Genome-wide association study reveals three susceptibility loci for common migraine in the general population

Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10(-6)) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10(-9); rs10166942, OR = 0.85, P = 5.5 × 10(-12); and rs11172113, OR = 0.90, P = 4.3 × 10(-9)). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.     

A genetic interaction network of five genes for human polycystic kidney and liver diseases defines polycystin-1 as the central determinant of cyst formation

Autosomal dominant polycystic liver disease results from mutations in PRKCSH or SEC63. The respective gene products, glucosidase IIβ and SEC63p, function in protein translocation and quality control pathways in the endoplasmic reticulum. Here we show that glucosidase IIβ and Sec63p are required in mice for adequate expression of a functional complex of the polycystic kidney disease gene products, polycystin-1 and polycystin-2. We find that polycystin-1 is the rate-limiting component of this complex and that there is a dose-response relationship between cystic dilation and levels of functional polycystin-1 following mutation of Prkcsh or Sec63. Reduced expression of polycystin-1 also serves to sensitize the kidney to cyst formation resulting from mutations in Pkhd1, the recessive polycystic kidney disease gene. Finally, we show that proteasome inhibition increases steady-state levels of polycystin-1 in cells lacking glucosidase IIβ and that treatment with a proteasome inhibitor reduces cystic disease in orthologous gene models of human autosomal dominant polycystic liver disease.     

The genome of the extremophile crucifer Thellungiella parvula

Thellungiella parvula is related to Arabidopsis thaliana and is endemic to saline, resource-poor habitats, making it a model for the evolution of plant adaptation to extreme environments. Here we present the draft genome for this extremophile species. Exclusively by next generation sequencing, we obtained the de novo assembled genome in 1,496 gap-free contigs, closely approximating the estimated genome size of 140 Mb. We anchored these contigs to seven pseudo chromosomes without the use of maps. We show that short reads can be assembled to a near-complete chromosome level for a eukaryotic species lacking prior genetic information. The sequence identifies a number of tandem duplications that, by the nature of the duplicated genes, suggest a possible basis for T. parvula's extremophile lifestyle. Our results provide essential background for developing genomically influenced testable hypotheses for the evolution of environmental stress tolerance.     

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.     

Common variation at 10p12.31 near MLLT10 influences meningioma risk

To identify susceptibility loci for meningioma, we conducted a genome-wide association study of 859 affected individuals (cases) and 704 controls with validation in two independent sample sets totaling 774 cases and 1,764 controls. We identified a new susceptibility locus for meningioma at 10p12.31 (MLLT10, rs11012732, odds ratio = 1.46, P(combined) = 1.88 × 10(-14)). This finding advances our understanding of the genetic basis of meningioma development.     

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 &delta;13C. 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&rdquo; ( Sarcobatus ) es un arbusto halof&iacute;tico de origen norteamericano con hojas suculentas. El g&eacute;nero consta de dos especies: Sarcobatus baileyi y Sarcobatus vermiculatus. Aunque S. vermiculatus es com&uacute;n en gran parte del oeste de Norteamerica, S. baileyi tiene una distribuci&oacute;n mucho m&aacute;s limitada. Se pensaba anteriormente que S. baileyi era end&eacute;mico a Nevada, pero aqu&iacute; documentamos y describimos una poblaci&oacute;n en el este de California, comparando su morfolog&iacute;a y ecolog&iacute;a con las de una poblaci&oacute;n adyacente de S. vermiculatus. Morfol&oacute;gicamente, S. baileyi es m&aacute;s peque&ntilde;a de altura, pero produce semillas m&aacute;s grandes. Sin embargo, menos semillas de S. baileyi germinaron y sobrevivieron a una incubaci&oacute;n en laboratorio de 20 d&iacute;as, comparado con S. vermiculatus. Sarcobatus baileyi opera con potenciales de agua mucho m&aacute;s 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 t&eacute;rminos de &delta;13C 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 car&aacute;cter no freatof&iacute;tico de S. baileyi de tierras altas, el cual contrasta claramente con el car&aacute;cter freatof&iacute;tico 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 h&aacute;bitats extremos. Investigaciones adicionales en ambientes comparables de bordes des&eacute;rticos deber&aacute;n llevarse a cabo para determinar la extensi&oacute;n S. baileyi en el este de California, adem&aacute;s de comparaciones de las dos especies en jard&iacute;n para comparar sus rasgos ecofisiol&oacute;gicos.