Nature Genetics

Mutations in the mitochondrial protease gene AFG3L2 cause dominant hereditary ataxia SCA28.

Publication Date: 2010 Mar 7 PMID: 20208537
Authors: Di Bella, D. - Lazzaro, F. - Brusco, A. - Plumari, M. - Battaglia, G. - Pastore, A. - Finardi, A. - Cagnoli, C. - Tempia, F. - Frontali, M. - Veneziano, L. - Sacco, T. - Boda, E. - Brussino, A. - Bonn, F. - Castellotti, B. - Baratta, S. - Mariotti, C. - Gellera, C. - Fracasso, V. - Magri, S. - Langer, T. - Plevani, P. - Di Donato, S. - Muzi-Falconi, M. - Taroni, F.
Journal: Nat Genet

Autosomal dominant spinocerebellar ataxias (SCAs) are genetically heterogeneous neurological disorders characterized by cerebellar dysfunction mostly due to Purkinje cell degeneration. Here we show that AFG3L2 mutations cause SCA type 28. Along with paraplegin, which causes recessive spastic paraplegia, AFG3L2 is a component of the conserved m-AAA metalloprotease complex involved in the maintenance of the mitochondrial proteome. We identified heterozygous missense mutations in five unrelated SCA families and found that AFG3L2 is highly and selectively expressed in human cerebellar Purkinje cells. m-AAA-deficient yeast cells expressing human mutated AFG3L2 homocomplex show respiratory deficiency, proteolytic impairment and deficiency of respiratory chain complex IV. Structure homology modeling indicates that the mutations may affect AFG3L2 substrate handling. This work identifies AFG3L2 as a novel cause of dominant neurodegenerative disease and indicates a previously unknown role for this component of the mitochondrial protein quality control machinery in protecting the human cerebellum against neurodegeneration.

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Nucleosome dynamics define transcriptional enhancers.

Publication Date: 2010 Mar 7 PMID: 20208536
Authors: He, H. H. - Meyer, C. A. - Shin, H. - Bailey, S. T. - Wei, G. - Wang, Q. - Zhang, Y. - Xu, K. - Ni, M. - Lupien, M. - Mieczkowski, P. - Lieb, J. D. - Zhao, K. - Brown, M. - Liu, X. S.
Journal: Nat Genet

Chromatin plays a central role in eukaryotic gene regulation. We performed genome-wide mapping of epigenetically marked nucleosomes to determine their position both near transcription start sites and at distal regulatory elements, including enhancers. In prostate cancer cells, where androgen receptor binds primarily to enhancers, we found that androgen treatment dismisses a central nucleosome present at androgen receptor binding sites that is flanked by a pair of marked nucleosomes. A new quantitative model built on the behavior of such nucleosome pairs correctly identified regions bound by the regulators of the immediate androgen response, including androgen receptor and FOXA1. More importantly, this model also correctly predicted previously unidentified binding sites for other transcription factors present after prolonged androgen stimulation, including OCT1 and NKX3-1. Therefore, quantitative modeling of enhancer structure provides a powerful predictive method to infer the identity of transcription factors involved in cellular responses to specific stimuli.

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Mixed linear model approach adapted for genome-wide association studies.

Publication Date: 2010 Mar 7 PMID: 20208535
Authors: Zhang, Z. - Ersoz, E. - Lai, C. Q. - Todhunter, R. J. - Tiwari, H. K. - Gore, M. A. - Bradbury, P. J. - Yu, J. - Arnett, D. K. - Ordovas, J. M. - Buckler, E. S.
Journal: Nat Genet

Mixed linear model (MLM) methods have proven useful in controlling for population structure and relatedness within genome-wide association studies. However, MLM-based methods can be computationally challenging for large datasets. We report a compression approach, called 'compressed MLM', that decreases the effective sample size of such datasets by clustering individuals into groups. We also present a complementary approach, 'population parameters previously determined' (P3D), that eliminates the need to re-compute variance components. We applied these two methods both independently and combined in selected genetic association datasets from human, dog and maize. The joint implementation of these two methods markedly reduced computing time and either maintained or improved statistical power. We used simulations to demonstrate the usefulness in controlling for substructure in genetic association datasets for a range of species and genetic architectures. We have made these methods available within an implementation of the software program TASSEL.

