RESUMEN
Several large-scale epidemiological surveys have reported increasing lifetime rates of psychopathology among recently born cohorts. In the case of Major Depressive Disorder (MDD) younger cohorts tend to manifest higher lifetime prevalences of the condition than older cohorts, at any given age. In some studies, cohort differences are so large that the youngest cohort exceeds the lifetime prevalence of the oldest cohort well before passing through their total period of risk. The data on lifetime prevalences that support the existence of secular differences, however, has typically been collected in cross-sectional studies. Thus, individuals are interviewed at a single point in time and asked to recall all prior psychopathology. Due to poor recall, this design may greatly underestimate earlier experiences. In fact, cohort differences are not limited to MDD; similar results have been reported for a wide range of psychopathology, suggesting methodological problems at data collection. We have conducted a simulation study to examine the magnitude of annual rates of forgetting that could produce the secular trends reported for MDD. Small, but constant annual rates produce striking, 'cohort effect-like' curves. The rates needed to reconstruct the reported effect are compatible with published values for test-retest studies of lifetime recall of MDD. This simulation study does not rule out the existence of a cohort effect in some psychiatric disorders, but stresses the possible limitations of using cross-sectional studies to investigate secular trends.
Asunto(s)
Trastorno Depresivo/epidemiología , Trastornos de la Memoria/epidemiología , Recuerdo Mental , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Simulación por Computador , Estudios Transversales , Trastorno Depresivo/diagnóstico , Trastorno Depresivo/psicología , Femenino , Humanos , Incidencia , Estudios Longitudinales , Masculino , Cómputos Matemáticos , Trastornos de la Memoria/diagnóstico , Trastornos de la Memoria/psicología , Persona de Mediana Edad , Modelos Estadísticos , Retención en Psicología , Riesgo , Análisis de SupervivenciaRESUMEN
Autosomal dominant polycystic kidney disease (ADPKD) is a disorder of adult onset manifested by bilaterally enlarged cystic kidneys frequently associated with progressive renal failure. The mutated gene (PKD1) responsible for 85 to 95% of cases has been localized to a small segment on the distal tip of the short arm of chromosome 16. A clinical spectrum of heritable connective tissue disorders that remain unclassifiable under the present nosology but that contain elements of the Marfan's syndrome have previously been described. The genetic localization and molecular basis of such overlap connective tissue disorders (OCTD) have not been elucidated. In this report, a kindred in which ADPKD and OCTD appear to cosegregate is described. The connective tissue phenotype in this family includes aortic root dilation, aortic and vertebral artery aneurysms with dissection, and aortic valve incompetence, as well as pectus abnormalities, pes planus, joint laxity, arachnodactyly, scoliosis, dolichostenomelia, and high arched palate. ADPKD was manifest primarily as bilateral renal cysts with or without renal failure. The DNA of all living family members was studied with markers recognizing polymorphic loci flanking the PKD1 region (3'HVR and O90a), as well as markers from the loci of chromosomes 15 and 5, associated with fibrillin genes FBN1 and FBN2, respectively. In this kindred of 20 family members traced through five generations, cosegregation of ADPKD and the OCTD phenotype was observed in 12 of 12 meioses and 3 of 3 phase known. Both markers for PKD1 were tightly linked to both ADPKD and OCTD, whereas there was no evidence for linkage with either fibrillin locus. In this family, the ADPKD and OCTD mutations are genetically linked. The presence of OCTD with ADPKD identifies a group of patients at significantly greater risk for sudden death from aortic root and other vascular aneurysmal dissection and rupture.
Asunto(s)
Cromosomas Humanos Par 16 , Enfermedades del Tejido Conjuntivo/genética , Riñón Poliquístico Autosómico Dominante/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Bases , Niño , Preescolar , Enfermedades del Tejido Conjuntivo/complicaciones , Cartilla de ADN/genética , Femenino , Ligamiento Genético , Marcadores Genéticos , Humanos , Masculino , Síndrome de Marfan/genética , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje , Fenotipo , Riñón Poliquístico Autosómico Dominante/complicacionesRESUMEN
Genetic factors play an important role in the pathophysiology of human essential hypertension. The remarkable success of molecular genetic techniques in identifying the basis for single gene disorders at the DNA level has encouraged investigators to apply similar techniques in an attempt to identify blood pressure genes. In contrast to single gene disorders, however, the study of blood pressure is complicated by its quantitative, complex, heterogeneous, and polygenic nature. This article examines current methods and strategies for identifying genetic determinants in human hypertension. The availability of highly polymorphic markers, the advances in quantitative trait analysis, and the mapping of blood pressure-determining genes in a polygenic rat model of hypertension suggest that molecular genetic research in human hypertension has come of age.
