Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

Lipoprotein(a), Lp(a), is a modified low-density lipoprotein particle that contains apolipoprotein(a), encoded by LPA, and is a highly heritable, causal risk factor for cardiovascular diseases that varies in concentrations across ancestries. Here, we use deep-coverage whole genome sequencing in 8392 individuals of European and African ancestry to discover and interpret both single-nucleotide variants and copy number (CN) variation associated with Lp(a). We observe that genetic determinants between Europeans and Africans have several unique determinants. The common variant rs12740374 associated with Lp(a) cholesterol is an eQTL for SORT1 and independent of LDL cholesterol. Observed associations of aggregates of rare non-coding variants are largely explained by LPA structural variation, namely the LPA kringle IV 2 (KIV2)-CN. Finally, we find that LPA risk genotypes confer greater relative risk for incident atherosclerotic cardiovascular diseases compared to directly measured Lp(a), and are significantly associated with measures of subclinical atherosclerosis in African Americans

Aerobic glycolysis as a marker of tumor aggressiveness: Preliminary data in high grade human brain tumors

Objectives. Glucose metabolism outside of oxidative phosphorylation, or aerobic glycolysis (AG), is a hallmark of active cancer cells that is not directly measured with standard 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). In this study, we characterized tumor regions with elevated AG defined based on PET measurements of glucose and oxygen metabolism. Methods. Fourteen individuals with high-grade brain tumors underwent structural MR scans and PET measurements of cerebral blood flow (CBF), oxygen (CMRO2) and glucose (CMRGlu) metabolism, and AG, using 15O-labeled CO, O2 and H2O, and FDG, and were compared to a normative cohort of 20 age-matched individuals. Results. Elevated AG was observed in most high-grade brain tumors and it was associated with decreased CMRO2 and CBF, but not with significant changes in CMRGlu. Elevated AG was a dramatic and early sign of tumor growth associated with decreased survival. AG changes associated with tumor growth were differentiated from the effects of nonneoplastic processes such as epileptic seizures. Conclusions. Our findings demonstrate that high-grade brain tumors exhibit elevated AG as a marker of tumor growth and aggressiveness. AG may detect areas of active tumor growth that are not evident on conventional FDG PET

Publisher Correction: Deep coverage whole genome sequences and plasma lipoprotein(a) in individuals of European and African ancestries.

The original version of this article contained an error in the name of the author Ramachandran S. Vasan, which was incorrectly given as Vasan S. Ramachandran. This has now been corrected in both the PDF and HTML versions of the article

A global soil spectral calibration library and estimation service

There is growing global interest in the potential for soil reflectance spectroscopy to fill an urgent need for more data on soil properties for improved decision-making on soil security at local to global scales. This is driven by the capability of soil spectroscopy to estimate a wide range of soil properties from a rapid, inexpensive, and highly reproducible measurement using only light. However, several obstacles are preventing wider adoption of soil spectroscopy. The biggest obstacles are the large variation in the soil analytical methods and operating procedures used in different laboratories, poor reproducibility of analyses within and amongst laboratories and a lack of soil physical archives. In addition, adoption is hindered by the expense and complexity of building soil spectral libraries and calibration models. The Global Soil Spectral Calibration Library and Estimation Service is proposed to overcome these obstacles by providing a freely available estimation service based on an open, high quality and diverse spectral calibration library and the extensive soil archives of the Kellogg Soil Survey Laboratory (KSSL) of the Natural Resources Conservation Service of the United States Department of Agriculture (USDA). The initiative is supported by the Global Soil Laboratory Network (GLOSOLAN) of the Global Soil Partnership and the Soil Spectroscopy for Global Good network, which provide additional support through dissemination of standards, capacity development and research. This service is a global public good which stands to benefit soil assessments globally, but especially developing countries where soil data and resources for conventional soil analyses are most limited

A genome-wide association study of anorexia nervosa.

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field

Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.</p

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk

Risk prediction model for waitlist mortality in patients with left ventricular assist devices

Background: Left ventricular assist devices (LVAD) are a bridge to heart transplantation (HT). Given limited donor organs, assessment of risk of waitlist mortality is important for waitlist prioritization for HT. We sought to derive and validate a risk prediction model for waitlist mortality in LVAD patients. Methods: Adult patients with a continuous-flow, centrifugal, durable LVAD listed or likely to be listed for HT in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) were included. The outcome was time to all-cause mortality within 2 years from implant. We considered 41 candidate predictors at 3 months post-implant. Univariate Fine-Gray models and 4 logistic regression techniques (logistic, LASSO, random forest, gradient boosting) were used to select variables for a final survival model using the Fine-Gray method. The model was validated in INTERMACS and in an independent cohort (European Registry for Patients with Mechanical Circulatory Support [EUROMACS]). Model discrimination and calibration were evaluated. Results: The INTERMACS cohort included 2364 patients with 268 (11%) deaths. A risk prediction model for waitlist mortality at 2 years was derived with area-under-the-curve (AUC) of 0.72 (95% CI 0.67–0.77). The EUROMACS cohort included 577 patients with 70 (12%) deaths. The model AUC was 0.62 (95% CI 0.55–0.70). The model predicted waitlist mortality when divided into low-, medium-, or high-risk groups in the INTERMACS (p&lt;0.001) and EUROMACS (p=0.0099) cohorts. Conclusions: We derived and validated a risk prediction model for waitlist mortality in LVAD patients using 2 independent cohorts. Our risk assessment model can inform HT prioritization in LVAD patents.</p