A genome-wide association study identifies novel gene associations with facial skin wrinkling and mole count in Latin Americans.

BACKGROUND: Genome-wide association studies (GWASs) have identified genes influencing skin ageing and mole count in Europeans, but little is known about the relevance of these (or other genes) in non-Europeans. OBJECTIVES: To conduct a GWAS for facial skin ageing and mole count in adults < 40 years old, of mixed European, Native American and African ancestry, recruited in Latin America. METHODS: Skin ageing and mole count scores were obtained from facial photographs of over 6000 individuals. After quality control checks, three wrinkling traits and mole count were retained for genetic analyses. DNA samples were genotyped with Illumina's HumanOmniExpress chip. Association testing was performed on around 8 703 729 single-nucleotide polymorphisms (SNPs) across the autosomal genome. RESULTS: Genome-wide significant association was observed at four genome regions: two were associated with wrinkling (in 1p13·3 and 21q21·2), one with mole count (in 1q32·3) and one with both wrinkling and mole count (in 5p13·2). Associated SNPs in 5p13·2 and in 1p13·3 are intronic within SLC45A2 and VAV3, respectively, while SNPs in 1q32·3 are near the SLC30A1 gene, and those in 21q21·2 occur in a gene desert. Analyses of SNPs in IRF4 and MC1R are consistent with a role of these genes in skin ageing. CONCLUSIONS: We replicate the association of wrinkling with variants in SLC45A2, IRF4 and MC1R reported in Europeans. We identify VAV3 and SLC30A1 as two novel candidate genes impacting on wrinkling and mole count, respectively. We provide the first evidence that SLC45A2 influences mole count, in addition to variants in this gene affecting melanoma risk in Europeans.

RNASEH1 gene variants are associated with autoimmune type 1 diabetes in Colombia.

BACKGROUND: In a previous work, we found linkage and association of type 1 diabetes (T1D) to a 12 known gene region at chromosome 2p25 in Colombian families. Here, we present further work on this candidate region. MATERIALS AND METHODS: Seventeen SNPs located on the 12 candidate genes, in 100 familial trios set, were tested by ARMS-tetraprimer-PCR or PCR-RFLP. Five extra SNPs in the vicinity of rs10186193 were typed. A replica phase included 97 novel familial trios, in whom diabetes-related auto-antibodies (AABs) were tested in sera of the patients. In addition to transmission disequilibrium tests, haplotype analyses were carried out using the unphased software. RESULTS: SNP rs10186193 (at RNASEH1 gene) showed association with T1D (P = 0.005). The additional five SNPs revealed that rs7607888 (P = 2.03 × 10-7), rs55981318 (P = 0.018), and rs1136545 (P = 1.93 × 10-9) were also associated with T1D. Haplotype analysis showed association for rs55981318-rs10186193 (P = 0.0005), rs7563960-rs7607888 (P = 0.0007), rs7607888-rs1136545 (P = 9.21 × 10-10), and rs1136545-rs11538545 (P = 6.67 × 10-8). In contrast, the new set of 97 familial trios tested for SNPs rs55981318, rs10186193, and rs7607888 did not support the previous finding; however, by combining the sample (197 trios), evidence of association of T1D with rs55981318 and rs7607888 was conclusive. In addition, a two-loci haplotype analysis of the combined sample showed significant association of RNASEH1 with T1D (P = 3.1 × 10-5). CONCLUSION: In conclusion, our analyses suggest that RNASEH1 gene variants associate with susceptibility/protection to T1D in Colombia.

Prevalencia y severidad de las lesiones precursoras de malignidad en una área de alto riesgo de cáncer gástrico. Pasto 2012 / Prevalence and severity of gastric cancer precursor lesions in a high risk area