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Common variants at 5q22 associate with pediatric eosinophilic esophagitis.

Publication Date: 2010 Mar 7 PMID: 20208534
Authors: Rothenberg, M. E. - Spergel, J. M. - Sherrill, J. D. - Annaiah, K. - Martin, L. J. - Cianferoni, A. - Gober, L. - Kim, C. - Glessner, J. - Frackelton, E. - Thomas, K. - Blanchard, C. - Liacouras, C. - Verma, R. - Aceves, S. - Collins, M. H. - Brown-Whitehorn, T. - Putnam, P. E. - Franciosi, J. P. - Chiavacci, R. M. - Grant, S. F. - Abonia, J. P. - Sleiman, P. M. - Hakonarson, H.
Journal: Nat Genet

Eosinophilic esophagitis (EoE) is an allergic disorder characterized by the accumulation of eosinophils in the esophagus. We report association of EoE with variants at chromosome 5q22 encompassing TSLP and WDR36 (rs3806932, combined P = 3.19 x 10(-9)). TSLP is overexpressed in esophageal biopsies from individuals with EoE compared with unaffected individuals, whereas WDR36 expression is unaltered between the two groups. These data implicate the 5q22 locus in the pathogenesis of EoE and identify TSLP as the most likely candidate gene in the region.

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Variance component model to account for sample structure in genome-wide association studies.

Publication Date: 2010 Mar 7 PMID: 20208533
Authors: Kang, H. M. - Sul, J. H. - Service, S. K. - Zaitlen, N. A. - Kong, S. Y. - Freimer, N. B. - Sabatti, C. - Eskin, E.
Journal: Nat Genet

Although genome-wide association studies (GWASs) have identified numerous loci associated with complex traits, imprecise modeling of the genetic relatedness within study samples may cause substantial inflation of test statistics and possibly spurious associations. Variance component approaches, such as efficient mixed-model association (EMMA), can correct for a wide range of sample structures by explicitly accounting for pairwise relatedness between individuals, using high-density markers to model the phenotype distribution; but such approaches are computationally impractical. We report here a variance component approach implemented in publicly available software, EMMA eXpedited (EMMAX), that reduces the computational time for analyzing large GWAS data sets from years to hours. We apply this method to two human GWAS data sets, performing association analysis for ten quantitative traits from the Northern Finland Birth Cohort and seven common diseases from the Wellcome Trust Case Control Consortium. We find that EMMAX outperforms both principal component analysis and genomic control in correcting for sample structure.

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Mutations in VIPAR cause an arthrogryposis, renal dysfunction and cholestasis syndrome phenotype with defects in epithelial polarization.

Publication Date: 2010 Feb 28 PMID: 20190753
Authors: Cullinane, A. R. - Straatman-Iwanowska, A. - Zaucker, A. - Wakabayashi, Y. - Bruce, C. K. - Luo, G. - Rahman, F. - Gurakan, F. - Utine, E. - Ozkan, T. B. - Denecke, J. - Vukovic, J. - Di Rocco, M. - Mandel, H. - Cangul, H. - Matthews, R. P. - Thomas, S. G. - Rappoport, J. Z. - Arias, I. M. - Wolburg, H. - Knisely, A. S. - Kelly, D. A. - Muller, F. - Maher, E. R. - Gissen, P.
Journal: Nat Genet

Arthrogryposis, renal dysfunction and cholestasis syndrome (ARC) is a multisystem disorder associated with abnormalities in polarized liver and kidney cells. Mutations in VPS33B account for most cases of ARC. We identified mutations in VIPAR (also called C14ORF133) in individuals with ARC without VPS33B defects. We show that VIPAR forms a functional complex with VPS33B that interacts with RAB11A. Knockdown of vipar in zebrafish resulted in biliary excretion and E-cadherin defects similar to those in individuals with ARC. Vipar- and Vps33b-deficient mouse inner medullary collecting duct (mIMDC-3) cells expressed membrane proteins abnormally and had structural and functional tight junction defects. Abnormal Ceacam5 expression was due to mis-sorting toward lysosomal degradation, but reduced E-cadherin levels were associated with transcriptional downregulation. The VPS33B-VIPAR complex thus has diverse functions in the pathways regulating apical-basolateral polarity in the liver and kidney.

