A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study

BACKGROUND:Blood lipid levels including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are highly heritable. Genome-wide association is a promising approach to map genetic loci related to these heritable phenotypes.METHODS:In 1087 Framingham Heart Study Offspring cohort participants (mean age 47 years, 52% women), we conducted genome-wide analyses (Affymetrix 100K GeneChip) for fasting blood lipid traits. Total cholesterol, HDL-C, and TG were measured by standard enzymatic methods and LDL-C was calculated using the Friedewald formula. The long-term averages of up to seven measurements of LDL-C, HDL-C, and TG over a ~30 year span were the primary phenotypes. We used generalized estimating equations (GEE), family-based association tests (FBAT) and variance components linkage to investigate the relationships between SNPs (on autosomes, with minor allele frequency [greater than or equal to]10%, genotypic call rate [greater than or equal to]80%, and Hardy-Weinberg equilibrium p [greater than or equal to] 0.001) and multivariable-adjusted residuals. We pursued a three-stage replication strategy of the GEE association results with 287 SNPs (P < 0.001 in Stage I) tested in Stage II (n ~1450 individuals) and 40 SNPs (P < 0.001 in joint analysis of Stages I and II) tested in Stage III (n~6650 individuals).RESULTS:Long-term averages of LDL-C, HDL-C, and TG were highly heritable (h2 = 0.66, 0.69, 0.58, respectively; each P < 0.0001). Of 70,987 tests for each of the phenotypes, two SNPs had p < 10-5 in GEE results for LDL-C, four for HDL-C, and one for TG. For each multivariable-adjusted phenotype, the number of SNPs with association p < 10-4 ranged from 13 to 18 and with p < 10-3, from 94 to 149. Some results confirmed previously reported associations with candidate genes including variation in the lipoprotein lipase gene (LPL) and HDL-C and TG (rs7007797; P = 0.0005 for HDL-C and 0.002 for TG). The full set of GEE, FBAT and linkage results are posted at the database of Genotype and Phenotype (dbGaP). After three stages of replication, there was no convincing statistical evidence for association (i.e., combined P < 10-5 across all three stages) between any of the tested SNPs and lipid phenotypes.CONCLUSION:Using a 100K genome-wide scan, we have generated a set of putative associations for common sequence variants and lipid phenotypes. Validation of selected hypotheses in additional samples did not identify any new loci underlying variability in blood lipids. Lack of replication may be due to inadequate statistical power to detect modest quantitative trait locus effects (i.e., < 1% of trait variance explained) or reduced genomic coverage of the 100K array. GWAS in FHS using a denser genome-wide genotyping platform and a better-powered replication strategy may identify novel loci underlying blood lipids.

Heinz-Günther Nesselrath et al. Einleitung in die griechische Philologie. Fritz Graf et al. Einleitung in die lateinische Philologie

info:eu-repo/semantics/published

Sequía e inundación en la hiperllanura pampeana : una mirada desde el lote al municipio

p.71-77

Sequía e inundación en la hiperllanura pampeana : una mirada desde el lote al municipio

p.71-77

Female-biased sex ratios in marine pelagic copepods: comment on Gusmao et al

Gusmão et al. (2013; Mar Ecol Prog Ser 482:279-298) review causes of sex ratio skew in pelagic copepods and in doing so repeatedly dispute the paper of Hirst et al. (2010) ‘Does predation control adult sex ratios and longevities in marine pelagic copepods?’ Here we respond to some important errors in their citation of our paper and briefly highlight where future work is needed in order to attribute the causes of strong sex ratio skew seen in some copepod families.

Interhemispheric gradient of atmospheric radiocarbon reveals natural variability of Southern Ocean winds

Tree ring Delta C-14 data (Reimer et al., 2004; McCormac et al., 2004) indicate that atmospheric Delta C-14 varied on multi-decadal to centennial timescales, in both hemispheres, over the period between AD 950 and 1830. The Northern and Southern Hemispheric Delta C-14 records display similar variability, but from the data alone is it not clear whether these variations are driven by the production of C-14 in the stratosphere (Stuiver and Quay, 1980) or by perturbations to exchanges between carbon reservoirs (Siegenthaler et al., 1980). As the sea-air flux of (CO2)-C-14 has a clear maximum in the open ocean regions of the Southern Ocean, relatively modest perturbations to the winds over this region drive significant perturbations to the interhemispheric gradient. In this study, model simulations are used to show that Southern Ocean winds are likely a main driver of the observed variability in the interhemispheric gradient over AD 950-1830, and further, that this variability may be larger than the Southern Ocean wind trends that have been reported for recent decades (notably 1980-2004). This interpretation also implies that there may have been a significant weakening of the winds over the Southern Ocean within a few decades of AD 1375, associated with the transition between the Medieval Climate Anomaly and the Little Ice Age. The driving forces that could have produced such a shift in the winds at the Medieval Climate Anomaly to Little Ice Age transition remain unknown. Our process-focused suite of perturbation experiments with models raises the possibility that the current generation of coupled climate and earth system models may underestimate the natural background multi-decadal- to centennial-timescale variations in the winds over the Southern Ocean.