Asunto(s)
Hipertensión/genética , Animales , Presión Sanguínea/genética , Modelos Animales de Enfermedad , Ligamiento Genético , Técnicas Genéticas , Humanos , Linaje , FenotipoRESUMEN
The "reverse genetic" approach to essential hypertension is complicated by the fact that blood pressure is a heterogeneous, quantitative, complex trait. One strategy is to use "intermediate phenotypes" that are not only associated with hypertension but that also have a simple mode of inheritance, compatible with the action of a single gene. Red cell sodium-lithium countertransport (SLC) is one of the best characterized intermediate phenotypes for hypertension. The similarity in stoichiometry and kinetics between SLC and Na+/H+ exchange has led to the proposal that the gene encoding the Na+/H+ antiporter (APNH) may be responsible for the individual variance in SLC. We have tested this hypothesis by both an association study and Haseman and Elston's sib pair method of linkage analysis, by using a polymorphism at the APNH locus detected by denaturing gradient gel electrophoresis. Both analytical techniques were performed before and after correction of SLC values for known covariates. There was no significant association between mean SLC values and any of the three possible genotypes of the APNH locus either before or after regressing out covariates (F = 0.64 and P greater than 0.52; F = 0.63 and P greater than 0.53, respectively). Linkage analysis similarly failed to demonstrate a relationship between the squared difference in SLC values and the identity by descent status for APNH as well as other loci that map close to APNH (D1S57, RH, and ALPL). Taking these results together, we conclude that mutations at the APNH locus are not responsible for the observed variation in SLC values.
Asunto(s)
Proteínas Portadoras/genética , Eritrocitos/metabolismo , Amilorida/farmacología , Transporte Biológico Activo , Proteínas Portadoras/efectos de los fármacos , Femenino , Ligamiento Genético , Humanos , Hipertensión/sangre , Hipertensión/genética , Litio/sangre , Masculino , Linaje , Fenotipo , Polimorfismo Genético , Sodio/sangre , Intercambiadores de Sodio-HidrógenoRESUMEN
The dopamine hypothesis is one of the major etiological hypotheses of schizophrenia. The well-established role of genetic factors in schizophrenia together with reports of increased D2 dopamine receptor densities in untreated schizophrenic patients support the D2 dopamine receptor gene as a strong candidate gene for schizophrenia. The recent cloning of the D2 dopamine receptor gene made it possible to test the involvement of the D2 dopamine receptor locus (DRD2) in a large Swedish and a smaller Californian schizophrenia pedigree. Using multipoint linkage analysis between schizophrenia and a genetic map that includes the DRD2 locus and assuming a dominant mode of inheritance, we were able to exclude the DRD2 locus with a lod score of -4.14 for the penetrance of 0.72 and with a lod score of -3.05 for the lower bound penetrance of 0.56. The area of exclusion (lod score, less than -2.00) extended 27 centimorgans. These results provide strong evidence against linkage of the D2 dopamine receptor gene region to schizophrenia in the two pedigrees investigated. We conclude that the genetic predisposition to schizophrenia in these pedigrees is not due to aberrations in the DRD2 locus or the porphobilinogen deaminase locus. Our results do not support the D2 dopamine receptor hypothesis of schizophrenia. However, they cannot exclude the possibility that other genes regulating aspects of D2 dopamine expression might be involved in the etiology of schizophrenia, such as the expression of two D2 dopamine receptor subtypes by alternative RNA splicing.
Asunto(s)
Ligamiento Genético , Receptores Dopaminérgicos/genética , Esquizofrenia/genética , California/epidemiología , Comparación Transcultural , Femenino , Humanos , Hidroximetilbilano Sintasa/genética , Escala de Lod , Masculino , Persona de Mediana Edad , Linaje , Porfirias/genética , Receptores Dopaminérgicos/fisiología , Esquizofrenia/epidemiología , Esquizofrenia/fisiopatología , Suecia/epidemiologíaRESUMEN
The Na+/H+ antiporter is a ubiquitous membrane-associated protein that plays an important role in the regulation of intracellular pH. APNH, a gene encoding the antiporter, has been cloned and mapped to the short arm of chromosome 1 by in situ hybridization. Using the polymerase chain reaction, we have amplified a 376 base pair fragment corresponding to the 5' end of APNH. We have detected a polymorphism within this fragment by denaturing gradient gel electrophoresis. Using polymorphisms at other 1p loci (ALPL, the gene for alkaline phosphatase, RH and D1S57), we have been able to map APNH telomeric to D1S57 and close to RH and ALPL by genetic linkage. APNH is a plausible candidate gene for human essential hypertension; the APNH polymorphism combined with a knowledge of its genetic map location allow this candidate to be tested in hypertensive kindreds and sib-pairs.
Asunto(s)
Proteínas Portadoras/genética , Cromosomas Humanos Par 1 , Alelos , Mapeo Cromosómico , Sondas de ADN , Femenino , Ligamiento Genético , Marcadores Genéticos , Humanos , Masculino , Linaje , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Intercambiadores de Sodio-HidrógenoRESUMEN
A cDNA clone of the beta subunit of human fibronectin receptor (FNRB) detects two different polymorphic loci: (a) a codominant system previously mapped to the pericentromeric region of chromosome 10, the site of the functional FNRB gene; and (b) a dominant system not linked to the first one or to any chromosome 10 marker tested. This second polymorphism is characterized by the presence or absence of a band (or a set of bands). We have used linkage analysis and biotin-labeled in situ hybridization to map this dominant polymorphism to the short arm of chromosome 19; we hypothesize that it may be due to the insertion of part of the cDNA from the chromosome 10 gene into chromosome 19. This "insertion" is polymorphic in all populations studied.
