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431.
Morgan NV Westaway SK Morton JE Gregory A Gissen P Sonek S Cangul H Coryell J Canham N Nardocci N Zorzi G Pasha S Rodriguez D Desguerre I Mubaidin A Bertini E Trembath RC Simonati A Schanen C Johnson CA Levinson B Woods CG Wilmot B Kramer P Gitschier J Maher ER Hayflick SJ 《Nature genetics》2006,38(7):752-754
Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis. 相似文献
432.
Beales PL Bland E Tobin JL Bacchelli C Tuysuz B Hill J Rix S Pearson CG Kai M Hartley J Johnson C Irving M Elcioglu N Winey M Tada M Scambler PJ 《Nature genetics》2007,39(6):727-729
Jeune asphyxiating thoracic dystrophy, an autosomal recessive chondrodysplasia, often leads to death in infancy because of a severely constricted thoracic cage and respiratory insufficiency; retinal degeneration, cystic renal disease and polydactyly may be complicating features. We show that IFT80 mutations underlie a subset of Jeune asphyxiating thoracic dystrophy cases, establishing the first association of a defective intraflagellar transport (IFT) protein with human disease. Knockdown of ift80 in zebrafish resulted in cystic kidneys, and knockdown in Tetrahymena thermophila produced shortened or absent cilia. 相似文献
433.
Cox A Dunning AM Garcia-Closas M Balasubramanian S Reed MW Pooley KA Scollen S Baynes C Ponder BA Chanock S Lissowska J Brinton L Peplonska B Southey MC Hopper JL McCredie MR Giles GG Fletcher O Johnson N dos Santos Silva I Gibson L Bojesen SE Nordestgaard BG Axelsson CK Torres D Hamann U Justenhoven C Brauch H Chang-Claude J Kropp S Risch A Wang-Gohrke S Schürmann P Bogdanova N Dörk T Fagerholm R Aaltonen K Blomqvist C Nevanlinna H Seal S Renwick A Stratton MR Rahman N Sangrajrang S Hughes D 《Nature genetics》2007,39(3):352-358
The Breast Cancer Association Consortium (BCAC) has been established to conduct combined case-control analyses with augmented statistical power to try to confirm putative genetic associations with breast cancer. We genotyped nine SNPs for which there was some prior evidence of an association with breast cancer: CASP8 D302H (rs1045485), IGFBP3 -202 C --> A (rs2854744), SOD2 V16A (rs1799725), TGFB1 L10P (rs1982073), ATM S49C (rs1800054), ADH1B 3' UTR A --> G (rs1042026), CDKN1A S31R (rs1801270), ICAM5 V301I (rs1056538) and NUMA1 A794G (rs3750913). We included data from 9-15 studies, comprising 11,391-18,290 cases and 14,753-22,670 controls. We found evidence of an association with breast cancer for CASP8 D302H (with odds ratios (OR) of 0.89 (95% confidence interval (c.i.): 0.85-0.94) and 0.74 (95% c.i.: 0.62-0.87) for heterozygotes and rare homozygotes, respectively, compared with common homozygotes; P(trend) = 1.1 x 10(-7)) and weaker evidence for TGFB1 L10P (OR = 1.07 (95% c.i.: 1.02-1.13) and 1.16 (95% c.i.: 1.08-1.25), respectively; P(trend) = 2.8 x 10(-5)). These results demonstrate that common breast cancer susceptibility alleles with small effects on risk can be identified, given sufficiently powerful studies. 相似文献
434.
Delous M Baala L Salomon R Laclef C Vierkotten J Tory K Golzio C Lacoste T Besse L Ozilou C Moutkine I Hellman NE Anselme I Silbermann F Vesque C Gerhardt C Rattenberry E Wolf MT Gubler MC Martinovic J Encha-Razavi F Boddaert N Gonzales M Macher MA Nivet H Champion G Berthélémé JP Niaudet P McDonald F Hildebrandt F Johnson CA Vekemans M Antignac C Rüther U Schneider-Maunoury S Attié-Bitach T Saunier S 《Nature genetics》2007,39(7):875-881
Cerebello-oculo-renal syndrome (CORS), also called Joubert syndrome type B, and Meckel (MKS) syndrome belong to the group of developmental autosomal recessive disorders that are associated with primary cilium dysfunction. Using SNP mapping, we identified missense and truncating mutations in RPGRIP1L (KIAA1005) in both CORS and MKS, and we show that inactivation of the mouse ortholog Rpgrip1l (Ftm) recapitulates the cerebral, renal and hepatic defects of CORS and MKS. In addition, we show that RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4, known genes associated with MKS, CORS and nephronophthisis (a related renal disorder and ciliopathy). In addition, the RPGRIP1L missense mutations found in CORS individuals diminishes the interaction between RPGRIP1L and nephrocystin-4. Our findings show that mutations in RPGRIP1L can cause the multiorgan phenotypic abnormalities found in CORS or MKS, which therefore represent a continuum of the same underlying disorder. 相似文献
435.
