Búsqueda genómica basada en el mapeo de homocigosidad y el uso de microarrays en 25 familias cubanas con trastorno afectivo bipolar muestra evidencias sugestivas de ligamiento en las regiones 6q26-27 y 17q25.3 / A genome-wide search for risk genes using homozygosity mapping and microarrays in 25 Eastern Cuban families with bipolar disorder shows suggestive evidence of linkage to chromosomes 6q26-q27 and 17q25.3

Se reportan los resultados de una búsqueda genómica utilizando una versión del GeneChip Mapping 10K Xba array de Affymetrix (con 10 043 marcadores SNPs), en 33 individuos con diagnóstico trastorno afectivo bipolar que son miembros de 25 famlias cubanas en las cuales los padres de los individuos enfermos son primos hermanos, primos segundos o primos terceros. En cada familia se genotipo el descendiente afectado, con el objetivo de identificar alelos de riesgo para el trastorno afectivo bipolar con efecto recesivo, en uno o más locis, mediante la búsqueda de segmentos cromosómicos homocigóticos idénticos por descendencia. Se encontraron evidencias sugestivas de ligamiento genético en las regiones cromosómicas 6q26-27 y 17q25.3. El hallazgo en el cromosoma 17q confirma resultados previos que obtuvimos en una búsqueda genómica anterior utilizando 1494 SNPs, mientras que lo encontrado en la región 6q podría representar un nuevo locus de susceptibilidad no reportado en la literatura con anterioridad. Otras regiones de potencial interés fueron localizadas en los cromosomas 2p14, 5q14.1, 10q21.1, 11q13.5-14.1 y14q24.1-24.2. Los resultados obtenidos sugieren que el mapeo de homocigosidad, utilizando el análisis de ligamiento paramétrico en individuos afectados descendientes de matrimonios consanguíneos, es una estrategia útil para la búsqueda de alelos de riesgo con un efecto recesivo en las enfermedades complejas…(AU)

A genome-wide linkage search for bipolar disorder susceptibility loci in a large and complex pedigree from the eastern part of Cuba.

We present results from a genome-wide scan of a six generation pedigree with 28 affected members with apparently dominant bipolar I disorder from eastern Cuba. Genotypes were obtained using the early access version of the Genechip Mapping 10K Xba array from AFFYMETRIX. Parametric and non-parametric linkage analyses under dominant and recessive models were performed using GENEHUNTER v2.1r5. Two phenotypic models were included in the analyses: bipolar I disorder and recurrent depressive disorder, or bipolar I disorder only. LOD scores were calculated for the entire family combined, and for four subdivisions of the family. For the entire family a suggestive parametric LOD score was obtained under the dominant model and the broader phenotype at 14q11.2-12 (LOD = 2.05). In the same region, a non-parametric LOD score close to genome-wide significance was also obtained, based on the entire family (NPL = 7.31, P-value = 0.07). For two individual branches of the pedigree, genome-wide significance (P < 0.005) was obtained with NPL scores of 8.71 and 12.99, respectively, also in the same region on chromosome 14. Chromosome 5q21.3-22.3 also showed close to genome-wide significant linkage for the complete pedigree (NPL = 7.26, P = 0.07), also supported by significant linkage in one individual branch (NPL = 9.86, P < 0.005). In addition, genome-wide significant nonparametric results (P-values <0.005) were obtained for individual branches at 5p13.1-q12.3, 6p22.3, 8q13.3-21.13, and 10q22.3-23.32. Finally, 2p25.1-25.3, 2p13.3-14, 3p14.2, 6p22.3-24.1, 7p14.1-14.2, 8q12.2-12.3, 10q21.1-21.2, 14q13.1-21.1, 15q15.1-21.2, and 22q12.3-13.32 showed suggestive linkage in the complete family. Most of these potential susceptibility loci overlap with, or are close, to previous linkage findings. The locus on 5q may, however, represent a novel susceptibility locus.

A novel presenilin 1 mutation (L174 M) in a large Cuban family with early onset Alzheimer disease.

We studied a Cuban family with presenile dementia (autosomal dominant) consisting of 281 members within six generations, the proband descended from a Spanish founder. Mean age at onset was 59 years of age. Memory impairment was the main symptom in all patients, additionally, ischemic episodes were described in 4 (n = 18) patients. Neuropathological examination of brain material (1 patient) revealed neuronal loss, amyloid plaques, and neurofibrillary tangles. Thirty DNA samples were genotyped (regions on chromosome 1, 3, 10, 12, 14, 17, 19, 20, and 21). A maximum Lod score of 3.79 at theta = 0 was obtained for marker D14S43, located in a 9-cM interval in which all patients shared the same haplotype. Sequencing of the PSEN1 gene revealed a heterozygous base substitution, C520A (exon 6), which is predicted to cause an amino acid change from leucine to methionine in the TMIII of the presenilin 1 protein. The mutation was found to co-segregate with the disease phenotype and the associated disease haplotype. The C --> A change was not observed in 80 control chromosomes from the Cuban population. Leucine at position 174 is highly conserved among species and is identical in presenilin 1 and presenilin 2 proteins. We propose the L174 M mutation might lead to an abnormal N-terminal and probably C-terminal fragments and malfunction of the protein complex. In conclusion, we found a novel PSEN1 mutation in a large family with clinical and pathological diagnosis of early onset familial Alzheimer disease, which may be relevant for other Hispanic populations.