Nature Genetics

Altered brain microRNA biogenesis contributes to phenotypic deficits in a 22q11-deletion mouse model.

Publication Date: 2008 May 11 PMID: 18469815
Authors: Stark, K. L. - Xu, B. - Bagchi, A. - Lai, W. S. - Liu, H. - Hsu, R. - Wan, X. - Pavlidis, P. - Mills, A. A. - Karayiorgou, M. - Gogos, J. A.
Journal: Nat Genet

Individuals with 22q11.2 microdeletions show behavioral and cognitive deficits and are at high risk of developing schizophrenia. We analyzed an engineered mouse strain carrying a chromosomal deficiency spanning a segment syntenic to the human 22q11.2 locus. We uncovered a previously unknown alteration in the biogenesis of microRNAs (miRNAs) and identified a subset of brain miRNAs affected by the microdeletion. We provide evidence that the abnormal miRNA biogenesis emerges because of haploinsufficiency of the Dgcr8 gene, which encodes an RNA-binding moiety of the 'microprocessor' complex and contributes to the behavioral and neuronal deficits associated with the 22q11.2 microdeletion.

post to: CiteULike

Regulatory change in YABBY-like transcription factor led to evolution of extreme fruit size during tomato domestication.

Publication Date: 2008 May 11 PMID: 18469814
Authors: Cong, B. - Barrero, L. S. - Tanksley, S. D.
Journal: Nat Genet

Plant domestication represents an accelerated form of evolution, resulting in exaggerated changes in the tissues and organs of greatest interest to humans (for example, seeds, roots and tubers). One of the most extreme cases has been the evolution of tomato fruit. Cultivated tomato plants produce fruit as much as 1,000 times larger than those of their wild progenitors. Quantitative trait mapping studies have shown that a relatively small number of genes were involved in this dramatic transition, and these genes control two processes: cell cycle and organ number determination. The key gene in the first process has been isolated and corresponds to fw2.2, a negative regulator of cell division. However, until now, nothing was known about the molecular basis of the second process. Here, we show that the second major step in the evolution of extreme fruit size was the result of a regulatory change of a YABBY-like transcription factor (fasciated) that controls carpel number during flower and/or fruit development.

post to: CiteULike

X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment.

Publication Date: 2008 May 11 PMID: 18469813
Authors: Dibbens, L. M. - Tarpey, P. S. - Hynes, K. - Bayly, M. A. - Scheffer, I. E. - Smith, R. - Bomar, J. - Sutton, E. - Vandeleur, L. - Shoubridge, C. - Edkins, S. - Turner, S. J. - Stevens, C. - O'Meara, S. - Tofts, C. - Barthorpe, S. - Buck, G. - Cole, J. - Halliday, K. - Jones, D. - Lee, R. - Madison, M. - Mironenko, T. - Varian, J. - West, S. - Widaa, S. - Wray, P. - Teague, J. - Dicks, E. - Butler, A. - Menzies, A. - Jenkinson, A. - Shepherd, R. - Gusella, J. F. - Afawi, Z. - Mazarib, A. - Neufeld, M. Y. - Kivity, S. - Lev, D. - Lerman-Sagie, T. - Korczyn, A. D. - Derry, C. P. - Sutherland, G. R. - Friend, K. - Shaw, M. - Corbett, M. - Kim, H. G. - Geschwind, D. H. - Thomas, P. - Haan, E. - Ryan, S. - McKee, S. - Berkovic, S. F. - Futreal, P. A. - Stratton, M. R. - Mulley, J. C. - Gecz, J.
Journal: Nat Genet

Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 (PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.

post to: CiteULike

De novo mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy.

Publication Date: 2008 May 11 PMID: 18469812
Authors: Saitsu, H. - Kato, M. - Mizuguchi, T. - Hamada, K. - Osaka, H. - Tohyama, J. - Uruno, K. - Kumada, S. - Nishiyama, K. - Nishimura, A. - Okada, I. - Yoshimura, Y. - Hirai, S. I. - Kumada, T. - Hayasaka, K. - Fukuda, A. - Ogata, K. - Matsumoto, N.
Journal: Nat Genet

Early infantile epileptic encephalopathy with suppression-burst (EIEE), also known as Ohtahara syndrome, is one of the most severe and earliest forms of epilepsy. Using array-based comparative genomic hybridization, we found a de novo 2.0-Mb microdeletion at 9q33.3-q34.11 in a girl with EIEE. Mutation analysis of candidate genes mapped to the deletion revealed that four unrelated individuals with EIEE had heterozygous missense mutations in the gene encoding syntaxin binding protein 1 (STXBP1). STXBP1 (also known as MUNC18-1) is an evolutionally conserved neuronal Sec1/Munc-18 (SM) protein that is essential in synaptic vesicle release in several species. Circular dichroism melting experiments revealed that a mutant form of the protein was significantly thermolabile compared to wild type. Furthermore, binding of the mutant protein to syntaxin was impaired. These findings suggest that haploinsufficiency of STXBP1 causes EIEE.

post to: CiteULike

The mouse X chromosome is enriched for multicopy testis genes showing postmeiotic expression.

Publication Date: 2008 May 4 PMID: 18454149
Authors: Mueller, J. L. - Mahadevaiah, S. K. - Park, P. J. - Warburton, P. E. - Page, D. C. - Turner, J. M.
Journal: Nat Genet

According to the prevailing view, mammalian X chromosomes are enriched in spermatogenesis genes expressed before meiosis and deficient in spermatogenesis genes expressed after meiosis. The paucity of postmeiotic genes on the X chromosome has been interpreted as a consequence of meiotic sex chromosome inactivation (MSCI)-the complete silencing of genes on the XY bivalent at meiotic prophase. Recent studies have concluded that MSCI-initiated silencing persists beyond meiosis and that most genes on the X chromosome remain repressed in round spermatids. Here, we report that 33 multicopy gene families, representing approximately 273 mouse X-linked genes, are expressed in the testis and that this expression is predominantly in postmeiotic cells. RNA FISH and microarray analysis show that the maintenance of X chromosome postmeiotic repression is incomplete. Furthermore, X-linked multicopy genes exhibit a similar degree of expression as autosomal genes. Thus, not only is the mouse X chromosome enriched for spermatogenesis genes functioning before meiosis, but in addition, approximately 18% of mouse X-linked genes are expressed in postmeiotic cells.

post to: CiteULike

Common variants near MC4R are associated with fat mass, weight and risk of obesity.

