Neonatal per- and polyfluoroalkyl substance exposure in relation to retinoblastoma.

BACKGROUND: Neonatal per- and polyfluoroalkyl substance (PFAS) exposure can disrupt hormonal homeostasis and induce neuro- and immunotoxicity in children. In this exploratory study, we investigated associations between PFAS levels in neonatal dried blood spots and retinoblastoma risk. MATERIALS AND METHODS: This study included 501 retinoblastoma cases born from 1983 to 2011 and 899 controls frequency-matched by birth year (20:1 matching ratio), born to 755 US-born and 366 Mexico-born mothers in California. Perfluorooctanesulfonic acid (PFOS), perflurooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) feature intensities were identified from neonatal blood spots from California newborn Genetic Disease Screening Program. Using logistic regression, we assessed whether an interquartile range (IQR) increase of PFAS levels or having above-mean levels of PFAS in blood affects retinoblastoma risk overall or its subtypes (i.e., unilateral, bilateral). We assessed children of US-born and Mexico-born mothers, separately. RESULTS AND DISCUSSION: Among all children, above-mean PFOS levels at birth increased the odds of retinoblastoma overall by 29% (95% Confidence Interval (CI): 1.00, 1.67) and unilateral retinoblastoma by 42% (95% CI: 1.03, 1.97). For children of Mexico-born mothers, we estimated the highest odds of retinoblastoma overall (adjusted odds ratio (aOR): 1.67; 95% CI: 1.06, 2.66) and bilateral retinoblastoma (aOR: 2.06; 95% CI: 1.12, 3.92) with above-mean PFOS levels. Among children of US-born mothers, higher PFOS levels increased the odds of unilateral retinoblastoma by 15% (95% CI: 0.99, 1.35) for each IQR increase and by 71% among children with above-mean PFOS levels (95% CI: 1.04, 2.90). In addition, for children of US-born mothers, PFOA increased the odds of retinoblastoma overall (aOR: 1.41; 95% CI: 1.00, 2.02 for above-mean levels, aOR: 1.06; 95% CI: 0.98, 1.16 per IQR increase). PFNA was not associated with retinoblastoma risk. CONCLUSIONS: Our results suggested that PFOS and PFOA might contribute to retinoblastoma risk in children born in California.

A gene based combination test using GWAS summary data.

BACKGROUND: Gene-based association tests provide a useful alternative and complement to the usual single marker association tests, especially in genome-wide association studies (GWAS). The way of weighting for variants in a gene plays an important role in boosting the power of a gene-based association test. Appropriate weights can boost statistical power, especially when detecting genetic variants with weak effects on a trait. One major limitation of existing gene-based association tests lies in using weights that are predetermined biologically or empirically. This limitation often attenuates the power of a test. On another hand, effect sizes or directions of causal genetic variants in real data are usually unknown, driving a need for a flexible yet robust methodology of gene based association tests. Furthermore, access to individual-level data is often limited, while thousands of GWAS summary data are publicly and freely available. RESULTS: To resolve these limitations, we propose a combination test named as OWC which is based on summary statistics from GWAS data. Several traditional methods including burden test, weighted sum of squared score test [SSU], weighted sum statistic [WSS], SNP-set Kernel Association Test [SKAT], and the score test are special cases of OWC. To evaluate the performance of OWC, we perform extensive simulation studies. Results of simulation studies demonstrate that OWC outperforms several existing popular methods. We further show that OWC outperforms comparison methods in real-world data analyses using schizophrenia GWAS summary data and a fasting glucose GWAS meta-analysis data. The proposed method is implemented in an R package available at https://github.com/Xuexia-Wang/OWC-R-package CONCLUSIONS: We propose a novel gene-based association test that incorporates four different weighting schemes (two constant weights and two weights proportional to normal statistic Z) and includes several popular methods as its special cases. Results of the simulation studies and real data analyses illustrate that the proposed test, OWC, outperforms comparable methods in most scenarios. These results demonstrate that OWC is a useful tool that adapts to the underlying biological model for a disease by weighting appropriately genetic variants and combination of well-known gene-based tests.

Including diverse and admixed populations in genetic epidemiology research.