Las lesiones precursoras de malignidad (gastritis crónica atrófica, metaplasia intestinal y displasia leve), según lo demuestran múltiples estudios, están claramente relacionadas con el riesgo que presentan como predictoras del cáncer gástrico y más aún en nuestra región considerada como de alto riesgo de esta patología. Se realizó un estudio prospectivo descriptivo con 212 pacientes entre 11 y 89 años de edad procedentes de la zona amarilla del departamento de Nariño, atendidos en el Centro de Investigaciones de Enfermedades Digestivas (CIED) del Centro Hospital La Rosa dependiente de la ESE Pasto Salud a quienes se tomaron 7 biopsias de mucosa gástrica sometidas a un procesamiento y coloración especial de Giemsa modificado para detectar lesiones precursoras de malignidad y presencia de Helicobacter Pylori. La prevalencia para gastritis crónica atrófica antrocorporal fue de 38,6%, metaplasia intestinal 24,4% y displasia leve 1,5%; presencia de infección para Helicobacter pylori en gastritis crónica atrófica 73,5%, para metaplasia intestinal 52% y displasia leve 100%; en relación a la severidad de las lesiones precursoras de malignidad de acuerdo a la escala de OLGA, 11,5% se clasificó como estadios III y IV; a excepción de un solo caso clínico todos fueron Helicobacter Pylori positivos. Se pone en consideración de la comunidad médica el protocolo del CIED para seguimiento y vigilancia de las lesiones precursoras de malignidad tratando de demostrar que la mayor estrategia sigue siendo la prevención para el control del cáncer gástrico en las regiones de alto riesgo.

Atrophic chronic gastritis (ACG), intestinal metaplasia (IM) and mild dysplasia (MD)) are all precursor lesions which have been clearly demonstrated by many studies to be related to risks for development of gastric cancer (GC). This is especially true in our region which is considered to be a high risk area for this disease. We conducted a prospective study of 212 patients between the ages of 11 and 89 years who were from the yellow zone of Nariño. Patients were cared for in the Centro de Investigaciones de Enfermedades Digestivas (CIED - Center for the Investigation of Digestive Diseases) at the Centro Hospital la Rosa which is part of the public health care system of Pasto. Seven gastric mucosa biopsies were taken from each subject and stained with specially modified Giemsa stain to detect precursor lesions and the presence of Helicobacter pylori. The prevalence of ACG was 38.6%, the prevalence of IM was 24.4%, and the prevalence of MD was 1.5%. Prevalence of H. pylori infections among patients with ACG was 73.5% while among patients with IM it was 52%, but prevalence rose to 100% among patients with MD. When severity of precursor lesions on the OLGA-staging (Operative Link for Gastritis Assessment) scale was 11.5%, lesions were classified as stage III and IV. With one exception, all of these patients were H. pylori positive. We would like to ask the medical community to consider CIED's Follow-up and Monitoring Protocol for precursor lesions in order to demonstrate that the best strategy continues to be GC prevention in high risk regions.

Increased plasma levels of total homocysteine but not asymmetric dimethylarginine in Hispanic subjects with ischemic stroke FREC-VI sub-study.

BACKGROUND AND PURPOSE: Despite sharing some metabolic and pathological mechanisms, the reported association between total homocysteine (tHcy), asymmetric dimethylarginine (ADMA) and stroke remains controversial, particularly in Hispanic populations from developing countries in which genetic, socioeconomic, and nutritional factors are different to those described in developed countries. Our objectives were to determine the relationships of these factors to stroke and to each other independent of other cardiovascular risk factors, and to explore potential sex differences. METHODS: This national (Colombia) multicenter case-control study included 238 cases and 238 controls to evaluate traditional and emerging risk factors for ischemic stroke including tHcy and ADMA plasma levels. RESULTS: The median plasma levels of tHcy were 8.48 µM for controls and 10.01 µM for cases (P<0.0001). Plasma levels of tHcy between 12 and 50µM were considered moderate hyperhomocysteinemia (HtHcy). There were no differences in plasma ADMA concentration between groups (P=0.40). Plasma levels of ADMA and creatinine were not correlated (P=0.47). After adjusting for confounding factors, the presence of HtHcy was strongly associated with stroke (OR 8.97; P<0.0001). The adjusted association between HtHcy and stroke in men (OR 9.98) was comparable to that in women (OR 8.98) (P=0.41). CONCLUSIONS: In this Hispanic population, with relatively normal renal function, plasma levels of tHcy but not ADMA were associated with stroke independent of other cardiovascular risk factors.

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.

Strong association of socioeconomic status with genetic ancestry in Latinos: implications for admixture studies of type 2 diabetes.