Publication Date: 2008 May 4 PMID: 18454148
Authors: Loos, R. J. - Lindgren, C. M. - Li, S. - Wheeler, E. - Zhao, J. H. - Prokopenko, I. - Inouye, M. - Freathy, R. M. - Attwood, A. P. - Beckmann, J. S. - Berndt, S. I. - Jacobs, K. B. - Chanock, S. J. - Hayes, R. B. - Bergmann, S. - Bennett, A. J. - Bingham, S. A. - Bochud, M. - Brown, M. - Cauchi, S. - Connell, J. M. - Cooper, C. - Smith, G. D. - Day, I. - Dina, C. - De, S. - Dermitzakis, E. T. - Doney, A. S. - Elliott, K. S. - Elliott, P. - Evans, D. M. - Sadaf Farooqi, I. - Froguel, P. - Ghori, J. - Groves, C. J. - Gwilliam, R. - Hadley, D. - Hall, A. S. - Hattersley, A. T. - Hebebrand, J. - Heid, I. M. - Lamina, C. - Gieger, C. - Illig, T. - Meitinger, T. - Wichmann, H. E. - Herrera, B. - Hinney, A. - Hunt, S. E. - Jarvelin, M. R. - Johnson, T. - Jolley, J. D. - Karpe, F. - Keniry, A. - Khaw, K. T. - Luben, R. N. - Mangino, M. - Marchini, J. - McArdle, W. L. - McGinnis, R. - Meyre, D. - Munroe, P. B. - Morris, A. D. - Ness, A. R. - Neville, M. J. - Nica, A. C. - Ong, K. K. - O'Rahilly, S. - Owen, K. R. - Palmer, C. N. - Papadakis, K. - Potter, S. - Pouta, A. - Qi, L. - Kraft, P. - Hankinson, S. E. - Hunter, D. J. - Hu, F. B. - Randall, J. C. - Rayner, N. W. - Ring, S. M. - Sandhu, M. S. - Scherag, A. - Sims, M. A. - Song, K. - Soranzo, N. - Speliotes, E. K. - Lyon, H. N. - Voight, B. F. - Ridderstrale, M. - Groop, L. - Syddall, H. E. - Teichmann, S. A. - Timpson, N. J. - Tobias, J. H. - Uda, M. - Scheet, P. - Sanna, S. - Abecasis, G. R. - Albai, G. - Nagaraja, R. - Schlessinger, D. - Ganz Vogel, C. I. - Wallace, C. - Waterworth, D. M. - Weedon, M. N. - Willer, C. J. - Jackson, A. U. - Tuomilehto, J. - Collins, F. S. - Boehnke, M. - Mohlke, K. L. - Wraight, V. L. - Yuan, X. - Zeggini, E. - Hirschhorn, J. N. - Strachan, D. P. - Ouwehand, W. H. - Caulfield, M. J. - Samani, N. J. - Frayling, T. M. - Vollenweider, P. - Waeber, G. - Mooser, V. - Deloukas, P. - McCarthy, M. I. - Wareham, N. J. - Barroso, I.
Journal: Nat Genet

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.

post to: CiteULike

Natural variation in Ghd7 is an important regulator of heading date and yield potential in rice.

Publication Date: 2008 May 4 PMID: 18454147
Authors: Xue, W. - Xing, Y. - Weng, X. - Zhao, Y. - Tang, W. - Wang, L. - Zhou, H. - Yu, S. - Xu, C. - Li, X. - Zhang, Q.
Journal: Nat Genet

Yield potential, plant height and heading date are three classes of traits that determine the productivity of many crop plants. Here we show that the quantitative trait locus (QTL) Ghd7, isolated from an elite rice hybrid and encoding a CCT domain protein, has major effects on an array of traits in rice, including number of grains per panicle, plant height and heading date. Enhanced expression of Ghd7 under long-day conditions delays heading and increases plant height and panicle size. Natural mutants with reduced function enable rice to be cultivated in temperate and cooler regions. Thus, Ghd7 has played crucial roles for increasing productivity and adaptability of rice globally.

post to: CiteULike

Common genetic variation near MC4R is associated with waist circumference and insulin resistance.

Publication Date: 2008 May 4 PMID: 18454146
Authors: Chambers, J. C. - Elliott, P. - Zabaneh, D. - Zhang, W. - Li, Y. - Froguel, P. - Balding, D. - Scott, J. - Kooner, J. S.
Journal: Nat Genet

We carried out a genome-wide association study (318,237 SNPs) for insulin resistance and related phenotypes in 2,684 Indian Asians, with further testing in 11,955 individuals of Indian Asian or European ancestry. We found associations of rs12970134 near MC4R with waist circumference (P = 1.7 x 10(-9)) and, independently, with insulin resistance. Homozygotes for the risk allele of rs12970134 have approximately 2 cm increased waist circumference. Common genetic variation near MC4R is associated with risk of adiposity and insulin resistance.

post to: CiteULike

Erratum: Fine mapping of regulatory loci for mammalian gene expression using radiation hybrids.

Publication Date: 2008 May PMID: 18443595
Authors: Park, C. C. - Ahn, S. - Bloom, J. S. - Lin, A. - Wang, R. T. - Wu, T. - Sekar, A. - Khan, A. H. - Farr, C. J. - Lusis, A. J. - Leahy, R. M. - Lange, K. - Smith, D. J.
Journal: Nat Genet

post to: CiteULike

SNP and haplotype mapping for genetic analysis in the rat.

Publication Date: 2008 May PMID: 18443594
Authors: Saar, K. - Beck, A. - Bihoreau, M. T. - Birney, E. - Brocklebank, D. - Chen, Y. - Cuppen, E. - Demonchy, S. - Dopazo, J. - Flicek, P. - Foglio, M. - Fujiyama, A. - Gut, I. G. - Gauguier, D. - Guigo, R. - Guryev, V. - Heinig, M. - Hummel, O. - Jahn, N. - Klages, S. - Kren, V. - Kube, M. - Kuhl, H. - Kuramoto, T. - Kuroki, Y. - Lechner, D. - Lee, Y. A. - Lopez-Bigas, N. - Lathrop, G. M. - Mashimo, T. - Medina, I. - Mott, R. - Patone, G. - Perrier-Cornet, J. A. - Platzer, M. - Pravenec, M. - Reinhardt, R. - Sakaki, Y. - Schilhabel, M. - Schulz, H. - Serikawa, T. - Shikhagaie, M. - Tatsumoto, S. - Taudien, S. - Toyoda, A. - Voigt, B. - Zelenika, D. - Zimdahl, H. - Hubner, N.
Journal: Nat Genet

The laboratory rat is one of the most extensively studied model organisms. Inbred laboratory rat strains originated from limited Rattus norvegicus founder populations, and the inherited genetic variation provides an excellent resource for the correlation of genotype to phenotype. Here, we report a survey of genetic variation based on almost 3 million newly identified SNPs. We obtained accurate and complete genotypes for a subset of 20,238 SNPs across 167 distinct inbred rat strains, two rat recombinant inbred panels and an F2 intercross. Using 81% of these SNPs, we constructed high-density genetic maps, creating a large dataset of fully characterized SNPs for disease gene mapping. Our data characterize the population structure and illustrate the degree of linkage disequilibrium. We provide a detailed SNP map and demonstrate its utility for mapping of quantitative trait loci. This community resource is openly available and augments the genetic tools for this workhorse of physiological studies.

post to: CiteULike

Jund is a determinant of macrophage activation and is associated with glomerulonephritis susceptibility.