The inclusion of ancestrally diverse participants in genetic studies can lead to new discoveries and is important to ensure equitable health care benefit from research advances. Here, members of the Ethical, Legal, Social, Implications (ELSI) committee of the International Genetic Epidemiology Society (IGES) offer perspectives on methods and analysis tools for the conduct of inclusive genetic epidemiology research, with a focus on admixed and ancestrally diverse populations in support of reproducible research practices. We emphasize the importance of distinguishing socially defined population categorizations from genetic ancestry in the design, analysis, reporting, and interpretation of genetic epidemiology research findings. Finally, we discuss the current state of genomic resources used in genetic association studies, functional interpretation, and clinical and public health translation of genomic findings with respect to diverse populations.

Kaolinite reduced Cd accumulation in peanut and remediate soil contaminated with both microplastics and cadmium.

Microplastics (MPs) increase the effective state of heavy metals (HMs) in soil and seriously threaten the yield and quality of peanuts (Arachis Hypogea L.). Kaolinite (KL) has the potential to ameliorate MP- and HM- contaminated soils, but the mechanism of action between them is not well understood. Therefore, 60-day experiments were conducted, where KL (1 %, 2 %) and MPs (0.1 %, 1 %) were individually or jointly mixed into soils with different cadmium (Cd) concentrations (0.5, 2.5, and 5.0 mg·kg-1) to cultivate peanuts in a greenhouse. Finally, soil-bioavailable Cd, peanut dry weight, peanut Cd concentrations, the pH, cation exchange capacity (CEC), dissolved organic carbon (DOC), microbial biomass carbon (MBC) and microbial biomass nitrogen (MBN) were determined. It was shown that MPs negatively affected the peanut dry weight and increased the content of soil-bioavailable Cd and Cd concentration in peanut. In the MP- and Cd-contaminated soils, KL mitigated the negative influence of MPs by increasing the dry weight of peanuts by 8.40 %-40.59 %, decreasing the soil-bioavailable Cd by 23.70-35.74 %, and significantly decreasing peanut Cd concentrations by 9.65-30.86 %. The presence of MPs decreased soil pH (7.69-7.87) and the CEC (20.96-23.95 cmol·L-1) and increased the soil DOC (1.84-2.26 mg·kg-1). KL significantly increased soil pH (7.79-8.03) and the CEC (24.96-28.28 cmol·L-1) and mitigated the adverse influence of MPs on the pH and CEC of Cd-contaminated soils. A regression path analysis (RPA) evidenced that KL decreased Cd accumulation in plants by changing the properties of soil contaminated with MPs and Cd. The research results revealed the mechanism of KL on peanut growth and Cd absorption in MP- and Cd-contaminated soil. The results of this study provide a foundation to improve the quality of MP- and HM-contaminated soils and realize safe peanut production.

Global evaluation of inhibitor impacts on ammonia and nitrous oxide emissions from agricultural soils: A meta-analysis.

Inhibitors are widely considered an efficient tool for reducing nitrogen (N) loss and improving N use efficiency, but their effectiveness is highly variable across agroecosystems. In this study, we synthesized 182 studies (222 sites) worldwide to evaluate the impacts of inhibitors (urease inhibitors [UI], nitrification inhibitors [NI] and combined inhibitors) on crop yields and gaseous N loss (ammonia [NH3 ] and nitrous oxide [N2 O] emissions) and explored their responses to different management and environmental factors including inhibitor application timing, fertilization regime, cropping system, water management, soil properties and climatic conditions using subgroup meta-analysis, meta-regression and multivariate analyses. The UI were most effective in enhancing crop yields (by 5%) and reducing NH3 volatilization (by 51%), whereas NI were most effective at reducing N2 O emissions (by 49%). The application of UI mitigates NH3 loss and increases crop yields especially in high NH3 -N loss scenarios, whereas NI application would minimize the net N2 O emissions and the resultant environmental impacts especially in low NH3 -N loss scenarios. Alternatively, the combined application of UI and NI enables producers to balance crop production and environmental conservation goals without pollution tradeoffs. The inhibitor efficacy for decreasing gaseous N loss was dependent upon soil and climatic conditions and management practices. Notably, both meta-regression and multivariate analyses suggest that inhibitors provide a greater opportunity for reducing fertilizer N inputs in high-N-surplus systems and presumably favor crop yield enhancement under soil N deficiency situations. The pursuit of an improved understanding of the interactions between plant-soil-climate-management systems and different types of inhibitors should continue to optimize the effectiveness of inhibitors for reducing environmental losses while increasing productivity.

Optimizing nitrogen management to mitigate gaseous losses and improve net benefits of an open-field Chinese cabbage system.