AIMS/HYPOTHESIS: Type 2 diabetes is more prevalent in US American minority populations of African or Native American descent than it is in European Americans. However, the proportion of this epidemiological difference that can be ascribed to genetic or environmental factors is unknown. To determine whether genetic ancestry is correlated with diabetes risk in Latinos, we estimated the proportion of European ancestry in case-control samples from Mexico and Colombia in whom socioeconomic status had been carefully ascertained. METHODS: We genotyped 67 ancestry-informative markers in 499 participants with type 2 diabetes and 197 controls from Medellín (Colombia), as well as in 163 participants with type 2 diabetes and 72 controls from central Mexico. Each participant was assigned a socioeconomic status scale via various measures. RESULTS: Although European ancestry was associated with lower diabetes risk in Mexicans (OR [95% CI] 0.06 [0.02-0.21], p = 2.0 x 10(-5)) and Colombians (OR 0.26 [0.08-0.78], p = 0.02), adjustment for socioeconomic status eliminated the association in the Colombian sample (OR 0.64 [0.19-2.12], p = 0.46) and significantly attenuated it in the Mexican sample (OR 0.17 [0.04-0.71], p = 0.02). Adjustment for BMI did not change the results. CONCLUSIONS/INTERPRETATION: The proportion of non-European ancestry is associated with both type 2 diabetes and lower socioeconomic status in admixed Latino populations from North and South America. We conclude that ancestry-directed search for genetic markers associated with type 2 diabetes in Latinos may benefit from information involving social factors, as these factors have a quantitatively important effect on type 2 diabetes risk relative to ancestry effects.

A narrow and highly significant linkage signal for severe bipolar disorder in the chromosome 5q33 region in Latin American pedigrees.

We previously reported linkage of bipolar disorder to 5q33-q34 in families from two closely related population isolates, the Central Valley of Costa Rica (CVCR) and Antioquia, Colombia (CO). Here we present follow up results from fine-scale mapping in large CVCR and CO families segregating severe bipolar disorder, BP-I, and in 343 population trios/duos from CVCR and CO. Employing densely spaced SNPs to fine map the prior linkage peak region increases linkage evidence and clarifies the position of the putative BP-I locus. We performed two-point linkage analysis with 1134 SNPs in an approximately 9 Mb region between markers D5S410 and D5S422. Combining pedigrees from CVCR and CO yields a LOD score of 4.9 at SNP rs10035961. Two other SNPs (rs7721142 and rs1422795) within the same 94 kb region also displayed LOD scores greater than 4. This linkage peak coincides with our prior microsatellite results and suggests a narrowed BP-I susceptibility regions in these families. To investigate if the locus implicated in the familial form of BP-I also contributes to disease risk in the population, we followed up the family results with association analysis in duo and trio samples, obtaining signals within 2 Mb of the peak linkage signal in the pedigrees; rs12523547 and rs267015 (P = 0.00004 and 0.00016, respectively) in the CO sample and rs244960 in the CVCR sample and the combined sample, with P = 0.00032 and 0.00016, respectively. It remains unclear whether these association results reflect the same locus contributing to BP susceptibility within the extended pedigrees.

[Relationship between methylenetetrahydrofolate reductase polymorphism and homocysteine levels in women with recurrent pregnancy loss: a nutrigenetic perspective]. / Relación entre los polimorfismos de la metilen-tetrahidrofolato-reductasa y los niveles de homocisteína en mujeres con pérdida gestacional recurrente: perspectiva desde la nutrigenética.

The objective of this study was to evaluate if there is any difference in the proportion of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms and the homocysteine levels in a group of women with recurrent pregnancy loss (RPL) and a control group. Ninety-three patients with diagnosis of three or more gestational losses and 206 healthy women with two or more children, were included. After acceptance of informed consent, samples of peripheral blood were taken to determine the genetic polymorphisms of MTHFR C677T and the plasmatic levels of homocysteine. The carriers of the homozygous mutation TT of MTHFR 677T polymorphism were 12.9% (12 of 93) in the group of patients and 14.6% (30 of 206) in the control group; 46.2% (43 of 93) and 40% (83 of 206) in the group of patients and controls respectively, were heterozygous CT for MTHFR gene. The levels of homocysteine were 7.2 micromol/ml in the group of patients and 7.7 mmol/l in controls. There was no relationship between MTHFR gene polymorphisms and the increase of homocysteine levels, nor of these one with RPL. From the nutrigenetics perspective we suggest that studies related to MTHFR polymorphisms and the risk of disease include the levels of folate and B6 and B12 vitamins participating in the tetrahydrofolate cycle for trying to establish a direct relation among the genotype, the level of metabolite and the clinical manifestations. In this regard, we recommend the administration of folic acid in women in search of pregnancy due to the high frequency of heterozygous and homozygous for MTHFR C677T mutation in our population.