Publication Date: 2008 May PMID: 18443593
Authors: Behmoaras, J. - Bhangal, G. - Smith, J. - McDonald, K. - Mutch, B. - Lai, P. C. - Domin, J. - Game, L. - Salama, A. - Foxwell, B. M. - Pusey, C. D. - Cook, H. T. - Aitman, T. J.
Journal: Nat Genet

Crescentic glomerulonephritis is an important cause of human kidney failure for which the underlying molecular basis is largely unknown. In previous studies, we mapped several susceptibility loci, Crgn1-Crgn7, for crescentic glomerulonephritis in the Wistar Kyoto (WKY) rat. Here we show by combined congenic, linkage and microarray studies that the activator protein-1 (AP-1) transcription factor JunD is a major determinant of macrophage activity and is associated with glomerulonephritis susceptibility. Introgression of Crgn2 from the nonsusceptible Lewis strain onto the WKY background leads to significant reductions in crescent formation, macrophage infiltration, Fc receptor-mediated macrophage activation and cytokine production. Haplotype analysis restricted the Crgn2 linkage interval to a 430-kb interval containing Jund, which is markedly overexpressed in WKY macrophages and glomeruli. Jund knockdown in rat and human primary macrophages led to significantly reduced macrophage activity and cytokine secretion, indicating conservation of JunD function in macrophage activation in rats and humans and suggesting in vivo inhibition of Jund as a possible new therapeutic strategy for diseases characterized by inflammation and macrophage activation.

post to: CiteULike

Integrated genomic approaches implicate osteoglycin (Ogn) in the regulation of left ventricular mass.

Publication Date: 2008 May PMID: 18443592
Authors: Petretto, E. - Sarwar, R. - Grieve, I. - Lu, H. - Kumaran, M. K. - Muckett, P. J. - Mangion, J. - Schroen, B. - Benson, M. - Punjabi, P. P. - Prasad, S. K. - Pennell, D. J. - Kiesewetter, C. - Tasheva, E. S. - Corpuz, L. M. - Webb, M. D. - Conrad, G. W. - Kurtz, T. W. - Kren, V. - Fischer, J. - Hubner, N. - Pinto, Y. M. - Pravenec, M. - Aitman, T. J. - Cook, S. A.
Journal: Nat Genet

Left ventricular mass (LVM) and cardiac gene expression are complex traits regulated by factors both intrinsic and extrinsic to the heart. To dissect the major determinants of LVM, we combined expression quantitative trait locus1 and quantitative trait transcript (QTT) analyses of the cardiac transcriptome in the rat. Using these methods and in vitro functional assays, we identified osteoglycin (Ogn) as a major candidate regulator of rat LVM, with increased Ogn protein expression associated with elevated LVM. We also applied genome-wide QTT analysis to the human heart and observed that, out of 22,000 transcripts, OGN transcript abundance had the highest correlation with LVM. We further confirmed a role for Ogn in the in vivo regulation of LVM in Ogn knockout mice. Taken together, these data implicate Ogn as a key regulator of LVM in rats, mice and humans, and suggest that Ogn modifies the hypertrophic response to extrinsic factors such as hypertension and aortic stenosis.

post to: CiteULike

Distribution and functional impact of DNA copy number variation in the rat.

Publication Date: 2008 May PMID: 18443591
Authors: Guryev, V. - Saar, K. - Adamovic, T. - Verheul, M. - van Heesch, S. A. - Cook, S. - Pravenec, M. - Aitman, T. - Jacob, H. - Shull, J. D.
Journal: Nat Genet

The abundance and dynamics of copy number variants (CNVs) in mammalian genomes poses new challenges in the identification of their impact on natural and disease phenotypes. We used computational and experimental methods to catalog CNVs in rat and found that they share important functional characteristics with those in human. In addition, 113 one-to-one orthologous genes overlap CNVs in both human and rat, 80 of which are implicated in human disease. CNVs are nonrandomly distributed throughout the genome. Chromosome 18 is a cold spot for CNVs as well as evolutionary rearrangements and segmental duplications, suggesting stringent selective mechanisms underlying CNV genesis or maintenance. By exploiting gene expression data available for rat recombinant inbred lines, we established the functional relationship of CNVs underlying 22 expression quantitative trait loci. These characteristics make the rat an excellent model for studying phenotypic effects of structural variation in relation to human complex traits and disease.

post to: CiteULike

Soluble epoxide hydrolase is a susceptibility factor for heart failure in a rat model of human disease.

Publication Date: 2008 May PMID: 18443590
Authors: Monti, J. - Fischer, J. - Paskas, S. - Heinig, M. - Schulz, H. - Gosele, C. - Heuser, A. - Fischer, R. - Schmidt, C. - Schirdewan, A. - Gross, V. - Hummel, O. - Maatz, H. - Patone, G. - Saar, K. - Vingron, M. - Weldon, S. M. - Lindpaintner, K. - Hammock, B. D. - Rohde, K. - Dietz, R. - Cook, S. A. - Schunck, W. H. - Luft, F. C. - Hubner, N.
Journal: Nat Genet

We aimed to identify genetic variants associated with heart failure by using a rat model of the human disease. We performed invasive cardiac hemodynamic measurements in F2 crosses between spontaneously hypertensive heart failure (SHHF) rats and reference strains. We combined linkage analyses with genome-wide expression profiling and identified Ephx2 as a heart failure susceptibility gene in SHHF rats. Specifically, we found that cis variation at Ephx2 segregated with heart failure and with increased transcript expression, protein expression and enzyme activity, leading to a more rapid hydrolysis of cardioprotective epoxyeicosatrienoic acids. To confirm our results, we tested the role of Ephx2 in heart failure using knockout mice. Ephx2 gene ablation protected from pressure overload-induced heart failure and cardiac arrhythmias. We further demonstrated differential regulation of EPHX2 in human heart failure, suggesting a cross-species role for Ephx2 in this complex disease.

post to: CiteULike

What everybody should know about the rat genome and its online resources.

Publication Date: 2008 May PMID: 18443589
Authors: Twigger, S. N. - Pruitt, K. D. - Fernandez-Suarez, X. M. - Karolchik, D. - Worley, K. C. - Maglott, D. R. - Brown, G. - Weinstock, G. - Gibbs, R. A. - Kent, J. - Birney, E. - Jacob, H. J.
Journal: Nat Genet

It has been four years since the original publication of the draft sequence of the rat genome. Five groups are now working together to assemble, annotate and release an updated version of the rat genome. As the prevailing model for physiology, complex disease and pharmacological studies, there is an acute need for the rat's genomic resources to keep pace with the rat's prominence in the laboratory. In this commentary, we describe the current status of the rat genome sequence and the plans for its impending 'upgrade'. We then cover the key online resources providing access to the rat genome, including the new SNP views at Ensembl, the RefSeq and Genes databases at the US National Center for Biotechnology Information, Genome Browser at the University of California Santa Cruz and the disease portals for cardiovascular disease and obesity at the Rat Genome Database.

post to: CiteULike

Progress and prospects in rat genetics: a community view.