The excessive and inappropriate application of nitrogen (N) fertilizer in open vegetable fields is a major anthropogenic source of gaseous N losses including nitrous oxide (N2O) and ammonia (NH3) emissions in China. A 2-yr Chinese cabbage (Brassica pekinensis L.) experiment was carried out to explore the impacts of optimized N management (reduced N application rate, controlled-release urea [CRF] and nitrification inhibitor [NI]) on cabbage yield, soil inorganic N, and N2O and NH3 emissions, and to assess their economic benefits by a cost-benefit analysis. Six treatments including i) no N fertilizer (CK), ii) conventional urea fertilizer at 400 kg N ha-1 based on farmers' practices (CN), iii) conventional urea at 320 kg N ha-1 (RN), iv) conventional urea (320 kg N ha-1) with the addition of NI (RN + NI), v) CRF at 320 kg N ha-1 (CR) and vi) CRF (320 kg N ha-1) with the addition of NI (CR + NI) were implemented in an open Chinese cabbage field. No significant differences were found in the cabbage yields and soil NH4+-N contents under different N fertilization treatments. Only CR + NI treatment had significantly lower soil NO3--N contents than CN by 17.6%-34.6% at the early growing stages of cabbage in both years. Compared with CN, the N2O emissions were significantly decreased by 8.61%, 34.4%, 37.8% and 46.6% under RN, RN + NI, CR and CR + NI, respectively, indicating that CR + NI favors N2O abatement especially when NH3 has been suppressed by other 4 R practices. Meanwhile, the NH3 volatilization was 20.6% higher under RN + NI and 30.8% and 17.3% lower under CR and CR + NI compared to CN, respectively, which implied that CR was the most effective treatment in reducing the NH3 volatilization and total gaseous N loss in high NH3-N loss scenarios. Moreover, the net benefit of RN decreased by $945 USD ha-1 and those of RN + NI, CR and CR + NI treatments increased by $855, $930 and $1004 USD ha-1 compared to CN, respectively. This study recommends CR + NI as the optimal N fertilizer management for the sustainable production of vegetables with the lowest environmental risks and the greatest economic benefits.

A fast and powerful eQTL weighted method to detect genes associated with complex trait using GWAS summary data.

Although genomewide association studies (GWASs) have identified many genetic variants underlying complex traits, a large fraction of heritability still remains unexplained. Integrative analysis that incorporates additional information, such as expression quantitativetrait locus (eQTL) data into sequencing studies (denoted as transcriptomewide association study [TWAS]), can aid the discovery of trait-associated genetic variants. However, general TWAS methods only incorporate one eQTL-derived weight (e.g., cis-effect), and thus can suffer a substantial loss of power when the single estimated cis-effect is not predictive for the effect size of a genetic variant or when there are estimation errors in the estimated cis-effect, or if the data are not consistent with the model assumption. In this study, we propose an omnibus test (OT) which utilizes a Cauchy association test to integrate association evidence demonstrated by three different traditional tests (burden test, quadratic test, and adaptive test) using GWAS summary data with multiple eQTL-derived weights. The p value of the proposed test can be calculated analytically, and thus it is fast and efficient. We applied our proposed test to two schizophrenia (SCZ) GWAS summary data sets and two lipids trait (HDL) GWAS summary data sets. Compared with the three traditional tests, our proposed OT can identify more trait-associated genes.

Biotic ligand modeling to predict the toxicity of HWO4- and WO42- on wheat root elongation in solution cultures: Effects of pH and accompanying anions.

Increasing evidence demonstrates that hexavalent tungsten (W(VI)) can affect the survival of various organisms. This study explored the influences of pH and common anions on W(VI) toxicity on wheat and established a biotic ligand model (BLM) for predicting W(VI) toxicity. It was found that as the pH value increased from 6.0 to 8.5, the EC50[W(VI)]T values increased greatly from 24.7 to 46.6 µM, indicating that increasing pH values can alleviate W(VI) toxicity. A linear relationship between the ratio of HWO4- to WO42- and EC50{WO42-} indicated that WO42- and HWO4- were two toxic species of W(VI). The toxicity of W(VI) decreased as the H2PO4- and SO42- activities increased but not when the activities of Cl- and NO3- increased, demonstrating that the competition from H2PO4- and SO42- significantly influenced W(VI) toxicity. By applying BLM theory, the stability constants for HWO4-, WO42-, H2PO4-, and SO42- were obtained: logKWO4BL = 4.08, logKHWO4BL = 6.44, logKH2PO4BL = 2.09, and logKSO4BL = 1.87, fWBL50% = 0.300, ß = 1.99. Results demonstrated that BLM outperformed the free metal activity model(FIAM) in predicting W(VI) toxicity when considering the influences of pH, W(VI) species, and H2PO4- and SO42- competition for active ligand sites.