Asunto(s)
Cromosomas Humanos Par 19 , Polimorfismo de Longitud del Fragmento de Restricción , Receptores Inmunológicos/genética , Mapeo Cromosómico , Etnicidad , Frecuencia de los Genes , Humanos , Escala de Lod , Receptores de FibronectinaRESUMEN
The beta subunit of the human fibronectin receptor (FNRB) is a transmembrane protein belonging to the VLA (very late antigens of activation) family. Using pGEM-32, a 2.5-kb partial cDNA clone corresponding to the 3' portion of the human FNRB locus, multiple restriction fragment length polymorphisms (RFLPs) were revealed on DNAs from unrelated Caucasians. RFLPs detected by five enzymes, BanII, HinfI, KpnI, BglII, and SacI, are of the simple two-allele form, and pairwise linkage analyses of these RFLPs with numerous known DNA markers from the chromosome-10 pericentromeric region not only confirmed the chromosome-10 assignment of the functional FNRB gene but also supported its localization at p11.2 suggested by in situ hybridization. An infrequent MspI RFLP was detected by pB/R2, a 4.6-kb genomic clone from the FNRB locus. Another type of DNA polymorphism was also revealed by the cDNA clone and it was visualized on the Southern blot analyses as the presence or absence of an extra band (or a set of extra bands). It seems to stem from a stretch of DNA sequence present in some individuals at one single locus but absent in others, and is of non-chromosome-10 origin based on linkage analyses with known chromosome 10 markers. This "presence/absence" type of polymorphism could be revealed by all of the 25 restriction enzymes tested and is similar in nature to that previously reported with one of the human dihydrofolate reductase pseudogenes, DHFRP1. Dissection of the pGEM-32 clone demonstrated that the region revealing the non-chromosome-10 sequences is within a fragment about 1.7 kb in length extending from about 600 nucleotides preceding the stop codon down to the end of the cloned FNRB 3' untranslated region. Due to its high polymorphism information content (PIC) value (0.71 for haplotypes of BanII, HinfI, and KpnI RFLPs) and proximity to the centromere. FNRB will prove to be a highly useful marker for genetic linkage studies of multiple endocrine neoplasia type 2A (MEN2A) as well as for chromosome-10 linkage studies in general.
Asunto(s)
Cromosomas Humanos Par 10 , ADN , Ligamiento Genético , Polimorfismo de Longitud del Fragmento de Restricción , Receptores Inmunológicos/genética , Mapeo Cromosómico , Cromosomas Humanos Par 1 , Cromosomas Humanos Par 17 , Cromosomas Humanos Par 21 , ADN/genética , ADN/aislamiento & purificación , Sondas de ADN , ADN de Neoplasias/genética , Femenino , Marcadores Genéticos , Haplotipos , Humanos , Masculino , Neoplasia Endocrina Múltiple/genética , Receptores de FibronectinaRESUMEN
Despite many years of research, the genetic factors in schizophrenia are not well understood. Recent developments in DNA technology allow new methods of testing genetic hypotheses in the etiology of this debilitating disorder. We have found evidence against linkage of schizophrenia in a Swedish kindred to markers on chromosome 5; another research group has reported positive evidence for linkage to this same chromosomal region in British and Icelandic families. This article presents a set of data expanded from our previous report, discusses the issue of heterogeneity, and reviews the current status of linkage studies in schizophrenia.
Asunto(s)
Cromosomas Humanos Par 5 , Ligamiento Genético , Esquizofrenia/genética , Humanos , Islandia , Escala de Lod , Polimorfismo de Longitud del Fragmento de Restricción , Suecia , Reino UnidoRESUMEN
Schizophrenia is a severe mental illness with a typically chronic course affecting nearly 1% of the human population. It is generally accepted that genetic factors have an important pathogenic role in a substantial portion of schizophrenia cases; however, despite decades of family studies, there is no agreed-upon mode of inheritance. The discovery of genetic aetiologic factors and resolution of the inheritance pattern(s) will undoubtably emerge from genetic linkage studies. With these objectives in mind, we undertook a linkage project, starting in 1985, in a previously well-documented kindred from north Sweden. Multipoint linkage analyses were used to screen the proximal long arm of chromosome 5 using restriction fragment length polymorphism (RFLP) markers at five loci and the distal long arm using RFLPs at two loci, one of which was the locus for the glucocorticoid receptor. We found strong evidence against linkage between schizophrenia and the seven loci. These results, together with the positive evidence for linkage of schizophrenia with markers in the proximal long arm of chromosome 5 lead us to conclude that the genetic factors underlying schizophrenia are heterogeneous.