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Multiple common variants for celiac disease influencing immune gene expression.

Publication Date: 2010 Feb 28 PMID: 20190752
Authors: Dubois, P. C. - Trynka, G. - Franke, L. - Hunt, K. A. - Romanos, J. - Curtotti, A. - Zhernakova, A. - Heap, G. A. - Adany, R. - Aromaa, A. - Bardella, M. T. - van den Berg, L. H. - Bockett, N. A. - de la Concha, E. G. - Dema, B. - Fehrmann, R. S. - Fernandez-Arquero, M. - Fiatal, S. - Grandone, E. - Green, P. M. - Groen, H. J. - Gwilliam, R. - Houwen, R. H. - Hunt, S. E. - Kaukinen, K. - Kelleher, D. - Korponay-Szabo, I. - Kurppa, K. - Macmathuna, P. - Maki, M. - Mazzilli, M. C. - McCann, O. T. - Mearin, M. L. - Mein, C. A. - Mirza, M. M. - Mistry, V. - Mora, B. - Morley, K. I. - Mulder, C. J. - Murray, J. A. - Nunez, C. - Oosterom, E. - Ophoff, R. A. - Polanco, I. - Peltonen, L. - Platteel, M. - Rybak, A. - Salomaa, V. - Schweizer, J. J. - Sperandeo, M. P. - Tack, G. J. - Turner, G. - Veldink, J. H. - Verbeek, W. H. - Weersma, R. K. - Wolters, V. M. - Urcelay, E. - Cukrowska, B. - Greco, L. - Neuhausen, S. L. - McManus, R. - Barisani, D. - Deloukas, P. - Barrett, J. C. - Saavalainen, P. - Wijmenga, C. - van Heel, D. A.
Journal: Nat Genet

We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMIS and TNFRSF14 having key roles in thymic T-cell selection. There was evidence to suggest associations for a further 13 regions. In an expression quantitative trait meta-analysis of 1,469 whole blood samples, 20 of 38 (52.6%) tested loci had celiac risk variants correlated (P < 0.0028, FDR 5%) with cis gene expression.

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Understanding variable expressivity in microdeletion syndromes.

Publication Date: 2010 Mar PMID: 20179732
Authors: Veltman, J. A. - Brunner, H. G.
Journal: Nat Genet

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Open chromatin and diabetes risk.

Publication Date: 2010 Mar PMID: 20179731
Authors: Groop, L.
Journal: Nat Genet

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Deciphering genetic susceptibility to frontotemporal lobar dementia.

Publication Date: 2010 Mar PMID: 20179730
Authors: Lambert, J. C. - Amouyel, P.
Journal: Nat Genet

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Variants in FAM13A are associated with chronic obstructive pulmonary disease.

Publication Date: 2010 Mar PMID: 20173748
Authors: Cho, M. H. - Boutaoui, N. - Klanderman, B. J. - Sylvia, J. S. - Ziniti, J. P. - Hersh, C. P. - DeMeo, D. L. - Hunninghake, G. M. - Litonjua, A. A. - Sparrow, D. - Lange, C. - Won, S. - Murphy, J. R. - Beaty, T. H. - Regan, E. A. - Make, B. J. - Hokanson, J. E. - Crapo, J. D. - Kong, X. - Anderson, W. H. - Tal-Singer, R. - Lomas, D. A. - Bakke, P. - Gulsvik, A. - Pillai, S. G. - Silverman, E. K.
Journal: Nat Genet

We performed a genome-wide association study for chronic obstructive pulmonary disease (COPD) in three population cohorts, including 2,940 cases and 1,380 controls who were current or former smokers with normal lung function. We identified a new susceptibility locus at 4q22.1 in FAM13A and replicated this association in one case-control group (n = 1,006) and two family-based cohorts (n = 3,808) (rs7671167, combined P = 1.2 x 10(-11), combined odds ratio in case-control studies 0.76, 95% confidence interval 0.69-0.83).

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Common variants in KCNN3 are associated with lone atrial fibrillation.

