Common variation at 3p22.1 and 7p15.3 influences multiple myeloma risk

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.     

Alhazen,Leonardo, and late-medieval speculation on the inversion of images in the eye

No one before Platter and Kepler proposed retinal reception of an inverted visual image. The dominant tradition in visual theory, especially that of Alhazen and his Western followers, subordinated the intra-ocular geometry of visual rays to the requirement for an upright image and to preconceptions about the precise nature of the visual spirit and its part in vision. Henry of Langenstein and an anonymous glossator in the late Middle Ages proposed alternatives to Alhazen, including the suggestion of double inversion of the image. Leonardo da Vinci was aware of both Alhazen's theory and Henry's contradiction, but perhaps not of the anonymous hypothesis of double inversion. Leonardo's visual ‘theory’ has more the character of a critique than of a theoretical alternative, and he did not transcend the medieval concept of visual spirit.     

Seed bank dynamics and habitat indicators of Arctomecon californica, a rare plant in a fragmented desert environment

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";}     

Genome-wide association study identifies three new melanoma susceptibility loci

We report a genome-wide association study for melanoma that was conducted by the GenoMEL Consortium. Our discovery phase included 2,981 individuals with melanoma and 1,982 study-specific control individuals of European ancestry, as well as an additional 6,426 control subjects from French or British populations, all of whom were genotyped for 317,000 or 610,000 single-nucleotide polymorphisms (SNPs). Our analysis replicated previously known melanoma susceptibility loci. Seven new regions with at least one SNP with P < 10(-5) and further local imputed or genotyped support were selected for replication using two other genome-wide studies (from Australia and Texas, USA). Additional replication came from case-control series from the UK and The Netherlands. Variants at three of the seven loci replicated at P < 10(-3): an SNP in ATM (rs1801516, overall P = 3.4 × 10(-9)), an SNP in MX2 (rs45430, P = 2.9 × 10(-9)) and an SNP adjacent to CASP8 (rs13016963, P = 8.6 × 10(-10)). A fourth locus near CCND1 remains of potential interest, showing suggestive but inconclusive evidence of replication (rs1485993, overall P = 4.6 × 10(-7) under a fixed-effects model and P = 1.2 × 10(-3) under a random-effects model). These newly associated variants showed no association with nevus or pigmentation phenotypes in a large British case-control series.     

Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function

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.     

Density and biomass of redband trout relative to stream shading and temperature in southwestern Idaho

Density and biomass of redband trout ( Oncorhynchus mykiss gairdneri ) relative to stream temperature were examined in headwater reaches of Big Jacks and Little Jacks Creeks in southwestern Idaho. Stream shading was greater (mean of 80% versus 46%) and solar insolation was lower (mean of 7.9 versus 15.1 mJ · m -2 · day -1 ) in Little Jacks Creek ( P P ≤ 0.07) but increased more rapidly and to higher levels (24° - 26° C) in Big Jacks Creek. Daily maximum water temperatures (23 km downstream of headwater springs) during July 1996 were lower in Little Jacks Creek (ranged from 18° to 22° C) than in Big Jacks Creek (20.2° to 26° C, P P -2 and 25.0 g · m -2 ) compared to Big Jacks Creek (0.3 fish · m -2 and 8.9 g · m -2 , P = 0.01). Trout density was negatively correlated with increases in water temperature ( P = 0.03) and solar insolation ( P = 0.09) in both streams. Trout biomass increased with stream shading and was negatively correlated with solar insolation ( P < 0.1). Warmer water temperatures in Big Jacks Creek were likely due to historical summerlong livestock grazing, which drastically reduced riparian shading.     

Genome-wide association study identifies a susceptibility locus for thoracic aortic aneurysms and aortic dissections spanning FBN1 at 15q21.1

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.     

Genome partitioning of genetic variation for complex traits using common SNPs

We estimate and partition genetic variation for height, body mass index (BMI), von Willebrand factor and QT interval (QTi) using 586,898 SNPs genotyped on 11,586 unrelated individuals. We estimate that ～45%, ～17%, ～25% and ～21% of the variance in height, BMI, von Willebrand factor and QTi, respectively, can be explained by all autosomal SNPs and a further ～0.5-1% can be explained by X chromosome SNPs. We show that the variance explained by each chromosome is proportional to its length, and that SNPs in or near genes explain more variation than SNPs between genes. We propose a new approach to estimate variation due to cryptic relatedness and population stratification. Our results provide further evidence that a substantial proportion of heritability is captured by common SNPs, that height, BMI and QTi are highly polygenic traits, and that the additive variation explained by a part of the genome is approximately proportional to the total length of DNA contained within genes therein.     

A copy number variation morbidity map of developmental delay

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.     

The value of data

Data citation and the derivation of semantic constructs directly from datasets have now both found their place in scientific communication. The social challenge facing us is to maintain the value of traditional narrative publications and their relationship to the datasets they report upon while at the same time developing appropriate metrics for citation of data and data constructs.