[Association between polymorphism of NUDT15 gene and hepatotoxicity induced by 6-MP in children with acute lymphoblastic leukemia].

OBJECTIVE: To investigate the association between single nucleotide polymorphism of NUDT15 gene (SNP rs116855232) and hepatotoxicity in children with acute lymphocytic leukemia (ALL). METHODS: A total of 135 children with ALL in Shandong Province were recruited in this study, and patients were divided into two groups based on the presence of liver injury. Genotypes of each patient were detected using PCR and Sanger sequencing. Clinical data and the average dose of 6-mercaptopurine (6-MP) were collected and analyzed by SPSS 19.0 software. RESULTS: Respectively, 99 patients were found with CC genotype, 32 patients with CT genotype and 4 patients with TT genotype. Compared with ALL patients without hepatotoxicity, there was a difference in genotypes between the two groups in the initial stage of chemotherapy for leukemia (Chi2 = 7.583, P = 0.023). In maintenance therapy stage there was also a difference between the two groups (Chi2 = 10.591, P = 0.005), and T allele was a risk factor for hepatotoxicity. CONCLUSION: The polymorphism of rs116855232 in NUDT15 gene was associated with hepatotoxicity induced by 6-mercaptopurine in children with ALL, and ALL patients with TT genotype should take a lower dose of 6-MP to avoided hepatotoxicity.

TS: a powerful truncated test to detect novel disease associated genes using publicly available gWAS summary data.

BACKGROUND: In the last decade, a large number of common variants underlying complex diseases have been identified through genome-wide association studies (GWASs). Summary data of the GWASs are freely and publicly available. The summary data is usually obtained through single marker analysis. Gene-based analysis offers a useful alternative and complement to single marker analysis. Results from gene level association tests can be more readily integrated with downstream functional and pathogenic investigations. Most existing gene-based methods fall into two categories: burden tests and quadratic tests. Burden tests are usually powerful when the directions of effects of causal variants are the same. However, they may suffer loss of statistical power when different directions of effects exist at the causal variants. The power of quadratic tests is not affected by the directions of effects but could be less powerful due to issues such as the large number of degree of freedoms. These drawbacks of existing gene based methods motivated us to develop a new powerful method to identify disease associated genes using existing GWAS summary data. METHODS AND RESULTS: In this paper, we propose a new truncated statistic method (TS) by utilizing a truncated method to find the genes that have a true contribution to the genetic association. Extensive simulation studies demonstrate that our proposed test outperforms other comparable tests. We applied TS and other comparable methods to the schizophrenia GWAS data and type 2 diabetes (T2D) GWAS meta-analysis summary data. TS identified more disease associated genes than comparable methods. Many of the significant genes identified by TS may have important mechanisms relevant to the associated traits. TS is implemented in C program TS, which is freely and publicly available online. CONCLUSIONS: The proposed truncated statistic outperforms existing methods. It can be employed to detect novel traits associated genes using GWAS summary data.

A general statistic to test an optimally weighted combination of common and/or rare variants.

Both genome-wide association study and next-generation sequencing data analyses are widely employed to identify disease susceptible common and/or rare genetic variants. Rare variants generally have large effects though they are hard to detect due to their low frequencies. Currently, many existing statistical methods for rare variants association studies employ a weighted combination scheme, which usually puts subjective weights or suboptimal weights based on some adhoc assumptions (e.g., ignoring dependence between rare variants). In this study, we analytically derived optimal weights for both common and rare variants and proposed a general and novel approach to test association between an optimally weighted combination of variants (G-TOW) in a gene or pathway for a continuous or dichotomous trait while easily adjusting for covariates. Results of the simulation studies show that G-TOW has properly controlled type I error rates and it is the most powerful test among the methods we compared when testing effects of either both rare and common variants or rare variants only. We also illustrate the effectiveness of G-TOW using the Genetic Analysis Workshop 17 (GAW17) data. Additionally, we applied G-TOW and other competitive methods to test disease-associated genes in real data of schizophrenia. The G-TOW has successfully verified genes FYN and VPS39 which are associated with schizophrenia reported in existing publications. Both of these genes are missed by the weighted sum statistic and the sequence kernel association test. Simulation study and real data analysis indicate that G-TOW is a powerful test.