Publication Date: 2010 Mar PMID: 20173747
Authors: Ellinor, P. T. - Lunetta, K. L. - Glazer, N. L. - Pfeufer, A. - Alonso, A. - Chung, M. K. - Sinner, M. F. - de Bakker, P. I. - Mueller, M. - Lubitz, S. A. - Fox, E. - Darbar, D. - Smith, N. L. - Smith, J. D. - Schnabel, R. B. - Soliman, E. Z. - Rice, K. M. - Van Wagoner, D. R. - Beckmann, B. M. - van Noord, C. - Wang, K. - Ehret, G. B. - Rotter, J. I. - Hazen, S. L. - Steinbeck, G. - Smith, A. V. - Launer, L. J. - Harris, T. B. - Makino, S. - Nelis, M. - Milan, D. J. - Perz, S. - Esko, T. - Kottgen, A. - Moebus, S. - Newton-Cheh, C. - Li, M. - Mohlenkamp, S. - Wang, T. J. - Kao, W. H. - Vasan, R. S. - Nothen, M. M. - MacRae, C. A. - Stricker, B. H. - Hofman, A. - Uitterlinden, A. G. - Levy, D. - Boerwinkle, E. - Metspalu, A. - Topol, E. J. - Chakravarti, A. - Gudnason, V. - Psaty, B. M. - Roden, D. M. - Meitinger, T. - Wichmann, H. E. - Witteman, J. C. - Barnard, J. - Arking, D. E. - Benjamin, E. J. - Heckbert, S. R. - Kaab, S.
Journal: Nat Genet

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

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Germline mutations in TMEM127 confer susceptibility to pheochromocytoma.

Publication Date: 2010 Mar PMID: 20154675
Authors: Qin, Y. - Yao, L. - King, E. E. - Buddavarapu, K. - Lenci, R. E. - Chocron, E. S. - Lechleiter, J. D. - Sass, M. - Aronin, N. - Schiavi, F. - Boaretto, F. - Opocher, G. - Toledo, R. A. - Toledo, S. P. - Stiles, C. - Aguiar, R. C. - Dahia, P. L.
Journal: Nat Genet

Pheochromocytomas, which are catecholamine-secreting tumors of neural crest origin, are frequently hereditary. However, the molecular basis of the majority of these tumors is unknown. We identified the transmembrane-encoding gene TMEM127 on chromosome 2q11 as a new pheochromocytoma susceptibility gene. In a cohort of 103 samples, we detected truncating germline TMEM127 mutations in approximately 30% of familial tumors and about 3% of sporadic-appearing pheochromocytomas without a known genetic cause. The wild-type allele was consistently deleted in tumor DNA, suggesting a classic mechanism of tumor suppressor gene inactivation. Pheochromocytomas with mutations in TMEM127 are transcriptionally related to tumors bearing NF1 mutations and, similarly, show hyperphosphorylation of mammalian target of rapamycin (mTOR) effector proteins. Accordingly, in vitro gain-of-function and loss-of-function analyses indicate that TMEM127 is a negative regulator of mTOR. TMEM127 dynamically associates with the endomembrane system and colocalizes with perinuclear (activated) mTOR, suggesting a subcompartmental-specific effect. Our studies identify TMEM127 as a tumor suppressor gene and validate the power of hereditary tumors to elucidate cancer pathogenesis.

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A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay.

Publication Date: 2010 Mar PMID: 20154674
Authors: Girirajan, S. - Rosenfeld, J. A. - Cooper, G. M. - Antonacci, F. - Siswara, P. - Itsara, A. - Vives, L. - Walsh, T. - McCarthy, S. E. - Baker, C. - Mefford, H. C. - Kidd, J. M. - Browning, S. R. - Browning, B. L. - Dickel, D. E. - Levy, D. L. - Ballif, B. C. - Platky, K. - Farber, D. M. - Gowans, G. C. - Wetherbee, J. J. - Asamoah, A. - Weaver, D. D. - Mark, P. R. - Dickerson, J. - Garg, B. P. - Ellingwood, S. A. - Smith, R. - Banks, V. C. - Smith, W. - McDonald, M. T. - Hoo, J. J. - French, B. N. - Hudson, C. - Johnson, J. P. - Ozmore, J. R. - Moeschler, J. B. - Surti, U. - Escobar, L. F. - El-Khechen, D. - Gorski, J. L. - Kussmann, J. - Salbert, B. - Lacassie, Y. - Biser, A. - McDonald-McGinn, D. M. - Zackai, E. H. - Deardorff, M. A. - Shaikh, T. H. - Haan, E. - Friend, K. L. - Fichera, M. - Romano, C. - Gecz, J. - DeLisi, L. E. - Sebat, J. - King, M. C. - Shaffer, L. G. - Eichler, E. E.
Journal: Nat Genet

