RESUMEN
Uterine leiomyomata (UL) are the most common neoplasms of the female reproductive tract and primary cause for hysterectomy, leading to considerable morbidity and high economic burden. Here we conduct a GWAS meta-analysis in 35,474 cases and 267,505 female controls of European ancestry, identifying eight novel genome-wide significant (P < 5 × 10-8) loci, in addition to confirming 21 previously reported loci, including multiple independent signals at 10 loci. Phenotypic stratification of UL by heavy menstrual bleeding in 3409 cases and 199,171 female controls reveals genome-wide significant associations at three of the 29 UL loci: 5p15.33 (TERT), 5q35.2 (FGFR4) and 11q22.3 (ATM). Four loci identified in the meta-analysis are also associated with endometriosis risk; an epidemiological meta-analysis across 402,868 women suggests at least a doubling of risk for UL diagnosis among those with a history of endometriosis. These findings increase our understanding of genetic contribution and biology underlying UL development, and suggest overlapping genetic origins with endometriosis.
Asunto(s)
Endometriosis/genética , Leiomioma/genética , Neoplasias Uterinas/genética , Adulto , Proteínas de la Ataxia Telangiectasia Mutada/genética , Endometriosis/epidemiología , Femenino , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Leiomioma/complicaciones , Leiomioma/epidemiología , Análisis de la Aleatorización Mendeliana , Menorragia/etiología , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Modelos de Riesgos Proporcionales , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/genética , Transducción de Señal , Telomerasa/genética , Neoplasias Uterinas/complicaciones , Neoplasias Uterinas/epidemiología , Población Blanca/genéticaRESUMEN
BACKGROUND: Recurrent miscarriage (RM) has been suggested to be caused by mutations in genes coding for various coagulation factors resulting in thrombophilia. Mouse models indicate that genes involved in the protein C anticoagulant pathway are essential for normal embryonic development. Loss of function of two of these genes, thrombomodulin (TM) and endothelial protein C receptor (EPCR), causes embryonic lethality in mice. The aim of this study was to determine whether variations in the human TM or EPCR genes are associated with an increased risk for RM. METHODS: Forty-six RM patients and 191 controls were screened for mutations in TM and EPCR using denaturing high-performance liquid chromatography (DHPLC). The partners of 40 RM patients were also screened. RESULTS: One exonic and one intronic variation in TM and two exonic and two intronic sequences in EPCR were detected. Four variants were common in both patients and controls. A previously identified truncating mutation in EPCR, suggested to have a role in pregnancy complications, was identified in two patients and one control. A novel deletion in the 3'UTR region of TM was detected, but its significance remains unsolved. CONCLUSIONS: These data suggest that mutations in the TM or EPCR genes are not a major cause of RM, although they may exert a modifier effect in combination with other variants.
Asunto(s)
Aborto Habitual/genética , Antígenos CD/genética , Receptores de Superficie Celular/genética , Trombomodulina/genética , Regiones no Traducidas 3'/genética , Adolescente , Adulto , Cromatografía Líquida de Alta Presión , Receptor de Proteína C Endotelial , Femenino , Variación Genética , Humanos , Mutación , EmbarazoAsunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Colestasis Intrahepática/genética , Exones/genética , Polimorfismo de Nucleótido Simple/genética , Complicaciones del Embarazo/etiología , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP , Estudios de Casos y Controles , Femenino , Finlandia , Humanos , Masculino , EmbarazoRESUMEN
The cooperatively breeding bell miner, Manorina melanophrys, differs from most other cooperative breeding species in the complexity of its social system, where discrete social organization occurs on at least three levels. Microsatellite markers were used to investigate the degree of genetic structure underlying the social organization of M. melanophrys by comparing colonies, coteries and nest contingents. The genetic data confirmed behavioural observations of M. melanophrys living in male kin-based groups between which females disperse short distances to breed. Estimates of FST revealed restricted gene flow between eight colonies located within 30 km that was significantly associated with geographical distance when the two most distant colonies were included. Within a high density colony significant differences were found between coteries; analysis of the degree of relatedness between coterie members showed that this is due to related individuals associating preferentially with each other. Similarly, the contingent of individuals attending a nest were generally close relatives of the young they were aiding, supporting models invoking kin selection as the selective agency mediating helping.