Relación entre los polimorfismos de la metilen-tetrahidrofolato-reductasa y los niveles de homocisteína en mujeres con pérdida gestacional recurrente: perspectiva desde la nutrigenética / Relationship between methylenetetrahydrofolate reductase polymorphism and homocysteine levels in women with recurrent pregnancy loss: a nutrigenetic perspective

El objetivo de este estudio fue evaluar si existe diferencia en la proporción de los polimorfismos de la metilen tetrahidrofolato reductasa (MTHFR) C677T y en los niveles de homocisteína, entre una población de mujeres con pérdida gestacional recurrente y un grupo control. Se incluyeron 93 pacientes con diagnóstico de tres o más pérdidas gestacionales y 206 mujeres sanas con dos o más hijos. Previa aceptación del consentimiento informado, a cada mujer se le tomó una muestra de sangre periférica tanto para la genotipificación de los polimorfismos de la MTHFR como para la medición de homocisteína en plasma. Las portadoras de la condición homocigota TT para el polimorfismo de la MTHFR 677T fueron 12,9% (12/93) en el grupo de pacientes y 14,6% (30/206) en el grupo control; un 46,2% (43/93) y 40% (83/206) en el grupo de pacientes y de controles respectivamente, fueron heterocigotos CT para el gen de la MTHFR. Los niveles promedio de homocisteína fueron 7,2 μmol/ml para las pacientes y 7,7 μmol/ml para los controles. No se encontró relación entre los polimorfismos del gen de la MTHFR y el aumento en los niveles de homocisteína, ni de éstos con la PGR. Desde la perspectiva de la nutrigenética, sugerimos que para estudiar la relación entre los polimorfismos de la MTHFR con determinada enfermedad, se tengan en cuenta los niveles de folatos, vitaminas B6 y B12 que intervienen en el ciclo de los tetrahidrofolatos con el fin de intentar establecer una relación más directa entre el genotipo, el nivel del metabolito y las manifestaciones clínicas. En este mismo sentido recomendamos el consumo de ácido fólico en las mujeres que estén buscando embarazo dado la alta frecuencia de heterocigotos y homocigotos para la mutación C677T de la MTHFR en nuestra población (AU)

The objective of this study was to evaluate if there is any difference in the proportion of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms and the homocysteine levels in a group of women with recurrent pregnancy loss (RPL) and a control group. Ninety-three patients with diagnosis of three or more gestational losses and 206 healthy women with two or more children, were included. After acceptance of informed consent, samples of peripheral blood were taken to determine the genetic polymorphisms of MTHFR C677T and the plasmatic levels of homocysteine. The carriers of the homozygous mutation TT of MTHFR 677T polymorphism were 12.9% (12 of 93) in the group of patients and 14.6% (30 of 206) in the control group; 46.2% (43 of 93) and 40% (83 of 206) in the group of patients and controls respectively, were heterozygous CT for MTHFR gene. The levels of homocysteine were 7.2 μmol/ml in the group of patients and 7.7 mmol/l in controls. There was no relationship between MTHFR gene polymorphisms and the increase of homocysteine levels, nor of these one with RPL. From the nutrigenetics perspective we suggest that studies related to MTHFR polymorphisms and the risk of disease include the levels of folate and B6 and B12 vitamins participating in the tetrahydrofolate cycle for trying to establish a direct relation among the genotype, the level of metabolite and the clinical manifestations. In this regard, we recommend the administration of folic acid in women in search of pregnancy due to the high frequency of heterozygous and homozygous for MTHFR C677T mutation in our population (AU)

Beta-2-adrenergic receptor polymorphisms and changes in lipids induced by metoprolol.