Broderick P Chubb D Johnson DC Weinhold N Försti A Lloyd A Olver B Ma YP Dobbins SE Walker BA Davies FE Gregory WA Child JA Ross FM Jackson GH Neben K Jauch A Hoffmann P Mühleisen TW Nöthen MM Moebus S Tomlinson IP Goldschmidt H Hemminki K Morgan GJ Houlston RS 《Nature genetics》2012,44(1):58-61
To identify risk variants for multiple myeloma, we conducted a genome-wide association study of 1,675 individuals with multiple myeloma and 5,903 control subjects. We identified risk loci for multiple myeloma at 3p22.1 (rs1052501 in ULK4; odds ratio (OR) = 1.32; P = 7.47 × 10(-9)) and 7p15.3 (rs4487645, OR = 1.38; P = 3.33 × 10(-15)). In addition, we observed a promising association at 2p23.3 (rs6746082, OR = 1.29; P = 1.22 × 10(-7)). Our study identifies new genomic regions associated with multiple myeloma risk that may lead to new etiological insights. 相似文献
436.
Protection of endangered desert plant species is frequently complicated by a lack of information about seeds, the most stress-resistant and populous life stage. We studied the relative locations of seeds and plants of a rare endangered herbaceous perennial, the Las Vegas bearpoppy ( Arctomecon californica ) in seven 1-ha sites randomly located within a 100-ha study area that was slated for development in Las Vegas, Nevada. We also measured the physical and biological attributes of the environment supporting the seeds and plants, including soil hardness, rock cover, cryptogamic crust cover, and associated vegetation. Arctomecon californica seed density was 0.651 seeds · m –2 , and seeds were found throughout the top 4 cm of soil. Seed viability among sites ranged from 26% to 79%; however, no significant changes between depths were detected. The spatial distribution of the seed bank coincided with the current A. californica adult distribution only in sites with both a high plant density and high numbers of seeds. Arctomecon californica adults occupied open areas within the gypsum environment that supported significantly less vegetative cover than the surrounding area. We observed a positive association between A. californica adults and shadscale ( Atriplex confertifolia ) and a negative association with 7 other plant species among sites. Sites with an indurated abiotic crust hosted higher numbers of A. californica adults than sites with softer soils. However, rock cover, cryptogamic crust cover, and soil hardness were poor explanatory factors for characterizing A. californica presence. We suggest that land managers should incorporate seed bank census into monitoring programs due to the extreme year-to-year fluctuations in A. californica plant population densities. A menudo la protección de especies de plantas desérticas en peligro de extinción se ve complicada por la falta de información sobre las semillas, la etapa de vida más abundante y resistente al estrés. Estudiamos la ubicación relativa de semillas y plantas de “Las Vegas bearpoppy” ( Arctomecon californica ), una planta perenne en peligro de extinción, en 7 sitios de 1 ha. localizados al azar dentro de un área de estudio de 100 ha que estaba destinada a la urbanización en Las Vegas, Nevada (E.U.A.). También medimos los atributos físicos y biológicos del ambiente que sostiene las semillas y plantas, tales como dureza del suelo, rocosidad, cobertura de costra cryptógama y vegetación asociada. La densidad de semillas de A. californica fue 0.651 semillas · m –2 y se observó en los 4 cm superiores del suelo. La viabilidad de las semillas varió del 26% al 79% entre los sitios; sin embargo, no detectamos cambios significativos entre profundidades. La distribución espacial del banco de semillas coincidió con la distribución actual de adultos de A. californica, sólo en sitios que tuvieron una alta densidad de plantas y altos números de semillas. Los adultos de A. californica ocuparon áreas abiertas dentro del ambiente de yeso que sostenía significativamente menos cobertura vegetal que las áreas circunvecinas. Observamos una asociación positiva entre los adultos de A. californica y el chamizo ( Atriplex confertifolia ) y una asociación negativa con siete otras especies de plantas entre sitios. Los sitios con una costra abiótica endurecida albergaron más adultos de A. californica que los sitios con suelos más blandos. No obstante, la cubierta rocosa, la costra cryptógama y la dureza del suelo fueron inadecuadas como factores para caracterizar la presencia de A. californica. Sugerimos que los manejadores de tierras deben incorporar censos de bancos de semillas en los programas de monitoreo, debido a las fluctuaciones extremas de un año a otro en la densidad poblacional de A. californica. Normal 0 MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman";} 相似文献
437.