Publication Date: 2008 May PMID: 18443588
Authors: Aitman, T. J. - Critser, J. K. - Cuppen, E. - Dominiczak, A. - Fernandez-Suarez, X. M. - Flint, J. - Gauguier, D. - Geurts, A. M. - Gould, M. - Harris, P. C. - Holmdahl, R. - Hubner, N. - Izsvak, Z. - Jacob, H. J. - Kuramoto, T. - Kwitek, A. E. - Marrone, A. - Mashimo, T. - Moreno, C. - Mullins, J. - Mullins, L. - Olsson, T. - Pravenec, M. - Riley, L. - Saar, K. - Serikawa, T. - Shull, J. D. - Szpirer, C. - Twigger, S. N. - Voigt, B. - Worley, K.
Journal: Nat Genet

The rat is an important system for modeling human disease. Four years ago, the rich 150-year history of rat research was transformed by the sequencing of the rat genome, ushering in an era of exceptional opportunity for identifying genes and pathways underlying disease phenotypes. Genome-wide association studies in human populations have recently provided a direct approach for finding robust genetic associations in common diseases, but identifying the precise genes and their mechanisms of action remains problematic. In the context of significant progress in rat genomic resources over the past decade, we outline achievements in rat gene discovery to date, show how these findings have been translated to human disease, and document an increasing pace of discovery of new disease genes, pathways and mechanisms. Finally, we present a set of principles that justify continuing and strengthening genetic studies in the rat model, and further development of genomic infrastructure for rat research.

post to: CiteULike

An ENU-induced mutant archive for gene targeting in rats.

Publication Date: 2008 May PMID: 18443587
Authors: Mashimo, T. - Yanagihara, K. - Tokuda, S. - Voigt, B. - Takizawa, A. - Nakajima, R. - Kato, M. - Hirabayashi, M. - Kuramoto, T. - Serikawa, T.
Journal: Nat Genet

post to: CiteULike

Year of the rat.

Publication Date: 2008 May PMID: 18443586
Authors:
Journal: Nat Genet

post to: CiteULike

An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors.

Publication Date: 2008 May PMID: 18443585
Authors: Ben-Porath, I. - Thomson, M. W. - Carey, V. J. - Ge, R. - Bell, G. W. - Regev, A. - Weinberg, R. A.
Journal: Nat Genet

Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear, however, whether these phenotypic similarities reflect the activity of common molecular pathways. Here, we analyze the enrichment patterns of gene sets associated with embryonic stem (ES) cell identity in the expression profiles of various human tumor types. We find that histologically poorly differentiated tumors show preferential overexpression of genes normally enriched in ES cells, combined with preferential repression of Polycomb-regulated genes. Moreover, activation targets of Nanog, Oct4, Sox2 and c-Myc are more frequently overexpressed in poorly differentiated tumors than in well-differentiated tumors. In breast cancers, this ES-like signature is associated with high-grade estrogen receptor (ER)-negative tumors, often of the basal-like subtype, and with poor clinical outcome. The ES signature is also present in poorly differentiated glioblastomas and bladder carcinomas. We identify a subset of ES cell-associated transcription regulators that are highly expressed in poorly differentiated tumors. Our results reveal a previously unknown link between genes associated with ES cell identity and the histopathological traits of tumors and support the possibility that these genes contribute to stem cell-like phenotypes shown by many tumors.

post to: CiteULike

Research Highlights.

Publication Date: 2008 May PMID: 18443584
Authors:
Journal: Nat Genet

post to: CiteULike

Salt wasting and blood pressure.

Publication Date: 2008 May PMID: 18443583
Authors: Devuyst, O.
Journal: Nat Genet

post to: CiteULike

Coevolution in the tumor microenvironment.

Publication Date: 2008 May PMID: 18443582
Authors: Weinberg, R. A.
Journal: Nat Genet

post to: CiteULike

From gene expression to disease risk.

Publication Date: 2008 May PMID: 18443581
Authors: Dermitzakis, E. T.
Journal: Nat Genet

post to: CiteULike

Principal component analysis of genetic data.

Publication Date: 2008 May PMID: 18443580
Authors: Reich, D. - Price, A. L. - Patterson, N.
Journal: Nat Genet

post to: CiteULike

Sizing up human height variation.

Publication Date: 2008 May PMID: 18443579
Authors: Visscher, P. M.
Journal: Nat Genet

post to: CiteULike

The beginning of the ends.

Publication Date: 2008 May PMID: 18443578
Authors: Forsburg, S. L.
Journal: Nat Genet

post to: CiteULike

Joshua Lederberg 1925-2008.

Publication Date: 2008 May PMID: 18443577
Authors: Crow, J. F.
Journal: Nat Genet

post to: CiteULike

Starting well in Europe.

Publication Date: 2008 May PMID: 18443576
Authors:
Journal: Nat Genet

post to: CiteULike

Identification of somatically acquired rearrangements in cancer using genome-wide massively parallel paired-end sequencing.

Publication Date: 2008 Apr 27 PMID: 18438408
Authors: Campbell, P. J. - Stephens, P. J. - Pleasance, E. D. - O'Meara, S. - Li, H. - Santarius, T. - Stebbings, L. A. - Leroy, C. - Edkins, S. - Hardy, C. - Teague, J. W. - Menzies, A. - Goodhead, I. - Turner, D. J. - Clee, C. M. - Quail, M. A. - Cox, A. - Brown, C. - Durbin, R. - Hurles, M. E. - Edwards, P. A. - Bignell, G. R. - Stratton, M. R. - Futreal, P. A.
Journal: Nat Genet

Human cancers often carry many somatically acquired genomic rearrangements, some of which may be implicated in cancer development. However, conventional strategies for characterizing rearrangements are laborious and low-throughput and have low sensitivity or poor resolution. We used massively parallel sequencing to generate sequence reads from both ends of short DNA fragments derived from the genomes of two individuals with lung cancer. By investigating read pairs that did not align correctly with respect to each other on the reference human genome, we characterized 306 germline structural variants and 103 somatic rearrangements to the base-pair level of resolution. The patterns of germline and somatic rearrangement were markedly different. Many somatic rearrangements were from amplicons, although rearrangements outside these regions, notably including tandem duplications, were also observed. Some somatic rearrangements led to abnormal transcripts, including two from internal tandem duplications and two fusion transcripts created by interchromosomal rearrangements. Germline variants were predominantly mediated by retrotransposition, often involving AluY and LINE elements. The results demonstrate the feasibility of systematic, genome-wide characterization of rearrangements in complex human cancer genomes, raising the prospect of a new harvest of genes associated with cancer using this strategy.

post to: CiteULike

Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer.