Polymorphisms Arg(16)Gly and Gln(27)Glu of the gene of adrenoreceptor beta(2)(ADRB2) are associated with altered sympathetic responses. This study evaluated the relationship between these polymorphisms and changes in lipids induced by metoprolol in hypertensive patients. 105 adults were enrolled. After serum lipid levels and genotype had been determined, metoprolol was administered orally. Genotyping was performed using a mini-sequencing technique. Allelic and genotypic frequencies were: Arg(16) (49.5%); Gly(16) (50.5%); Gln(27) (89%); Glu(27) (11%); Arg(16)Arg (28.6%); Arg(16)Gly (41.9%); Gly(16)Gly (29.5%); Gln(27)Gln (81%); Gln(27)Glu (16.1%), and Glu(27)Glu (2.9%). Ninety patients concluded the study. There were no significant differences between the demographic, pharmacological and biochemical variables evaluated, grouped by their genotype in positions 16 and 27 of the ADRB2 gene. We did not find differences in lipid profiles in the whole group, but when we compared these profiles within each genotypic subgroup, we found that total cholesterol diminished (p = 0.03) in the patients with the native Gln(27)Gln genotype, whereas in the Gln(27)Glu heterozygous triglycerides increased (p = 0.025). We only found 3 patients homozygous for Glu(27)Glu and 2 of them were treated with diet and antidyslipidemic drugs. These results suggest that the polymorphism of codon 27 constitutes the target of the changes in lipids induced by beta-adrenergic receptor antagonists.

Inherited thrombophilia is associated with deep vein thrombosis in a Colombian population.

The development of venous thromboembolism is influenced by a variety of genetic and environmental risk factors. A few studies have ascertained whether thrombophilic defects are risk factors for venous thromboembolism in Latin American populations with a variable degree of admixture, such as the Colombian population. To address this issue, we conducted a case-control study involving 100 consecutive patients with deep vein thrombosis and 114 healthy controls from the Hospital Universitario San Vicente de Paúl, Medellín, Colombia. Activated protein C resistance (APC resistance) was detected in 25/99 patients vs. 6/114 controls (OR = 6.08, 95% CI = 2.23-17.47). Ten of 100 patients carried the factor V Leiden mutation vs. 1/114 controls (OR = 12.56, 95% CI = 1.61-267). APC resistance was associated with the factor V Leiden mutation in only 10/25 patients. The prothrombin G20210A mutation was found in 4/100 patients, but none of the controls (P < 0.05). There was no significant difference in the proportion of homozygous carriers of methylenetetrahydrofolate reductase C677T variant among patients and controls. In conclusion, in our studied population, factor V Leiden, APC resistance, and prothrombin G20210A were associated with an increased risk of deep vein thrombosis. However, the frequencies of these thrombophilic defects and of APC resistance associated with factor V Leiden was lower than the corresponding frequencies previously reported for Caucasian populations. Further study is required to assess the influence of ethnicity on thrombophilia.

[Genetic linkage analysis of Gilles de la Tourette Syndrome in a Colombian family]. / Análisis de ligamiento genético del síndrome de Gilles de la Tourette en una familia colombiana.

INTRODUCTION: Gilles de la Tourette Syndrome (GTS) is a chronic neuropsychiatric disorder characterized by phonic and motor tics. Although its physiopathologic bases are unknown, the cortical-striatal-thalamic-cortical circuit has been studied. The association of GTS with attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), motors tics (MT) or phonics tics (PT), the high family aggregation, and the concordance studies in twins, support the genetics bases of this disorder. Currently, GTS is accepted as a complex disorder and the associated disorders could be alternative expressions of the same syndrome. AIM: To evaluate genetic linkage to 2p11, 6p24, 11q23, 20q13 and 21q22 regions in an Antioquian family with enough power to detect linkage. PATIENTS AND METHODS: With the Linkage program and using autosomic dominant, recessive and additive inheritance models, the genetic linkage was calculated; two phenotypic spectra was considered: one broad spectrum including affected individuals with GTS, ADHD, OCD, MT, and PT, and a narrow spectrum with only GTS. RESULTS: The most probable inheritance pattern for a susceptibility locus in GTS and its associated disorders in this family is autosomic additive. The presence of a locus involved in GTS in the 2p11 region has been rejected. CONCLUSION: The linkage values for D20S1085 and D6S477 markers are suggestive and therefore it is not possible reject that these markers will be in linkage disequilibrium with genes involved in the GTS, ADHD, OCD, MT, and PT etiology.