Association of GSTM1 null variant with anthracycline-related cardiomyopathy after childhood cancer-A Children's Oncology Group ALTE03N1 report.

BACKGROUND: Anthracycline-related cardiomyopathy is a leading cause of late morbidity in childhood cancer survivors. Glutathione S-transferases (GSTs) are a class of phase II detoxification enzymes that facilitate the elimination of anthracyclines. As free-radical scavengers, GSTs could play a role in oxidative damage-induced cardiomyopathy. Associations between the GSTµ1 (GSTM1) null genotype and iron-overload-related cardiomyopathy have been reported in patients with thalassemia. METHODS: The authors sought to identify an association between the GSTM1 null genotype and anthracycline-related cardiomyopathy in childhood cancer survivors and to corroborate the association by examining GSTM1 gene expression in peripheral blood and human-induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) from survivors with and without cardiomyopathy. GSTM1 gene deletion was examined by polymerase chain reaction in 75 survivors who had clinically validated cardiomyopathy (cases) and in 92 matched survivors without cardiomyopathy (controls). Conditional logistic regression analysis adjusting for sex, age at cancer diagnosis, chest radiation, and anthracycline dose was used to assess the association between genotype and cardiomyopathy. Proprietary bead array technology and quantitative real-time polymerase chain reaction were used to measure GSTM1 expression levels in samples from 20 cases and 20 matched controls. hiPSC-CMs from childhood cancer survivors (3 with cardiomyopathy, 3 without cardiomyopathy) also were examined for GSTM1 gene expression levels. RESULTS: A significant association was observed between the risk of cardiomyopathy and the GSTM1 null genotype (odds ratio, 2.7; 95% CI, 1.3-5.9; P = .007). There was significant downregulation of GSTM1 expression in cases compared with controls (average relative expression, 0.67 ± 0.57 vs 1.33 ± 1.33, respectively; P = .049). hiPSC-CMs from patients who had cardiomyopathy revealed reduced GSTM1 expression (P = .007). CONCLUSIONS: The current findings could facilitate the identification of childhood cancer survivors who are at risk for anthracycline-related cardiomyopathy.

Test Gene-Environment Interactions for Multiple Traits in Sequencing Association Studies.

MOTIVATION: The risk of many complex diseases is determined by an interplay of genetic and environmental factors. The examination of gene-environment interactions (G×Es) for multiple traits can yield valuable insights about the etiology of the disease and increase power in detecting disease-associated genes. However, the methods for testing G×Es for multiple traits are very limited. METHOD: We developed novel approaches to test G×Es for multiple traits in sequencing association studies. We first perform a transformation of multiple traits by using either principal component analysis or standardization analysis. Then, we detect the effects of G×Es using novel proposed tests: testing the effect of an optimally weighted combination of G×Es (TOW-GE) and/or variable weight TOW-GE (VW-TOW-GE). Finally, we employ Fisher's combination test to combine the p values. RESULTS: Extensive simulation studies show that the type I error rates of the proposed methods are well controlled. Compared to the interaction sequence kernel association test (ISKAT), TOW-GE is more powerful when there are only rare risk and protective variants; VW-TOW-GE is more powerful when there are both rare and common variants. Both TOW-GE and VW-TOW-GE are robust to directions of effects of causal G×Es. Application to the COPDGene Study demonstrates that our proposed methods are very effective. CONCLUSIONS: Our proposed methods are useful tools in the identification of G×Es for multiple traits. The proposed methods can be used not only to identify G×Es for common variants, but also for rare variants. Therefore, they can be employed in identifying G×Es in both genome-wide association studies and next-generation sequencing data analyses.

Highly Stable Copper(I)-Thiacalix[4]arene-Based Frameworks for Highly Efficient Catalysis of Click Reactions in Water.