Publication Date: 2008 Apr 27 PMID: 18438407
Authors: Stacey, S. N. - Manolescu, A. - Sulem, P. - Thorlacius, S. - Gudjonsson, S. A. - Jonsson, G. F. - Jakobsdottir, M. - Bergthorsson, J. T. - Gudmundsson, J. - Aben, K. K. - Strobbe, L. J. - Swinkels, D. W. - van Engelenburg, K. C. - Henderson, B. E. - Kolonel, L. N. - Le Marchand, L. - Millastre, E. - Andres, R. - Saez, B. - Lambea, J. - Godino, J. - Polo, E. - Tres, A. - Picelli, S. - Rantala, J. - Margolin, S. - Jonsson, T. - Sigurdsson, H. - Jonsdottir, T. - Hrafnkelsson, J. - Johannsson, J. - Sveinsson, T. - Myrdal, G. - Grimsson, H. N. - Sveinsdottir, S. G. - Alexiusdottir, K. - Saemundsdottir, J. - Sigurdsson, A. - Kostic, J. - Gudmundsson, L. - Kristjansson, K. - Masson, G. - Fackenthal, J. D. - Adebamowo, C. - Ogundiran, T. - Olopade, O. I. - Haiman, C. A. - Lindblom, A. - Mayordomo, J. I. - Kiemeney, L. A. - Gulcher, J. R. - Rafnar, T. - Thorsteinsdottir, U. - Johannsson, O. T. - Kong, A. - Stefansson, K.
Journal: Nat Genet

We carried out a genome-wide association study of breast cancer predisposition with replication and refinement studies involving 6,145 cases and 33,016 controls and identified two SNPs (rs4415084 and rs10941679) on 5p12 that confer risk, preferentially for estrogen receptor (ER)-positive tumors (OR = 1.27, P = 2.5 x 10(-12) for rs10941679). The nearest gene, MRPS30, was previously implicated in apoptosis, ER-positive tumors and favorable prognosis. A recently reported signal in FGFR2 was also found to associate specifically with ER-positive breast cancer.

post to: CiteULike

Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn's disease.

Publication Date: 2008 Apr 27 PMID: 18438406
Authors: Fisher, S. A. - Tremelling, M. - Anderson, C. A. - Gwilliam, R. - Bumpstead, S. - Prescott, N. J. - Nimmo, E. R. - Massey, D. - Berzuini, C. - Johnson, C. - Barrett, J. C. - Cummings, F. R. - Drummond, H. - Lees, C. W. - Onnie, C. M. - Hanson, C. E. - Blaszczyk, K. - Inouye, M. - Ewels, P. - Ravindrarajah, R. - Keniry, A. - Hunt, S. - Carter, M. - Watkins, N. - Ouwehand, W. - Lewis, C. M. - Cardon, L. - Lobo, A. - Forbes, A. - Sanderson, J. - Jewell, D. P. - Mansfield, J. C. - Deloukas, P. - Mathew, C. G. - Parkes, M. - Satsangi, J.
Journal: Nat Genet

We report results of a nonsynonymous SNP scan for ulcerative colitis and identify a previously unknown susceptibility locus at ECM1. We also show that several risk loci are common to ulcerative colitis and Crohn's disease (IL23R, IL12B, HLA, NKX2-3 and MST1), whereas autophagy genes ATG16L1 and IRGM, along with NOD2 (also known as CARD15), are specific for Crohn's disease. These data provide the first detailed illustration of the genetic relationship between these common inflammatory bowel diseases.

post to: CiteULike

Replication of signals from recent studies of Crohn's disease identifies previously unknown disease loci for ulcerative colitis.

Publication Date: 2008 Apr 27 PMID: 18438405
Authors: Franke, A. - Balschun, T. - Karlsen, T. H. - Hedderich, J. - May, S. - Lu, T. - Schuldt, D. - Nikolaus, S. - Rosenstiel, P. - Krawczak, M. - Schreiber, S.
Journal: Nat Genet

Following up on recent genome-wide association studies (GWAS) of Crohn's disease, we investigated 50 previously reported susceptibility loci in a German sample of individuals with Crohn's disease (n = 1,850) or ulcerative colitis (n = 1,103) and healthy controls (n = 1,817). Among these loci, we identified variants in 3p21.31, NKX2-3 and CCNY as susceptibility factors for both diseases, whereas variants in PTPN2, HERC2 and STAT3 were associated only with ulcerative colitis in our sample collection.

post to: CiteULike

A structural-maintenance-of-chromosomes hinge domain-containing protein is required for RNA-directed DNA methylation.

Publication Date: 2008 May PMID: 18425128
Authors: Kanno, T. - Bucher, E. - Daxinger, L. - Huettel, B. - Bohmdorfer, G. - Gregor, W. - Kreil, D. P. - Matzke, M. - Matzke, A. J.
Journal: Nat Genet

RNA-directed DNA methylation (RdDM) is a process in which dicer-generated small RNAs guide de novo cytosine methylation at the homologous DNA region. To identify components of the RdDM machinery important for Arabidopsis thaliana development, we targeted an enhancer active in meristems for methylation, which resulted in silencing of a downstream GFP reporter gene. This silencing system also features secondary siRNAs, which trigger methylation that spreads beyond the targeted enhancer region. A screen for mutants defective in meristem silencing and enhancer methylation retrieved six dms complementation groups, which included the known factors DRD1 (ref. 3; a SNF2-like chromatin-remodeling protein) and Pol IVb subunits. Additionally, we identified a previously unknown gene DMS3 (At3g49250), encoding a protein similar to the hinge-domain region of structural maintenance of chromosomes (SMC) proteins. This finding implicates a putative chromosome architectural protein that can potentially link nucleic acids in facilitating an RNAi-mediated epigenetic modification involving secondary siRNAs and spreading of DNA methylation.

post to: CiteULike

Interpreting principal component analyses of spatial population genetic variation.

Publication Date: 2008 May PMID: 18425127
Authors: Novembre, J. - Stephens, M.
Journal: Nat Genet

Nearly 30 years ago, Cavalli-Sforza et al. pioneered the use of principal component analysis (PCA) in population genetics and used PCA to produce maps summarizing human genetic variation across continental regions. They interpreted gradient and wave patterns in these maps as signatures of specific migration events. These interpretations have been controversial, but influential, and the use of PCA has become widespread in analysis of population genetics data. However, the behavior of PCA for genetic data showing continuous spatial variation, such as might exist within human continental groups, has been less well characterized. Here, we find that gradients and waves observed in Cavalli-Sforza et al.'s maps resemble sinusoidal mathematical artifacts that arise generally when PCA is applied to spatial data, implying that the patterns do not necessarily reflect specific migration events. Our findings aid interpretation of PCA results and suggest how PCA can help correct for continuous population structure in association studies.

post to: CiteULike

SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation.

Publication Date: 2008 May PMID: 18425126
Authors: Blewitt, M. E. - Gendrel, A. V. - Pang, Z. - Sparrow, D. B. - Whitelaw, N. - Craig, J. M. - Apedaile, A. - Hilton, D. J. - Dunwoodie, S. L. - Brockdorff, N. - Kay, G. F. - Whitelaw, E.
Journal: Nat Genet

X-chromosome inactivation is the mammalian dosage compensation mechanism by which transcription of X-linked genes is equalized between females and males. In an N-ethyl-N-nitrosourea (ENU) mutagenesis screen on mice for modifiers of epigenetic reprogramming, we identified the MommeD1 (modifier of murine metastable epialleles) mutation as a semidominant suppressor of variegation. MommeD1 shows homozygous female-specific mid-gestation lethality and hypomethylation of the X-linked gene Hprt1, suggestive of a defect in X inactivation. Here we report that the causative point mutation lies in a previously uncharacterized gene, Smchd1 (structural maintenance of chromosomes hinge domain containing 1). We find that SmcHD1 is not required for correct Xist expression, but localizes to the inactive X and has a role in the maintenance of X inactivation and the hypermethylation of CpG islands associated with the inactive X. This finding links a group of proteins normally associated with structural aspects of chromosome biology with epigenetic gene silencing.

post to: CiteULike

Skint1, the prototype of a newly identified immunoglobulin superfamily gene cluster, positively selects epidermal gammadelta T cells.