Análisis de ligamiento genético del síndrome de Gilles de la Tourette en una familia colombiana / Genetic linkage analysis of Gilles de la Tourette syndrome in a colombian family

Introducción. El síndrome de Gilles de la Tourette (SGT) es un trastorno neuropsiquiátrico crónico caracterizado por la presencia de tics fónicos y motores. Aunque sus causas fisiopatológicas se desconocen, se ha involucrado al circuito corticoestriado-talamocortical. La evidencia genética del SGT se sustenta por estudios de concordancia entre gemelos, por su alta agregación familiar y por su asociación con el trastorno-obsesivo compulsivo (TOC), el trastorno de déficit de atención con hiperactividad (TDAH) y los tics motores (TM) o fónicos (TF). Actualmente se acepta que el SGT es una enfermedad compleja y los trastornos asociados pueden ser expresiones alternativas del mismo síndrome. Objetivo. Evaluar el ligamiento genético en las regiones 2p11, 6p24, 11q23, 20q13 y 21q22, en una familia antioqueña con suficiente poder para detectar ligamiento. Pacientes y métodos. Mediante el programa Linkage se calculó el ligamiento genético bajo los modelos de herencia autosómico dominante, recesivo y aditivo, y se evaluaron dos espectros fenotípicos: uno amplio que incluía como afectados a individuos con SGT, TDAH, TOC, TM, y TF, y uno estrecho que incluía sólo a individuos con SGT. Resultados. El patrón de herencia más probable para un locus de susceptibilidad al SGT y sus trastornos asociados, en esta familia, es el autosómico aditivo. Se descarta la presencia de un locus involucrado en SGT en la región 2p11. Conclusión. Los valores de ligamiento obtenidos con los marcadores D20S1085 y D6S477 son sugestivos y, por lo tanto, no se puede descartar que estos marcadores se encuentren en desequilibrio de ligamiento con genes involucrados en la etiología del SGT, TDAH, TOC, TM, y TF (AU)

Introduction. Gilles de la Tourette Syndrome (GTS) is a cronic neuropsychiatric disorder characterized by fonic and motor tics. Although its physiopathologic bases are unknown, the cortical-striatal-talamic-cortical circuit has been studied. The association of GTS with attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), motors tics (MT) or phonics tics (PT), the high family aggregation, and the concordance studies in twins, support the genetics bases of this disorder. Currently, GTS is accepted as a complex disorder and the associated disorders could be alternative expressions of the same syndrome. Aim. To evaluate genetic linkage to 2p11, 6p24, 11q23, 20q13 and 21q22 regions in an Antioquian family with enough power to detect linkage. Patients and methods. With the Linkage program and using autosomic dominant, recessive and additive inheritance models, the genetic linkage was calculated; two phenotypic spectra was considered: one broad spectrum including affected individuals with GTS, ADHD, OCD, MT, and PT, and a narrow spectrum with only GTS. Results. The most probable inheritance pattern for a susceptibility locus in GTS and its associated disorders in this family is autosomic additive. The presence of a locus involved in GTS in the 2p11 region has been rejected. Conclusion. The linkage values for D20S1085 and D6S477 markers are suggestive and therefore it is not possible reject that these markers will be in linkage disequilibrium with genes involved in the GTS, ADHD, OCD, MT, and PT etiology (AU)

A novel SCN1A mutation associated with severe GEFS+ in a large South American pedigree.

Generalized epilepsy with febrile seizures plus (GEFS+) is an inherited epileptic syndrome with a marked clinical and genetic heterogeneity. Here we report the molecular characterization of a large pedigree with a severe clinical form of GEFS+. Genetic linkage analysis implied the involvement of the FEB3 in the disease phenotype of this family (parametric two-point lod-score of 2.2). Sequencing of the SCN1A gene revealed a novel aspartic acid for glycine substitution at position 1742 of this sodium channel subunit. The amino-acid replacement lies in the pore-forming region of domain IV of SCN1A. Our observations are consistent with the genotype-phenotype correlation studies suggesting that mutations in the pore-forming loop of SCN1A can lead to a clinically more severe epileptic syndrome.