Environmentally friendly metal-organic frameworks (MOFs) have gained considerable attention for their potential use as heterogeneous catalysts. Herein, two CuI -based MOFs, namely, [Cu4 Cl4 L]⋅CH3 OH⋅1.5 H2 O (1-Cl) and [Cu4 Br4 L]⋅DMF⋅0.5 H2 O (1-Br), were assembled with new functionalized thiacalix[4]arenes (L) and halogen anions X- (X=Cl and Br) under solvothermal conditions. Remarkably, catalysts 1-Cl and 1-Br exhibit great stability in aqueous solutions over a wide pH range. Significantly, MOFs 1-Cl and 1-Br, as recycled heterogeneous catalysts, are capable of highly efficient catalysis for click reactions in water. The MOF structures, especially the exposed active CuI sites and 1D channels, play a key role in the improved catalytic activities. In particular, their catalytic activities in water are greatly superior to those in organic solvents or even in mixed solvents. This work proposes an attractive route for the design and self-assembly of environmentally friendly MOFs with high catalytic activity and reusability in water.

[Galectin-3 Expression and Its Clinical Significance in Acute Myeloid Leukemia with Positive AML1/ETO Fusion Gene].

OBJECTIVE: To investigate the mRNA expression of galectin-3 and its clinical significance in acute myeloid leukemia (AML) patients carrying AML1/ETOfusion gene. METHODS: RQ-PCR method was used to detect the expression of galectin-3 mRNA in bone marrow mononuclear cells of 53 AML patients with AML1/ETO+, ELISA was used to detect the expression of galectin-3 protein in peripheral blood, and the correlations of galectin-3 expression with clinical and laboratory features and outcomes were analyzed. RESULTS: The mRNA and protein levels of galectin-3 were significantly higher in newly diagnosed AML1/ETO+ AML patients compared with the control ( P<0.001). Galectin-3 mRNA and protein expressions were positively correlated (r=0.732, P<0.001). Galectin-3 protein was significantly decreased during the period of complete remission (CR)( P<0.001). The mRNA expression of galectin-3 was negatively correlated with the count of white blood cells ( P=0.014), and positively correlated with CD34 expression and additional cytogenetic aberrations (ACA) ( P=0.001, P=0.026). There was no significant difference in CR, partial remission (PR), induction death (early mortality) between galectin-3 high-expression group and low-expression group ( P>0.05), but there was significant difference in recurrence rate between the two groups ( P=0.029). The median overall survival (OS) rate and disease-free survival (DFS) rate were shortened in the high-expression group ( P=0.007, P=0.015) and the cumulative incidence of relapse was increased ( P=0.045), but there was no significant difference in the cumulative incidence of CM(155mm]mortality ( P>0.05). Cox regression analysis suggested galectin-3 mRNA level an independent indicator of OS and DFS in AML1/ETO+ AML patients. CONCLUSION: Bone marrow galectin-3 mRNA level may be an important reference index for evaluating the prognosis and guiding the treatment of AML1/ETO+ AML patients.

Methods and results from the genome-wide association group at GAW20.

BACKGROUND: This paper summarizes the contributions from the Genome-wide Association Study group (GWAS group) of the GAW20. The GWAS group contributions focused on topics such as association tests, phenotype imputation, and application of empirical kinships. The goals of the GWAS group contributions were varied. A real or a simulated data set based on the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study was employed by different methods. Different outcomes and covariates were considered, and quality control procedures varied throughout the contributions. RESULTS: The consideration of heritability and family structure played a major role in some contributions. The inclusion of family information and adaptive weights based on data were found to improve power in genome-wide association studies. It was proven that gene-level approaches are more powerful than single-marker analysis. Other contributions focused on the comparison between pedigree-based kinship and empirical kinship matrices, and investigated similar results in heritability estimation, association mapping, and genomic prediction. A new approach for linkage mapping of triglyceride levels was able to identify a novel linkage signal. CONCLUSIONS: This summary paper reports on promising statistical approaches and findings of the members of the GWAS group applied on real and simulated data which encompass the current topics of epigenetic and pharmacogenomics.

Soil organic carbon and total nitrogen stocks in alpine ecosystems of Altun Mountain National Nature Reserve in dry China.

