| 1. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 2. |
- Noh, Hyun Ji, et al.
(författare)
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Integrating evolutionary and regulatory information with multispecies approach implicates genes and pathways in obsessive-compulsive disorder
- 2017
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Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Obsessive-compulsive disorder is a severe psychiatric disorder linked to abnormalities in glutamate signaling and the cortico-striatal circuit. We sequenced coding and regulatory elements for 608 genes potentially involved in obsessive-compulsive disorder in human, dog, and mouse. Using a new method that prioritizes likely functional variants, we compared 592 cases to 560 controls and found four strongly associated genes, validated in a larger cohort. NRXN1 and HTR2A are enriched for coding variants altering postsynaptic protein-binding domains. CTTNBP2 (synapse maintenance) and REEP3 (vesicle trafficking) are enriched for regulatory variants, of which at least six (35%) alter transcription factor-DNA binding in neuroblastoma cells. NRXN1 achieves genome-wide significance (p = 6.37 x 10(-11)) when we include 33,370 population-matched controls. Our findings suggest synaptic adhesion as a key component in compulsive behaviors, and show that targeted sequencing plus functional annotation can identify potentially causative variants, even when genomic data are limited.
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| 3. |
- Tang, Guoping, et al.
(författare)
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Estimating potential forest NPP, biomass and their climatic sensitivity in New England using a dynamic ecosystem model
- 2010
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Ingår i: Ecosphere. - 2150-8925. ; 1:6, s. 1-20
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Tidskriftsartikel (refereegranskat)abstract
- Abstract in UndeterminedAccurate estimation of forest net primary productivity (NPP), biomass, and their sensitivity to changes in temperature and precipitation is important for understanding the fluxes and pools of terrestrial carbon resulting from anthropogenically driven climate change. The objectives of this study were to (1) estimate potential forest NPP and biomass for New England using a regional ecosystem model, (2) compare modeled forest NPP and biomass with other reported data for New England, and (3) examine the sensitivity of modeled forest NPP to historical climatic variation. We addressed these objectives using the regional ecosystem model LPJ-GUESS implemented with eight plant functional types representing New England forests. We ran the model using 30-arc second spatial resolution climate data in monthly time-steps for the period 1901-2006. The modeled forest NPP and biomass were compared to empirically-based MODIS and FIA estimates of NPP and U.S. forest biomass. Our results indicate that forest NPP in New England averages 428 g C.m(-2).yr(-1) and ranges from 333 to 541 g C.m(-2).yr(-1) for the baseline period (1971-2000), while forest biomass averages 135 Mg/ha and ranges from 77 to 242 Mg/ha. Modeled forest biomass decreased at a rate of 0.11 Mg/ha (R-2 = 0.74) per year in the period 1901-1949 but increased at a rate of 0.25 Mg/ha (R-2 = 0.95) per year in the period 1950-2006. Estimates of NPP and biomass depend on forest type: spruce-fir had the lowest mean of 395 g C.m(-2).yr(-1) and oak forest had the highest mean of 468 g C.m(-2).yr(-1). Similarly, forest biomass was highest in oak (153 Mg/ha) and lowest in red-jack pine (118 Mg/ha) forests. The modeled NPP for New England agrees well with FIA-based estimates from similar forests in the mid-Atlantic region but was smaller than MODIS NPP estimates for New England. Nevertheless, the modeled inter-annual variability of NPP was strongly correlated with the MODIS NPP data. The modeled biomass agrees well with U.S. forest biomass data for New England but was less than FIA-based estimates in the mid-Atlantic region. For the region as a whole, the modeled NPP and biomass are within the ranges of MODIS-and FIA-based estimates. Forest NPP was sensitive to changes in temperature and precipitation: NPP was positively related to temperatures in April, May and October but negatively related to summer temperature. Increases in precipitation in the growing season enhanced forest NPP.
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| 4. |
- Tang, Guoping, et al.