A CLN5 mutation causing an atypical neuronal ceroid lipofuscinosis of juvenile onset.

Three related patients from Colombia presented with a juvenile-onset neuronal ceroid lipofuscinosis. Electron microscopy of one case showed condensed fingerprint profiles, and genetic analyses identified a novel missense mutation in CLN5. The authors demonstrate the existence of pathogenic CLN5 mutations outside northern Europe and that mutations in this gene can lead to an atypical late-onset neuronal ceroid lipofuscinosis disease, in addition to the late infantile form first described in Finland.

[Clinical characterisation and power simulations to detect genetic linkage in attention deficit hyperactivity disorder in Antioquian families]. / Caracterización clínica y simulaciones de poder para ligamiento genético en el trastorno por déficit de atención con hiperactividad en familias antioqueñas.

INTRODUCTION: Attention deficit hyperactivity disorder (ADHD) is a neurobehavioural disorder whose essential characteristic is a persistent pattern of inattention or hyperactivity and impulsiveness. Recent studies into prevalence carried out on the Antioquian population by our group found an overall prevalence of 15.8%, which confirms ADHD as one of the most frequent problems in infancy. The cause of this disorder is still not altogether clear; familial aggregation of ADHD points towards a genetic component. Although to date no model of inheritance has been defined, its high prevalence rate, the difficulties involved in its diagnosis and its effects on the cognitive functions, as well as the social and educational repercussions, make this disorder a problem in children's public health. AIMS: Our aim was to carry out power simulations to detect genetic linkage. PATIENTS AND METHODS: The Slink programme, which is part of Linkage package, was used in six families from the city of Medellín Antioquia, which is a region where a founding effect is likely to have taken place; this makes it a strategic zone for genetic linkage studies in complex diseases such as ADHD. RESULTS: Assuming the population to be homogenous, the lod score (Z) is greater than 3 (Z>3) and individual lod score values of between 0 and 6 were obtained for each family. CONCLUSIONS: In this paper we discuss the benefits of having multigenerational families, in Antioquia, to conduct gene mapping studies and we examine the different strategies to be developed with the findings reported here.

Caracterización clínica y simulaciones de poder para ligamiento genético en el trastorno por déficit de atención con hiperactividad en familias antioqueñas / Clinical characterisation and power simulations to detect genetic linkage in attention deficit hyperactivity disorder in antioquian families

Introducción. El trastorno por déficit de atención con hiperactividad (TDAH) es un trastorno neurocomportamental cuya característica esencial es un patrón persistente de inatención o hiperactividad e impulsividad. En algunos estudios recientes sobre prevalencia realizados por nuestro grupo en la población antioqueña se ha encontrado una prevalencia total del 15,8 por ciento; esto confirma al TDAH como uno de los problemas más frecuentes en la infancia. La causa del trastorno todavía no se ha esclarecido; la agregación familiar del TDAH sugiere un componente genético; aunque todavía no se ha definido un modelo de herencia, su alta prevalencia, sus dificultades en el diagnóstico y sus efectos en las funciones cognitivas, sociales y escolares, convierten a este trastorno en un problema de salud pública infantil. Objetivos. Realizar las simulaciones de poder para detectar ligamiento genético. Pacientes y métodos. Se empleó el programa Slink del paquete Linkage, en seis familias de la ciudad de Medellín-Antioquia, en cuya zona, probablemente, ocurrió un efecto fundador; ello la ubica como una zona estratégica para estudios de ligamiento genético en enfermedades complejas, como el TDAH Resultados. El lod score(Z), asumiendo la homogeneidad de la población, es mayor de 3 (Z > 3), y se obtienen valores individuales por familia que oscilan entre 0 y 6. Conclusiones. En este estudio se discuten los beneficios de tener familias multigeneracionales en Antioquia, para realizar estudios de cartografiado de genes, y se examinan las diferentes estrategias que se deberían desarrollar a partir de los hallazgos aquí presentados (AU)