Publication Date: 2008 May PMID: 18408721
Authors: Boyden, L. M. - Lewis, J. M. - Barbee, S. D. - Bas, A. - Girardi, M. - Hayday, A. C. - Tigelaar, R. E. - Lifton, R. P.
Journal: Nat Genet

B cells, alphabeta T cells and gammadelta T cells are conserved lymphocyte subtypes encoding their antigen receptors from somatically rearranged genes. alphabeta T cells undergo positive selection in the thymus by engagement of their T cell receptors (TCRs) with self-peptides presented by major histocompatibility complex molecules. The molecules that select gammadelta T cells are unknown. Vgamma5+Vdelta1+ cells comprise 90% of mouse epidermal gammadelta T cells. By mapping and genetic complementation using a strain showing loss of Vgamma5+Vdelta1+ cells due to a failure of thymic selection, we show that this defect is caused by mutation in Skint1, a newly identified gene expressed in thymus and skin that encodes a protein with immunoglobulin-like and transmembrane domains. Skint1 is the prototypic member of a rapidly evolving family of at least 11 genes in mouse, with greatest similarity to the butyrophilin genes. These findings define a new family of proteins mediating key epithelial-immune interactions.

post to: CiteULike

No evidence of clonal somatic genetic alterations in cancer-associated fibroblasts from human breast and ovarian carcinomas.

Publication Date: 2008 May PMID: 18408720
Authors: Qiu, W. - Hu, M. - Sridhar, A. - Opeskin, K. - Fox, S. - Shipitsin, M. - Trivett, M. - Thompson, E. R. - Ramakrishna, M. - Gorringe, K. L. - Polyak, K. - Haviv, I. - Campbell, I. G.
Journal: Nat Genet

There is increasing evidence showing that the stromal cells surrounding cancer epithelial cells, rather than being passive bystanders, might have a role in modifying tumor outgrowth. The molecular basis of this aspect of carcinoma etiology is controversial. Some studies have reported a high frequency of genetic aberrations in carcinoma-associated fibroblasts (CAFs), whereas other studies have reported very low or zero mutation rates. Resolution of this contentious area is of critical importance in terms of understanding both the basic biology of cancer as well as the potential clinical implications of CAF somatic alterations. We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis of CAFs derived from breast and ovarian carcinomas using a 500K SNP array platform. Our data show conclusively that LOH and copy number alterations are extremely rare in CAFs and cannot be the basis of the carcinoma-promoting phenotypes of breast and ovarian CAFs.

post to: CiteULike

Exposing the fitness contribution of duplicated genes.

Publication Date: 2008 May PMID: 18408719
Authors: DeLuna, A. - Vetsigian, K. - Shoresh, N. - Hegreness, M. - Colon-Gonzalez, M. - Chao, S. - Kishony, R.
Journal: Nat Genet

Duplicate genes from the whole-genome duplication (WGD) in yeast are often dispensable--removing one copy has little or no phenotypic consequence. It is unknown, however, whether such dispensability reflects insignificance of the ancestral function or compensation from paralogs. Here, using precise competition-based measurements of the fitness cost of single and double deletions, we estimate the exposed fitness contribution of WGD duplicate genes in metabolism and bound the importance of their ancestral pre-duplication function. We find that the functional overlap between paralogs sufficiently explains the apparent dispensability of individual WGD genes. Furthermore, the lower bound on the fitness value of the ancestral function, which is estimated by the degree of synergistic epistasis, is at least as large as the average fitness cost of deleting single non-WGD genes. These results suggest that most metabolic functions encoded by WGD genes are important today and were also important at the time of duplication.

post to: CiteULike

Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA).

Publication Date: 2008 May PMID: 18408718
Authors: Finberg, K. E. - Heeney, M. M. - Campagna, D. R. - Aydinok, Y. - Pearson, H. A. - Hartman, K. R. - Mayo, M. M. - Samuel, S. M. - Strouse, J. J. - Markianos, K. - Andrews, N. C. - Fleming, M. D.
Journal: Nat Genet

Iron deficiency is usually attributed to chronic blood loss or inadequate dietary intake. Here, we show that iron deficiency anemia refractory to oral iron therapy can be caused by germline mutations in TMPRSS6, which encodes a type II transmembrane serine protease produced by the liver that regulates the expression of the systemic iron regulatory hormone hepcidin. These findings demonstrate that TMPRSS6 is essential for normal systemic iron homeostasis in humans.

post to: CiteULike

Rare independent mutations in renal salt handling genes contribute to blood pressure variation.

Publication Date: 2008 May PMID: 18391953
Authors: Ji, W. - Foo, J. N. - O'Roak, B. J. - Zhao, H. - Larson, M. G. - Simon, D. B. - Newton-Cheh, C. - State, M. W. - Levy, D. - Lifton, R. P.
Journal: Nat Genet

The effects of alleles in many genes are believed to contribute to common complex diseases such as hypertension. Whether risk alleles comprise a small number of common variants or many rare independent mutations at trait loci is largely unknown. We screened members of the Framingham Heart Study (FHS) for variation in three genes-SLC12A3 (NCCT), SLC12A1 (NKCC2) and KCNJ1 (ROMK)-causing rare recessive diseases featuring large reductions in blood pressure. Using comparative genomics, genetics and biochemistry, we identified subjects with mutations proven or inferred to be functional. These mutations, all heterozygous and rare, produce clinically significant blood pressure reduction and protect from development of hypertension. Our findings implicate many rare alleles that alter renal salt handling in blood pressure variation in the general population, and identify alleles with health benefit that are nonetheless under purifying selection. These findings have implications for the genetic architecture of hypertension and other common complex traits.

post to: CiteULike

Genome-wide association analysis identifies 20 loci that influence adult height.

Publication Date: 2008 May PMID: 18391952
Authors: Weedon, M. N. - Lango, H. - Lindgren, C. M. - Wallace, C. - Evans, D. M. - Mangino, M. - Freathy, R. M. - Perry, J. R. - Stevens, S. - Hall, A. S. - Samani, N. J. - Shields, B. - Prokopenko, I. - Farrall, M. - Dominiczak, A. - Johnson, T. - Bergmann, S. - Beckmann, J. S. - Vollenweider, P. - Waterworth, D. M. - Mooser, V. - Palmer, C. N. - Morris, A. D. - Ouwehand, W. H. - Zhao, J. H. - Li, S. - Loos, R. J. - Barroso, I. - Deloukas, P. - Sandhu, M. S. - Wheeler, E. - Soranzo, N. - Inouye, M. - Wareham, N. J. - Caulfield, M. - Munroe, P. B. - Hattersley, A. T. - McCarthy, M. I. - Frayling, T. M.
Journal: Nat Genet

Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 x 10(-7), with 10 reaching P < 1 x 10(-10)). Combined, the 20 SNPs explain approximately 3% of height variation, with a approximately 5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait.

post to: CiteULike

Many sequence variants affecting diversity of adult human height.