(författare)
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Potential future dynamics of carbon fluxes and pools in New England forests and their climatic sensitivities: A model-based study
- 2014
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Ingår i: Global Biogeochemical Cycles. - 0886-6236. ; 28:3, s. 286-299
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Tidskriftsartikel (refereegranskat)abstract
- Projections of terrestrial carbon (C) dynamics must account for interannual variation in ecosystem C exchange associated with climate change, increasing atmospheric CO2 concentration, and species dynamics. We used a dynamic ecosystem model to (i) project the potential dynamics of C in New England forests under nine climate change scenarios (CCSs) for the 21st century and (ii) examine the sensitivity of potential C dynamics to changes in climate and atmospheric CO2 concentration. Our results indicated that forest net primary productivity (NPP) and soil heterotrophic respiration (RH) averaged 428 and 279gC/m(2)/yr and New England forests sequestered CO2 by 149gC/m(2)/yr in the baseline period (1971-2000). Under the nine future CCSs, NPP and RH were modeled to increase by an average rate of 0.85 and 0.56gC/m(2)/yr(2) during 1971-2099. The asymmetric increase in NPP and RH resulted in New England forests sequestering atmospheric CO2 at a net rate of 0.29gC/m(2)/yr(2) with increases in vegetation and soil C. Simulations also indicated that climate warming alone decreases NPP, resulting in a net efflux of C from forests. In contrast, increasing precipitation by itself stimulates CO2 sequestration by forests. At the individual cell level, however, changes in temperature or precipitation can either positively or negatively affect consequent C dynamics. Elevation of CO2 levels was found to be the biggest driver for modeled future enhancement of C sequestration. Without the elevation of CO2 levels, climate warming has the potential to change New England forests from C sinks to sources in the late 21st century. Key Points Carbon sequestration in New England forests Complexity of climatic sensitivities of carbon dynamics Future potential carbon dynamics
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| 5. |
- Tang, Guoping, et al.
(författare)
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The potential transient dynamics of forests in New England under historical and projected future climate change
- 2012
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Ingår i: Climatic Change. - : Springer Science and Business Media LLC. - 0165-0009 .- 1573-1480. ; 114:2, s. 357-377
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Tidskriftsartikel (refereegranskat)abstract
- Projections of vegetation distribution that incorporate the transient responses of vegetation to climate change are likely to be more efficacious than those that assume an equilibrium between climate and vegetation. We examine the non-equilibrium dynamics of a temperate forest region under historic and projected future climate change using the dynamic ecosystem model LPJ-GUESS. We parameterized LPJ-GUESS for the New England region of the United Sates utilizing eight forest cover types that comprise the regionally dominant species. We developed a set of climate data at a monthly-step and a 30-arc second spatial resolution to run the model. These datasets consist of past climate observations for the period 1901-2006 and three general circulation model projections for the period 2007-2099. Our baseline (1971-2000) simulation reproduces the distribution of forest types in our study region as compared to the National Land Cover Data 2001 (Kappa statistic = 0.54). Under historic and nine future climate change scenarios, maple-beech-basswood, oaks and aspen-birch were modeled to move upslope at an estimated rate of 0.2, 0.3 and 0.5 m yr(-1) from 1901 to 2006, and continued this trend at an accelerated rate of around 0.5, 0.9 and 1.7 m yr(-1) from 2007 to 2099. Spruce-fir and white pine-cedar were modeled to contract to mountain ranges and cooler regions of our study region under projected future climate change scenarios. By the end of the 21(st) century, 60% of New England is projected to be dominated by oaks relative to 21% at the beginning of the 21(st) century, while northern New England is modeled to be dominated by aspen-birch. In mid and central New England, maple-beech-basswood, yellow birch-elm and hickories co-occur and form novel species associations. In addition to warming-induced northward and upslope shifts, climate change causes more complex changes in our simulations, such as reversed conversions between forest types that currently share similar bioclimatic ranges. These results underline the importance of considering community interactions and transient dynamics in modeling studies of climate change impacts on forest ecosystems.
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| 6. |
- Tang, Ruqi, et al.
(författare)
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Candidate genes and functional noncoding variants identified in a canine model of obsessive-compulsive disorder
- 2014
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 15:3, s. R25-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Obsessive-compulsive disorder (OCD), a severe mental disease manifested in time-consuming repetition of behaviors, affects 1 to 3% of the human population. While highly heritable, complex genetics has hampered attempts to elucidate OCD etiology. Dogs suffer from naturally occurring compulsive disorders that closely model human OCD, manifested as an excessive repetition of normal canine behaviors that only partially responds to drug therapy. The limited diversity within dog breeds makes identifying underlying genetic factors easier. Results: We use genome-wide association of 87 Doberman Pinscher cases and 63 controls to identify genomic loci associated with OCD and sequence these regions in 8 affected dogs from high-risk breeds and 8 breed-matched controls. We find 119 variants in evolutionarily conserved sites that are specific to dogs with OCD. These case-only variants are significantly more common in high OCD risk breeds compared to breeds with no known psychiatric problems. Four genes, all with synaptic function, have the most case-only variation: neuronal cadherin (CDH2), catenin alpha2 (CTNNA2), ataxin-1 (ATXN1), and plasma glutamate carboxypeptidase (PGCP). In the 2 Mb gene desert between the cadherin genes CDH2 and DSC3, we find two different variants found only in dogs with OCD that disrupt the same highly conserved regulatory element. These variants cause significant changes in gene expression in a human neuroblastoma cell line, likely due to disrupted transcription factor binding. Conclusions: The limited genetic diversity of dog breeds facilitates identification of genes, functional variants and regulatory pathways underlying complex psychiatric disorders that are mechanistically similar in dogs and humans.
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