The Altun Mountain National Nature Reserve (AMNNR), characterized by complex topography, is located on the northern edge of the Qinghai-Tibetan Plateau. The stocks of soil organic carbon (SOC) and total nitrogen (TN) are critically important for carbon and nitrogen sequestration in dry alpine ecosystems of the AMNNR, which is a "natural laboratory" for assessing the carbon and nitrogen storage without human disturbance. We explored the stocks of SOC and TN in soils of different dry alpine ecosystems by sampling 23 sites across the AMNNR during 2013. The results showed that the SOC and TN stocks of AMNNR varied significantly with ecosystem types. The SOC stocks of 0-15 cm were highest in the alpine wet meadow (7.96 kg/m2), followed by alpine steppe (2.63 kg/m2). The stocks of SOC and TN in 0-5 and 5-10 cm soils of alpine wet meadow were significantly (P < 0.05) higher than those in the soils of other dry alpine ecosystems. In the whole AMNNR, total storage of SOC and TN were approximately 80.97 and 4.48 Tg, 34.25% of SOC and 24.01% of TN were stored in the alpine steppe, 21.51% of SOC and 26.01% of TN were stored in the alpine scrub, the largest ecosystem in the AMNNR. Our findings suggested it is important to protect the soil and vegetation of the dry alpine ecosystems, particularly the alpine wet meadow and alpine scrub to promote the carbon storage.

Clinical impact of galectin-3 in newly diagnosed t (15;17)(q22;q21)/PML-RARa acute promyelocytic leukemia treated with all-trans retinoic acid and arsenic trioxide-based regimens.

Increased galectin-3 expression has been currently showed to be associated with poor prognosis in some hematological malignancies, such as acute myeloid leukemia, diffuse large B cell lymphoma. However, little is known about the clinical significance of galectin-3 in patients with acute promyelocytic leukemia (APL). We investigated the concentration of serum galectin-3 and characterized the relationship between galectin-3 and outcome in patients with APL. Higher galectin-3 levels were detected in patients with APL compared with the healthy controls (p < 0.001). Higher galectin-3 levels were closely associated with older ages (p < 0.001), the medical history of psoriasis (p = 0.036), coagulopathy (p = 0.042), and CD34 expression (p = 0.004). Compared with patients with lower galectin-3 levels, those with higher galectin-3 levels had significant shorter overall survival (p = 0.028) and relapse-free survival (p = 0.001). Multivariate analysis showed that serum galectin-3 was an independent unfavorable factor for relapse-free survival in patients with APL treated with all-trans retinoic acid and arsenic trioxide-based frontline therapy. Clinical impact of galectin-3 should be further investigated in patients with APL.

Gene Mapping in Admixed Families: A Cautionary Note on the Interpretation of the Transmission Disequilibrium Test and a Possible Solution.

A family-based study design is commonly used in gene mapping studies of complex human diseases. Most family-based studies use the transmission of alleles to assess evidence of association. It is generally believed that the transmission disequilibrium test (TDT) is robust against spurious association due to population stratification or admixture. While this is true when population stratification is due to discrete population structure, one should use the TDT-type methods with caution when they are applied to admixed populations in which population structure exists in local genomic regions. In a recently admixed population, such as African Americans and Hispanic Americans, the linkage disequilibrium coefficient between a marker and disease loci in the parental generation contains a spurious component from the admixture process. In this paper, we show that the general belief that family-based design would guard against spurious association caused by population stratification does not always hold in admixed populations. It is safe to use the TDT as a test of association when population stratification is due to global genome ancestry difference. However, when population stratification is due to local ancestry difference in certain genomic regions, the use of the TDT as a test of association can lead to spurious association. Second, we present a statistical framework for fine mapping of disease-associated genetic variants in admixed families. Unlike the TDT and other family-based association tests, this method does not rely on transmission disequilibrium and therefore can control local ancestry difference between transmitted and untransmitted alleles. Through simulations, we show that this method can control type I error rates under a wide range of population stratification mechanisms.

A powerful approach to test an optimally weighted combination of rare variants in admixed populations.

Population stratification has long been recognized as an issue in genetic association studies because unrecognized population stratification can lead to both false-positive and false-negative findings and can obscure true association signals if not appropriately corrected. This issue can be even worse in rare variant association analyses because rare variants often demonstrate stronger and potentially different patterns of stratification than common variants. To correct for population stratification in genetic association studies, we proposed a novel method to Test the effect of an Optimally Weighted combination of variants in Admixed populations (TOWA) in which the analytically derived optimal weights can be calculated from existing phenotype and genotype data. TOWA up weights rare variants and those variants that have strong associations with the phenotype. Additionally, it can adjust for the direction of the association, and allows for local ancestry difference among study subjects. Extensive simulations show that the type I error rate of TOWA is under control in the presence of population stratification and it is more powerful than existing methods. We have also applied TOWA to a real sequencing data. Our simulation studies as well as real data analysis results indicate that TOWA is a useful tool for rare variant association analyses in admixed populations.