Publication Date: 2008 May PMID: 18391951
Authors: Gudbjartsson, D. F. - Walters, G. B. - Thorleifsson, G. - Stefansson, H. - Halldorsson, B. V. - Zusmanovich, P. - Sulem, P. - Thorlacius, S. - Gylfason, A. - Steinberg, S. - Helgadottir, A. - Ingason, A. - Steinthorsdottir, V. - Olafsdottir, E. J. - Olafsdottir, G. H. - Jonsson, T. - Borch-Johnsen, K. - Hansen, T. - Andersen, G. - Jorgensen, T. - Pedersen, O. - Aben, K. K. - Witjes, J. A. - Swinkels, D. W. - den Heijer, M. - Franke, B. - Verbeek, A. L. - Becker, D. M. - Yanek, L. R. - Becker, L. C. - Tryggvadottir, L. - Rafnar, T. - Gulcher, J. - Kiemeney, L. A. - Kong, A. - Thorsteinsdottir, U. - Stefansson, K.
Journal: Nat Genet

Adult human height is one of the classical complex human traits. We searched for sequence variants that affect height by scanning the genomes of 25,174 Icelanders, 2,876 Dutch, 1,770 European Americans and 1,148 African Americans. We then combined these results with previously published results from the Diabetes Genetics Initiative on 3,024 Scandinavians and tested a selected subset of SNPs in 5,517 Danes. We identified 27 regions of the genome with one or more sequence variants showing significant association with height. The estimated effects per allele of these variants ranged between 0.3 and 0.6 cm and, taken together, they explain around 3.7% of the population variation in height. The genes neighboring the identified loci cluster in biological processes related to skeletal development and mitosis. Association to three previously reported loci are replicated in our analyses, and the strongest association was with SNPs in the ZBTB38 gene.

post to: CiteULike

Identification of ten loci associated with height highlights new biological pathways in human growth.

Publication Date: 2008 May PMID: 18391950
Authors: Lettre, G. - Jackson, A. U. - Gieger, C. - Schumacher, F. R. - Berndt, S. I. - Sanna, S. - Eyheramendy, S. - Voight, B. F. - Butler, J. L. - Guiducci, C. - Illig, T. - Hackett, R. - Heid, I. M. - Jacobs, K. B. - Lyssenko, V. - Uda, M. - Boehnke, M. - Chanock, S. J. - Groop, L. C. - Hu, F. B. - Isomaa, B. - Kraft, P. - Peltonen, L. - Salomaa, V. - Schlessinger, D. - Hunter, D. J. - Hayes, R. B. - Abecasis, G. R. - Wichmann, H. E. - Mohlke, K. L. - Hirschhorn, J. N.
Journal: Nat Genet

Height is a classic polygenic trait, reflecting the combined influence of multiple as-yet-undiscovered genetic factors. We carried out a meta-analysis of genome-wide association study data of height from 15,821 individuals at 2.2 million SNPs, and followed up the strongest findings in >10,000 subjects. Ten newly identified and two previously reported loci were strongly associated with variation in height (P values from 4 x 10(-7) to 8 x 10(-22)). Together, these 12 loci account for approximately 2% of the population variation in height. Individuals with < or =8 height-increasing alleles and > or =16 height-increasing alleles differ in height by approximately 3.5 cm. The newly identified loci, along with several additional loci with strongly suggestive associations, encompass both strong biological candidates and unexpected genes, and highlight several pathways (let-7 targets, chromatin remodeling proteins and Hedgehog signaling) as important regulators of human stature. These results expand the picture of the biological regulation of human height and of the genetic architecture of this classical complex trait.

post to: CiteULike

Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1.

Publication Date: 2008 May PMID: 18385676
Authors: Amos, C. I. - Wu, X. - Broderick, P. - Gorlov, I. P. - Gu, J. - Eisen, T. - Dong, Q. - Zhang, Q. - Gu, X. - Vijayakrishnan, J. - Sullivan, K. - Matakidou, A. - Wang, Y. - Mills, G. - Doheny, K. - Tsai, Y. Y. - Chen, W. V. - Shete, S. - Spitz, M. R. - Houlston, R. S.
Journal: Nat Genet

To identify risk variants for lung cancer, we conducted a multistage genome-wide association study. In the discovery phase, we analyzed 315,450 tagging SNPs in 1,154 current and former (ever) smoking cases of European ancestry and 1,137 frequency-matched, ever-smoking controls from Houston, Texas. For replication, we evaluated the ten SNPs most significantly associated with lung cancer in an additional 711 cases and 632 controls from Texas and 2,013 cases and 3,062 controls from the UK. Two SNPs, rs1051730 and rs8034191, mapping to a region of strong linkage disequilibrium within 15q25.1 containing PSMA4 and the nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5, were significantly associated with risk in both replication sets. Combined analysis yielded odds ratios of 1.32 (P < 1 x 10(-17)) for both SNPs. Haplotype analysis was consistent with there being a single risk variant in this region. We conclude that variation in a region of 15q25.1 containing nicotinic acetylcholine receptors genes contributes to lung cancer risk.

post to: CiteULike

A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3.

Publication Date: 2008 May PMID: 18372905
Authors: Tomlinson, I. P. - Webb, E. - Carvajal-Carmona, L. - Broderick, P. - Howarth, K. - Pittman, A. M. - Spain, S. - Lubbe, S. - Walther, A. - Sullivan, K. - Jaeger, E. - Fielding, S. - Rowan, A. - Vijayakrishnan, J. - Domingo, E. - Chandler, I. - Kemp, Z. - Qureshi, M. - Farrington, S. M. - Tenesa, A. - Prendergast, J. G. - Barnetson, R. A. - Penegar, S. - Barclay, E. - Wood, W. - Martin, L. - Gorman, M. - Thomas, H. - Peto, J. - Bishop, D. T. - Gray, R. - Maher, E. R. - Lucassen, A. - Kerr, D. - Evans, D. G. - Schafmayer, C. - Buch, S. - Volzke, H. - Hampe, J. - Schreiber, S. - John, U. - Koessler, T. - Pharoah, P. - van Wezel, T. - Morreau, H. - Wijnen, J. T. - Hopper, J. L. - Southey, M. C. - Giles, G. G. - Severi, G. - Castellvi-Bel, S. - Ruiz-Ponte, C. - Carracedo, A. - Castells, A. - Forsti, A. - Hemminki, K. - Vodicka, P. - Naccarati, A. - Lipton, L. - Ho, J. W. - Cheng, K. K. - Sham, P. C. - Luk, J. - Agundez, J. A. - Ladero, J. M. - de la Hoya, M. - Caldes, T. - Niittymaki, I. - Tuupanen, S. - Karhu, A. - Aaltonen, L. - Cazier, J. B. - Campbell, H. - Dunlop, M. G. - Houlston, R. S.
Journal: Nat Genet

To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.

post to: CiteULike

Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon.