Introduction. Attention deficit hyperactivity disorder (ADHD) is a neurobehavioural disorder whose essential characteristic is a persistent pattern of inattention or hyperactivity and impulsiveness. Recent studies into prevalence carried out on the Antioquian population by our group found an overall prevalence of 15.8%, which confirms ADHD as one of the most frequent problems in infancy. The cause of this disorder is still not altogether clear; familial aggregation of ADHD points towards a genetic component. Although to date no model of inheritance has been defined, its high prevalence rate, the difficulties involved in its diagnosis and its effects on the cognitive functions, as well as the social and educational repercussions, make this disorder a problem in children’s public health. Aims. Our aim was to carry out power simulations to detect genetic linkage. Patients and methods. The Slink programme, which is part of Linkage package, was used in six families from the city of Medellín-Antioquia, which is a region where a founding effect is likely to have taken place; this makes it a strategic zone for genetic linkage studies in complex diseases such as ADHD. Results. Assuming the population to be homogenous, the lod score (Z) is greater than 3 (Z > 3) and individual lod score values of between 0 and 6 were obtained for each family. Conclusions. In this paper we discuss the benefits of having multigenerational families, in Antioquia, to conduct gene mapping studies and we examine the different strategies to be developed with the findings reported here (AU)

Y-chromosome biallelic polymorphisms and Native American population structure.

It has been proposed that women had a higher migration rate than men throughout human evolutionary history. However, in a recent study of South American natives using mtDNA restriction fragment polymorphisms and Y-chromosome microsatellites we failed to detect a significant difference in estimates of migration rates between the sexes. As the high mutation rate of microsatellites might affect estimates of population structure, we now examine biallelic polymorphisms in both mtDNA and the Y-chromosome. Analyses of these markers in Amerinds from North, Central and South America agree with our previous findings in not supporting a higher migration rate for women in these populations. Furthermore, they underline the importance of genetic drift in the evolution of Amerinds and suggest the existence of a North to South gradient of increasing drift in the Americas.

Mutations in FOXL2 underlying BPES (types 1 and 2) in Colombian families.

We report the genetic characterization of one family with blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) type 1 and two families with BPES type 2 from a historically isolated population in northwest Colombia. Linkage and haplotype analyses indicate that BPES in these families is linked to 3q23. Mutation screening of FOXL2 in the family with BPES type 1 revealed a novel 394C --> T nonsense mutation which deletes the forkhead DNA binding domain. The two families with BPES type 2 both carry an in-frame 30 bp duplication that leads to the elongation of a polyalanine tract. This duplication has been previously reported in Europe, where recurrent mutation has been demonstrated in unrelated familial and sporadic BPES cases. The recurrent nature of this duplication seems to relate to the secondary structure of this DNA region. The genotype-phenotype correlation seen in the Colombian families is consistent with the recent proposal that BPES type 1 is caused by truncating mutations leading to haploinsufficiency, while BPES type 2 is due to mutations generating elongated protein products.

Loci geneticos asociados al trastorno bipolar: estudios en poblacion colombiana / Genetic loci associated to bipolar disorder: studies in colombian population

Objetivos: Caracterizar una muestra de familias y tríos de una población colombiana aislada para mapear loci involucrados en la vulnerabilidad al Trastorno Afectivo Bipolar tipo I (TAB- I). Métodos: Se recolectan tríos y genealogías utilizando las entrevistas FIGS-DIGS en miembros de las familias y posibles afectados. El poder para detectar ligamiento (PDL) se estima por simulación. El modelo utilizado asume una frecuencia para el alelo afectado de 0.003, penetrancias de 0.01,0.81 y 0.9 y un marcador de cuatro alelos a 5cM del locus. Resultados: Se identificaron 28 familias con TAB-I, con 3.603 individuos y 160 afectados, y 246 tríos. Asumiendo homogeneidad genética y teniendo en cuenta la evidencia genética del mestizaje, las simulaciones mostraron PDL significativos de 100 por ciento para un LOD-score>3. Estamos examinando el desequilibrio promedio en tríos y tamizando en familias los cromosomas 12,18 y 21. Conclusión: Tenemos un grupo significativo de familias y trios pertenecientes a una población aislada con un poder para detectar ligamiento al Trastorno Afectivo Bipolar. Esto permite realizar estudios de ligamiento buscando genes involucrados en la vulnerabilidad al TAB-I en población Colombiana