission disequilibrium test (TDT) was applied to single marker and haplotype data. Association to clinical dimensions (identified by factor analysis) was evaluated using a quantitative transmission disequilibrium test (QTDT). Results: We found significant association between eight SNPs in the NOS1AP gene region to schizophrenia (minimum p value = 0.004). The QTDT analysis of clinical dimensions revealed an association to a dimension consisting mainly of negative symptoms (minimum p value 0.001). Conclusions: Our findings are consistent with a role for NOS1AP in susceptibility to schizophrenia, especially for the ‘negative syndrome’ of the disorder.

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.

Consensus paper of the WFSBP Task Force on Genetics: genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response

Abstract Major depressive disorder (MDD) is a heritable disease with a heavy personal and socio-economic burden. Antidepressants of different classes are prescribed to treat MDD, but reliable and reproducible markers of efficacy are not available for clinical use. Further complicating treatment, the diagnosis of MDD is not guided by objective criteria, resulting in the risk of under- or overtreatment. A number of markers of MDD and antidepressant response have been investigated at the genetic, epigenetic, gene expression and protein levels. Polymorphisms in genes involved in antidepressant metabolism (cytochrome P450 isoenzymes), antidepressant transport (ABCB1), glucocorticoid signalling (FKBP5) and serotonin neurotransmission (SLC6A4 and HTR2A) were among those included in the first pharmacogenetic assays that have been tested for clinical applicability. The results of these investigations were encouraging when examining patient-outcome improvement. Furthermore, a nine-serum biomarker panel (including BDNF, cortisol and soluble TNF-α receptor type II) showed good sensitivity and specificity in differentiating between MDD and healthy controls. These first diagnostic and response-predictive tests for MDD provided a source of optimism for future clinical applications. However, such findings should be considered very carefully because their benefit/cost ratio and clinical indications were not clearly demonstrated. Future tests may include combinations of different types of biomarkers and be specific for MDD subtypes or pathological dimensions.

Genetics of schizophrenia: A consensus paper of the WFSBP task force on genetics

Abstract Objectives: Schizophrenia is a severe psychiatric disease affecting about 1% of the general population. The relative contribution of genetic factors has been estimated to be up to 80%. The mode of inheritance is complex, non-Mendelian, and in most cases involving the combined action of large numbers of genes. Methods: This review summarises recent efforts to identify genetic variants associated with schizophrenia detected, e.g., through genome-wide association studies, studies on copy-number variants or next-generation sequencing. Results: A large, new body of evidence on genetics of schizophrenia has accumulated over recent years. Many new robustly associated genetic loci have been detected. Furthermore, there is consensus that at least a dozen microdeletions and microduplications contribute to the disease. Genetic overlap between schizophrenia, other psychiatric disorders, and neurodevelopmental syndromes raised new questions regarding the current classification of psychiatric and neurodevelopmental diseases. Conclusions: Future studies will address especially the functional characterisation of genetic variants. This will hopefully open the doors to our understanding of the pathophysiology of schizophrenia and other related diseases. Complementary, integrated systems biology approaches to genomics, transcriptomics, proteomics and metabolomics may also play crucial roles in enabling a precision medicine approach to the treatment of individual patients.

Genome-Wide Linkage Scan of Bipolar Disorder in a Colombian Population Isolate Replicates Loci on Chromosomes 7p21–22, 1p31, 16p12 and 21q21–22 and Identifies a Novel Locus on Chromosome 12q

Background/Aims: Bipolar disorder (BP) is a severe psychiatric illness, characterised by alternating episodes of depression and mania, which ranks among the top ten causes of morbidity and life-long disability world-wide. We have previously performed a whole-genome linkage scan on 6 pedigrees segregating severe BP from the well-characterised population isolate of Antioquia, Colombia. We recently collected genotypes for the same set of 382 autosomal microsatellite markers in 9 additional Antioquian BP pedigrees. Here, we report the analysis of the combined pedigree set. Methods: Linkage analysis using both parametric and nonparametric approaches was conducted for 3 different diagnostic models: severe BP only (BPI); mood disorders (BPI, BPII and major depression); and psychosis (operationally defined by the occurrence of at least 1 episode of hallucinations and/or delusions). Results and Conclusion: For BPI only, the most interesting result was obtained for chromosome 7p21.1–p22.2 under a recessive model of inheritance (heterogeneity LOD score = 2.80), a region that had previously been linked to BP in a study on Portuguese Island families. For both BPI and mood disorders, nonparametric analyses identified a locus on chromosome 12ct–q14 (nonparametric linkage = 2.55 and 2.35, respectively). This locus has not previously been reported as a candidate region for BP. Additional candidate regions were found on chromosomes 1p22–31 (mood disorders) and 21q21–22 (BPI), 2 loci that have repeatedly been implicated in BP susceptibility. Linkage analysis of psychosis as a phenotype identified candidate regions on chromosomes 2q24–31 and 16p12–q12. The finding on chromosome 16p is noteworthy because the same locus has been implicated by genome-wide association analyses of BP.