Publication Date: 2008 May PMID: 18372904
Authors: Haigis, K. M. - Kendall, K. R. - Wang, Y. - Cheung, A. - Haigis, M. C. - Glickman, J. N. - Niwa-Kawakita, M. - Sweet-Cordero, A. - Sebolt-Leopold, J. - Shannon, K. M. - Settleman, J. - Giovannini, M. - Jacks, T.
Journal: Nat Genet

Kras is commonly mutated in colon cancers, but mutations in Nras are rare. We have used genetically engineered mice to determine whether and how these related oncogenes regulate homeostasis and tumorigenesis in the colon. Expression of K-Ras(G12D) in the colonic epithelium stimulated hyperproliferation in a Mek-dependent manner. N-Ras(G12D) did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis. In the context of an Apc-mutant colonic tumor, activation of K-Ras led to defects in terminal differentiation and expansion of putative stem cells within the tumor epithelium. This K-Ras tumor phenotype was associated with attenuated signaling through the MAPK pathway, and human colon cancer cells expressing mutant K-Ras were hypersensitive to inhibition of Raf, but not Mek. These studies demonstrate clear phenotypic differences between mutant Kras and Nras, and suggest that the oncogenic phenotype of mutant K-Ras might be mediated by noncanonical signaling through Ras effector pathways.

post to: CiteULike

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

Publication Date: 2008 May PMID: 18372903
Authors: Zeggini, E. - Scott, L. J. - Saxena, R. - Voight, B. F. - Marchini, J. L. - Hu, T. - de Bakker, P. I. - Abecasis, G. R. - Almgren, P. - Andersen, G. - Ardlie, K. - Bostrom, K. B. - Bergman, R. N. - Bonnycastle, L. L. - Borch-Johnsen, K. - Burtt, N. P. - Chen, H. - Chines, P. S. - Daly, M. J. - Deodhar, P. - Ding, C. J. - Doney, A. S. - Duren, W. L. - Elliott, K. S. - Erdos, M. R. - Frayling, T. M. - Freathy, R. M. - Gianniny, L. - Grallert, H. - Grarup, N. - Groves, C. J. - Guiducci, C. - Hansen, T. - Herder, C. - Hitman, G. A. - Hughes, T. E. - Isomaa, B. - Jackson, A. U. - Jorgensen, T. - Kong, A. - Kubalanza, K. - Kuruvilla, F. G. - Kuusisto, J. - Langenberg, C. - Lango, H. - Lauritzen, T. - Li, Y. - Lindgren, C. M. - Lyssenko, V. - Marvelle, A. F. - Meisinger, C. - Midthjell, K. - Mohlke, K. L. - Morken, M. A. - Morris, A. D. - Narisu, N. - Nilsson, P. - Owen, K. R. - Palmer, C. N. - Payne, F. - Perry, J. R. - Pettersen, E. - Platou, C. - Prokopenko, I. - Qi, L. - Qin, L. - Rayner, N. W. - Rees, M. - Roix, J. J. - Sandbaek, A. - Shields, B. - Sjogren, M. - Steinthorsdottir, V. - Stringham, H. M. - Swift, A. J. - Thorleifsson, G. - Thorsteinsdottir, U. - Timpson, N. J. - Tuomi, T. - Tuomilehto, J. - Walker, M. - Watanabe, R. M. - Weedon, M. N. - Willer, C. J. - Illig, T. - Hveem, K. - Hu, F. B. - Laakso, M. - Stefansson, K. - Pedersen, O. - Wareham, N. J. - Barroso, I. - Hattersley, A. T. - Collins, F. S. - Groop, L. - McCarthy, M. I. - Boehnke, M. - Altshuler, D.
Journal: Nat Genet

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). 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 identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.

post to: CiteULike

TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis.

Publication Date: 2008 May PMID: 18372902
Authors: Kabashi, E. - Valdmanis, P. N. - Dion, P. - Spiegelman, D. - McConkey, B. J. - Vande Velde, C. - Bouchard, J. P. - Lacomblez, L. - Pochigaeva, K. - Salachas, F. - Pradat, P. F. - Camu, W. - Meininger, V. - Dupre, N. - Rouleau, G. A.
Journal: Nat Genet

Recently, TDP-43 was identified as a key component of ubiquitinated aggregates in amyotrophic lateral sclerosis (ALS), an adult-onset neurological disorder that leads to the degeneration of motor neurons. Here we report eight missense mutations in nine individuals--six from individuals with sporadic ALS (SALS) and three from those with familial ALS (FALS)--and a concurring increase of a smaller TDP-43 product. These findings further corroborate that TDP-43 is involved in ALS pathogenesis.

post to: CiteULike

Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21.

Publication Date: 2008 May PMID: 18372901
Authors: Tenesa, A. - Farrington, S. M. - Prendergast, J. G. - Porteous, M. E. - Walker, M. - Haq, N. - Barnetson, R. A. - Theodoratou, E. - Cetnarskyj, R. - Cartwright, N. - Semple, C. - Clark, A. J. - Reid, F. J. - Smith, L. A. - Kavoussanakis, K. - Koessler, T. - Pharoah, P. D. - Buch, S. - Schafmayer, C. - Tepel, J. - Schreiber, S. - Volzke, H. - Schmidt, C. O. - Hampe, J. - Chang-Claude, J. - Hoffmeister, M. - Brenner, H. - Wilkening, S. - Canzian, F. - Capella, G. - Moreno, V. - Deary, I. J. - Starr, J. M. - Tomlinson, I. P. - Kemp, Z. - Howarth, K. - Carvajal-Carmona, L. - Webb, E. - Broderick, P. - Vijayakrishnan, J. - Houlston, R. S. - Rennert, G. - Ballinger, D. - Rozek, L. - Gruber, S. B. - Matsuda, K. - Kidokoro, T. - Nakamura, Y. - Zanke, B. W. - Greenwood, C. M. - Rangrej, J. - Kustra, R. - Montpetit, A. - Hudson, T. J. - Gallinger, S. - Campbell, H. - Dunlop, M. G.
Journal: Nat Genet

In a genome-wide association study to identify loci associated with colorectal cancer (CRC) risk, we genotyped 555,510 SNPs in 1,012 early-onset Scottish CRC cases and 1,012 controls (phase 1). In phase 2, we genotyped the 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. We then genotyped the five highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from seven populations, and identified a previously unreported association, rs3802842 on 11q23 (OR = 1.1; P = 5.8 x 10(-10)), showing population differences in risk. We also replicated and fine-mapped associations at 8q24 (rs7014346; OR = 1.19; P = 8.6 x 10(-26)) and 18q21 (rs4939827; OR = 1.2; P = 7.8 x 10(-28)). Risk was greater for rectal than for colon cancer for rs3802842 (P < 0.008) and rs4939827 (P < 0.009). Carrying all six possible risk alleles yielded OR = 2.6 (95% CI = 1.75-3.89) for CRC. These findings extend our understanding of the role of common genetic variation in CRC etiology.

post to: CiteULike