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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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 ≥10%, genotypic call rate ≥80%, and Hardy-Weinberg equilibrium p ≥ 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).</p> <p>Results</p> <p>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^-5in 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^-4ranged 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 (<it>LPL</it>) 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 <b>d</b>ata<b>b</b>ase of <b>G</b>enotype <b>a</b>nd <b>P</b>henotype (dbGaP). After three stages of replication, there was no convincing statistical evidence for association (i.e., combined P < 10^-5across all three stages) between any of the tested SNPs and lipid phenotypes.</p> <p>Conclusion</p> <p>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.</p

Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

Genome-wide association (GWA) studies have identified multiple new genomic loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)1-11. Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to discover loci at which common alleles have modest effects, we performed meta-analysis of three T2D GWA scans encompassing 10,128 individuals of European-descent and ~2.2 million SNPs (directly genotyped and imputed). Replication testing was performed in an independent sample with an effective sample size of up to 53,975. At least six new loci with robust evidence for association were detected, including the JAZF1 (p=5.0×10−14), CDC123/CAMK1D (p=1.2×10−10), TSPAN8/LGR5 (p=1.1×10−9), THADA (p=1.1×10−9), ADAMTS9 (p=1.2×10−8), and NOTCH2 (p=4.1×10−8) gene regions. The large number of loci with relatively small effects indicates the value of large discovery and follow-up samples in identifying additional clues about the inherited basis of T2D

Reservoir-scale Sequence Stratigraphy And Facies Variation Within The Mississippian Leadville Limestone, Southwestern San Juan Mountains, Colorado

Based on observations from seven measured stratigraphic sections and 230 thin sections over 37.3 kilometers, we recognize two sequences that encompass six parasquences and six distinct facies. The facies include bioturbated peloidal packstones, containing ostracods, rare occurrences of planar laminations, plane tabular cross bedding, microbial laminations and fine grain silt and sand. This facies is inferred to have been deposited in a semi-restricted lagoon environment. Interbedded microbial boundstones and finely crystalline dolomitic mudstone facies contain dolomitic microbial laminations, rare stromatolites, rip-up clasts, mudcracks, and soft sediment deformation. This facies was likely deposited in a supratidal setting. The medium grained, well-rounded quartz arenites and sand-rich packstone facies range from 5-40 cm thick and can be traced throughout the study area which may be marginal marine to eolian. There are three variations of grainstones. First, peloidal grainstones containing planar laminations, plane tabular cross bedding, ostracods and discontinuous lenses of black chert and gray chert. This is interpreted to have been deposited in a shallow beach/tidal flat setting. A second variety includes skeletal/peloidal grainstones containing bi-directional current ripples, crinoids and other skeletal fragments. This indicates deposition in an open marine tidal setting. Crinoidal grainstones contain rugose corals, brachiopods, one-meter thick sets of plane tabular cross bedding, and grey chert. This facies was deposited in an open-marine shoal environment. Within this reservoir-scale study, lateral variations of facies thicknesses were larger than then lateral variations of parasequence thicknesses. Grainstone facies thicken towards the northern sections, whereas thicker dolomitic mudstones/microbial boundstones dominate in southern sections. Similar facies variations may occur in the subsurface where total thickness may not vary significantly, but younger, grain-rich facies prograde to fill in depositional lows. When this sequence-scale facies variation is synthesized with the susceptibility of facies to diagenesis and fracturing, reservoir characterization and predictability should be significantly enhanced

The Effects of Lake Powell on Sediment Aggradation in the Lower Reaches of the San Juan

This study focuses on the Lower San Juan River in south eastern Utah between Government Rapid at river mile (RM) 63.9, to Clay Hills at RM 83.5 (river miles after Whitis and Martin, 2009). Here we document the on-lapping layers of sediment that have been aggrading upstream from Lake Powell since the drop of the reservoir, and the effects on stream morphology. The decrease in stream gradient in this reach has apparently induced a self-reinforcing feedback that slows current and increases sediment storage in the river channel. Repeat photography that contrasts pre-dam photographs from Miser (1921) and other sources was conducted at 11 locations. In the most upstream reach studied, from Government Rapid to the mouth of Slickhorn Canyon (RM 63.9 to 66.5) repeat photography at four locations (RM 63.9,64.4,64.41,and 66.5) indicates no vertical change from aggradation has occurred. The rapid which existed at the mouth of Slickhorn canyon is now gone, but repeat photographs show that there has not been aggradation outside the previous channel. Directly downstream of Slickhorn Canyon, there is a noticeable change in stream bank material and vegetation, along with an addition of sandbars located within the river channel. Along with these changes, the elevation of the water surface and sandbars at low flows (550-800cfs) are significantly higher than surveyed channel elevations from Miser (1921). Two miles below Slickhorn at Grand Gulch (RM70.5) the channel is now 24 ft. above 1921 and 1955 levels. Below Grand Gulch the thickness of post dam sediment increases to a maximum thickness of 80 ft. by RM 82, with location (RM) and thickness in feet as follows: RM70.5 +26.5’, RM71.9+38.4’, RM76+57.5’, RM76.5+56.1’,RM76.9+55.1,RM78.5+60’, and RM82+80’. These new data combined with previous surveys (Miser, 1921 and the 1986 Lake Powell Sediment Survey) delineate the thickness of the sediment wedge. The resultant lower stream gradients are correlated with a shift in stream bank vegetation types from willow-dominated (Salix exiqua) to seep-willow and reedgrass-dominated (Baccharis salicina and Phragmites australis). This documented case of sediment aggradation has implications for the hydrology, stream morphology, aquatic and riparian ecology of river systems that are upstream of reservoirs

Facies Heterogeneity and Petrography of the Downdip Evaporitic Wedge in the Akah Interval of the Pennsylvannian Paradox Basin

This outcrop-based research compares and contrasts the facies associations of downdip evaporitic wedges of the late Carboniferous Akah interval (Moscovian) along the east and west margins of the Paradox basin in southwestern Colorado and southeastern Utah. These wedges contain shallow marine carbonates, organic-rich dolomites and evaporites which were deposited along the margin of a temporarily restricted, rapidly subsiding basin subject to episodic desiccation and flooding. The stratigraphic sequences and downdip restricted geometries in each locale are generally similar, yet the facies are encased by siliciclastic deltaics on the tectonically active eastern margin, and shallow water carbonates on the western side ramp margin. The deposits in the western lowstand wedge are in the same sequence as highstand stromatolitic build-ups located 12 miles to the west on the shallow shelf. On both sides of the basin, laminations of organic-rich dolomite and gypsum underlie large packages of massive and laminated gypsum deposits. Associated with these evaporites, are microbial, dolomitic packstones that include oomoldic coated grains on the west and oncolites on the east. Facies from both sides characterize a restricted, organic-rich, shallow subaqueous, evaporative shoreline environment. Such facies exhibit characteristics similar to the modern intertidal and supratidal sabkha settings in Abu Dhabi U.A.E., lagoonal settings of the Holocene along the Red Sea, the modern intertidal salina settings in the West Caicos Islands and late Triassic Abu Ruweis Formation in Jordan

The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.

Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified &gt;300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection