Identification of low-frequency variants associated with gout and serum uric acid levels

We tested 16 million SNPs, identified through whole-genome sequencing of 457 Icelanders, for association with gout and serum uric acid levels. Genotypes were imputed into 41,675 chip-genotyped Icelanders and their relatives, for effective sample sizes of 968 individuals with gout and 15,506 individuals for whom serum uric acid measurements were available. We identified a low-frequency missense variant (c.1580C>G) in ALDH16A1 associated with gout (OR = 3.12, P = 1.5 × 10(-16), at-risk allele frequency = 0.019) and serum uric acid levels (effect = 0.36 s.d., P = 4.5 × 10(-21)). We confirmed the association with gout by performing Sanger sequencing on 6,017 Icelanders. The association with gout was stronger in males relative to females. We also found a second variant on chromosome 1 associated with gout (OR = 1.92, P = 0.046, at-risk allele frequency = 0.986) and serum uric acid levels (effect = 0.48 s.d., P = 4.5 × 10(-16)). This variant is close to a common variant previously associated with serum uric acid levels. This work illustrates how whole-genome sequencing data allow the detection of associations between low-frequency variants and complex traits.     

Genome-wide association study identifies a new melanoma susceptibility locus at 1q21.3

We performed a genome-wide association study of melanoma in a discovery cohort of 2,168 Australian individuals with melanoma and 4,387 control individuals. In this discovery phase, we confirm several previously characterized melanoma-associated loci at MC1R, ASIP and MTAP-CDKN2A. We selected variants at nine loci for replication in three independent case-control studies (Europe: 2,804 subjects with melanoma, 7,618 control subjects; United States 1: 1,804 subjects with melanoma, 1,026 control subjects; United States 2: 585 subjects with melanoma, 6,500 control subjects). The combined meta-analysis of all case-control studies identified a new susceptibility locus at 1q21.3 (rs7412746, P = 9.0 × 10(-11), OR in combined replication cohorts of 0.89 (95% CI 0.85-0.95)). We also show evidence suggesting that melanoma associates with 1q42.12 (rs3219090, P = 9.3 × 10(-8)). The associated variants at the 1q21.3 locus span a region with ten genes, and plausible candidate genes for melanoma susceptibility include ARNT and SETDB1. Variants at the 1q21.3 locus do not seem to be associated with human pigmentation or measures of nevus density.     

Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease

Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease.     

Comparative ecology of Sarcobatus baileyi and Sarcobatus vermiculatus in estern California

Greasewood ( Sarcobatus ) is a succulent-leaved, halophytic shrub of North American origin. The genus comprises 2 species: Sarcobatus baileyi and Sarcobatus vermiculatus. Sarcobatus vermiculatus is common throughout much of western North America, but S. baileyi is much more limited in distribution and was previously thought to be endemic to Nevada. Here we document and describe a S. baileyi population in eastern California, comparing its morphology and ecology to an adjacent S. vermiculatus population. Morphologically, S. baileyi is smaller in stature but produces larger seeds; however, fewer S. baileyi seeds germinated and survived a 20-day laboratory incubation compared to seeds of S. vermiculatus. Sarcobatus baileyi has higher leaf Na concentrations and operates at much lower plant water potentials than S. vermiculatus under field conditions; however, no significant differences were observed between the 2 species in long-term water-use efficiency as measured by leaf δ13C. Leaf Na concentrations were very low in both species. Overall, these species differ greatly in a number of traits that are consistent with the upland, nonphreatophytic character of S. baileyi, which is in stark contrast to the phreatophytic character of S. vermiculatus. Both species, however, are very salt tolerant and have low leaf N concentrations, indicating the low nutrient availability and the potentially high salinity of their extreme habitats. Further investigation of comparable desert ridge environments should be conducted to determine the extent of S. baileyi in eastern California, and common garden comparisons of the 2 species should be conducted to compare their ecophysiological traits. El ";greasewood” ( Sarcobatus ) es un arbusto halofítico de origen norteamericano con hojas suculentas. El género consta de dos especies: Sarcobatus baileyi y Sarcobatus vermiculatus. Aunque S. vermiculatus es común en gran parte del oeste de Norteamerica, S. baileyi tiene una distribución mucho más limitada. Se pensaba anteriormente que S. baileyi era endémico a Nevada, pero aquí documentamos y describimos una población en el este de California, comparando su morfología y ecología con las de una población adyacente de S. vermiculatus. Morfológicamente, S. baileyi es más pequeña de altura, pero produce semillas más grandes. Sin embargo, menos semillas de S. baileyi germinaron y sobrevivieron a una incubación en laboratorio de 20 días, comparado con S. vermiculatus. Sarcobatus baileyi opera con potenciales de agua mucho más bajos que los de S. vermiculatus en condiciones de campo y tiene mayores concentraciones de Na en sus hojas. No obstante, no se observaron diferencias significativas en la eficiencia del uso de agua a largo plazo, medida en términos de δ13C entre las 2 especies. Las concentraciones de N en las hojas fueron muy bajas en ambas especies. En general, estas especies difieren mucho en varios rasgos que son consistentes con el carácter no freatofítico de S. baileyi de tierras altas, el cual contrasta claramente con el carácter freatofítico de S. vermiculatus. Ambas especies, sin embargo, son bastante tolerantes a la sal y tienen concentraciones bajas de N en hojas, lo cual indica la baja disponibilidad de nutrientes y la potencial alta salinidad en sus hábitats extremos. Investigaciones adicionales en ambientes comparables de bordes desérticos deberán llevarse a cabo para determinar la extensión S. baileyi en el este de California, además de comparaciones de las dos especies en jardín para comparar sus rasgos ecofisiológicos.     

Environmental effects on Common Snipe winnowing and calling (activity)

Our objective was to clarify the effects of 10 identified variables on snipe activity (winnowing and calling) by demonstrating correlations between the variables and snipe activity. We monitored snipe at 2 study areas in southwestern Montana and northwestern Wyoming at all hours of the day and night during the 1996 and 1997 breeding seasons. We measured 10 variables at established points along transects that were situated through the middle of each study site (8 study sites total). A total of 1200 monitoring periods were conducted throughout the course of this study. Effects of each factor on snipe activity were considered by examining general trends in each factor's graphical representation. Our results identified 6 factors (season, time of day, lunar cycle, solar radiation, wind speed, and temperature) that are associated with snipe activity. Snipe were most active early in the breeding season during 2 twilight periods during the first and last quarters of the lunar cycle. Low solar radiation levels, wind speeds, and temperatures were also most ideal conditions for snipe activity. All 6 factors should be considered when attempting to detect, survey, or estimate snipe populations.     

Temporal activity patterns of Dipodomys ordii population

Temporal activity patterns for Dipodomys ordii were generally bimodal during the summer, with the highest peak occurring during early predawn hours when conditions were optimum for water conservation. Removal of dominant members in the population resulted in a substantial shift in the activity pattern to increased activity during the evening hours.     

Pocket gophers ( Thomomys talpoides ) in successional stages of spruce-fir forest in Idaho

This study examined (1) the relative abundance of the pocket gopher ( Thomomys talpoides ) in four successive stages (1–10, 11–39, 40–79, and 80+ years following disturbance) of spruce-fir forest; (2) the relationship between number of gopher sign (mounds and earth plugs) with gopher density; and (3) a method of sampling pocket gopher populations using a 500 by 4 m strip transect. The number of gopher mounds was significantly correlated with the number of earth plugs. Data were pooled and a categorical log linear analysis used to test for significant differences in pocket gopher sign between the four successive stages. The 1–10 and the 80+ -year-old sites had significantly more gopher sign than the 11–39 and the 40–79 year-old sites. No significant differences were found between the 11–39 and the 40–79-year-old sites, or between the 1–10 and the 80+ -year-old sites. The difference in population densities may be due to understory vegetation differences between the successional stages. There was a significant correlation between amount of gopher sign and gophers caught in each of the study sites. This indicates that counts of pocket gopher sign may be used to estimate pocket gopher density. The strip transect is recommended as the most appropriate method when sampling heterogeneous habitats or when there is cause to suspect gopher populations may be aggregated within the area rather than spaced randomly or regularly.     

Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis

Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.     

The role of innate immune-stimulated epithelial apoptosis during gastrointestinal inflammatory diseases

The maintenance of mucosal barrier equilibrium in the intestine requires a delicate and dynamic balance between enterocyte loss by apoptosis and the generation of new cells by proliferation from stem cell precursors at the base of the intestinal crypts. When the balance shifts towards either excessive or insufficient apoptosis, a broad range of gastrointestinal diseases can manifest. Recent work from a variety of laboratories has provided evidence in support of a role for receptors of the innate immune system, including Toll-like receptors 2, 4, and 9 as well as the intracellular pathogen recognition receptor NOD2/CARD15, in the initiation of enterocyte apoptosis. The subsequent induction of enterocyte apoptosis in response to the activation of these innate immune receptors plays a key role in the development of various intestinal diseases, including necrotizing enterocolitis, Crohn’s disease, ulcerative colitis, and intestinal cancer. This review will detail the regulatory pathways that govern enterocyte apoptosis, and will explore the role of the innate immune system in the induction of enterocyte apoptosis in gastrointestinal disease.