Soler Artigas M Loth DW Wain LV Gharib SA Obeidat M Tang W Zhai G Zhao JH Smith AV Huffman JE Albrecht E Jackson CM Evans DM Cadby G Fornage M Manichaikul A Lopez LM Johnson T Aldrich MC Aspelund T Barroso I Campbell H Cassano PA Couper DJ Eiriksdottir G Franceschini N Garcia M Gieger C Gislason GK Grkovic I Hammond CJ Hancock DB Harris TB Ramasamy A Heckbert SR Heliövaara M Homuth G Hysi PG James AL Jankovic S Joubert BR Karrasch S Klopp N Koch B Kritchevsky SB Launer LJ Liu Y Loehr LR 《Nature genetics》2011,43(11):1082-1090
Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function. 相似文献
438.
Lemaire SA McDonald ML Guo DC Russell L Miller CC Johnson RJ Bekheirnia MR Franco LM Nguyen M Pyeritz RE Bavaria JE Devereux R Maslen C Holmes KW Eagle K Body SC Seidman C Seidman JG Isselbacher EM Bray M Coselli JS Estrera AL Safi HJ Belmont JW Leal SM Milewicz DM 《Nature genetics》2011,43(10):996-1000
Although thoracic aortic aneurysms and dissections (TAAD) can be inherited as a single-gene disorder, the genetic predisposition in the majority of affected people is poorly understood. In a multistage genome-wide association study (GWAS), we compared 765 individuals who had sporadic TAAD (STAAD) with 874 controls and identified common SNPs at a 15q21.1 locus that were associated with STAAD, with odds ratios of 1.6-1.8 that achieved genome-wide significance. We followed up 107 SNPs associated with STAAD with P < 1 × 10(-5) in the region, in two separate STAAD cohorts. The associated SNPs fall into a large region of linkage disequilibrium encompassing FBN1, which encodes fibrillin-1. FBN1 mutations cause Marfan syndrome, whose major cardiovascular complication is TAAD. This study shows that common genetic variants at 15q21.1 that probably act via FBN1 are associated with STAAD, suggesting a common pathogenesis of aortic disease in Marfan syndrome and STAAD. 相似文献
439.
Cooper GM Coe BP Girirajan S Rosenfeld JA Vu TH Baker C Williams C Stalker H Hamid R Hannig V Abdel-Hamid H Bader P McCracken E Niyazov D Leppig K Thiese H Hummel M Alexander N Gorski J Kussmann J Shashi V Johnson K Rehder C Ballif BC Shaffer LG Eichler EE 《Nature genetics》2011,43(9):838-846
To understand the genetic heterogeneity underlying developmental delay, we compared copy number variants (CNVs) in 15,767 children with intellectual disability and various congenital defects (cases) to CNVs in 8,329 unaffected adult controls. We estimate that ~14.2% of disease in these children is caused by CNVs >400 kb. We observed a greater enrichment of CNVs in individuals with craniofacial anomalies and cardiovascular defects compared to those with epilepsy or autism. We identified 59 pathogenic CNVs, including 14 new or previously weakly supported candidates, refined the critical interval for several genomic disorders, such as the 17q21.31 microdeletion syndrome, and identified 940 candidate dosage-sensitive genes. We also developed methods to opportunistically discover small, disruptive CNVs within the large and growing diagnostic array datasets. This evolving CNV morbidity map, combined with exome and genome sequencing, will be critical for deciphering the genetic basis of developmental delay, intellectual disability and autism spectrum disorders. 相似文献
440.
Johnson LN 《Cellular and molecular life sciences : CMLS》2008,65(15):2271-2276