We report the identification of a recurrent, 520-kb 16p12.1 microdeletion associated with childhood developmental delay. The microdeletion was detected in 20 of 11,873 cases compared with 2 of 8,540 controls (P = 0.0009, OR = 7.2) and replicated in a second series of 22 of 9,254 cases compared with 6 of 6,299 controls (P = 0.028, OR = 2.5). Most deletions were inherited, with carrier parents likely to manifest neuropsychiatric phenotypes compared to non-carrier parents (P = 0.037, OR = 6). Probands were more likely to carry an additional large copy-number variant when compared to matched controls (10 of 42 cases, P = 5.7 x 10(-5), OR = 6.6). The clinical features of individuals with two mutations were distinct from and/or more severe than those of individuals carrying only the co-occurring mutation. Our data support a two-hit model in which the 16p12.1 microdeletion both predisposes to neuropsychiatric phenotypes as a single event and exacerbates neurodevelopmental phenotypes in association with other large deletions or duplications. Analysis of other microdeletions with variable expressivity indicates that this two-hit model might be more generally applicable to neuropsychiatric disease.

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Common variants at 7p21 are associated with frontotemporal lobar degeneration with TDP-43 inclusions.

Publication Date: 2010 Mar PMID: 20154673
Authors: Van Deerlin, V. M. - Sleiman, P. M. - Martinez-Lage, M. - Chen-Plotkin, A. - Wang, L. S. - Graff-Radford, N. R. - Dickson, D. W. - Rademakers, R. - Boeve, B. F. - Grossman, M. - Arnold, S. E. - Mann, D. M. - Pickering-Brown, S. M. - Seelaar, H. - Heutink, P. - van Swieten, J. C. - Murrell, J. R. - Ghetti, B. - Spina, S. - Grafman, J. - Hodges, J. - Spillantini, M. G. - Gilman, S. - Lieberman, A. P. - Kaye, J. A. - Woltjer, R. L. - Bigio, E. H. - Mesulam, M. - Al-Sarraj, S. - Troakes, C. - Rosenberg, R. N. - White, C. L. 3rd - Ferrer, I. - Llado, A. - Neumann, M. - Kretzschmar, H. A. - Hulette, C. M. - Welsh-Bohmer, K. A. - Miller, B. L. - Alzualde, A. - de Munain, A. L. - McKee, A. C. - Gearing, M. - Levey, A. I. - Lah, J. J. - Hardy, J. - Rohrer, J. D. - Lashley, T. - Mackenzie, I. R. - Feldman, H. H. - Hamilton, R. L. - Dekosky, S. T. - van der Zee, J. - Kumar-Singh, S. - Van Broeckhoven, C. - Mayeux, R. - Vonsattel, J. P. - Troncoso, J. C. - Kril, J. J. - Kwok, J. B. - Halliday, G. M. - Bird, T. D. - Ince, P. G. - Shaw, P. J. - Cairns, N. J. - Morris, J. C. - McLean, C. A. - DeCarli, C. - Ellis, W. G. - Freeman, S. H. - Frosch, M. P. - Growdon, J. H. - Perl, D. P. - Sano, M. - Bennett, D. A. - Schneider, J. A. - Beach, T. G. - Reiman, E. M. - Woodruff, B. K. - Cummings, J. - Vinters, H. V. - Miller, C. A. - Chui, H. C. - Alafuzoff, I. - Hartikainen, P. - Seilhean, D. - Galasko, D. - Masliah, E. - Cotman, C. W. - Tunon, M. T. - Martinez, M. C. - Munoz, D. G. - Carroll, S. L. - Marson, D. - Riederer, P. F. - Bogdanovic, N. - Schellenberg, G. D. - Hakonarson, H. - Trojanowski, J. Q. - Lee, V. M.
Journal: Nat Genet

Frontotemporal lobar degeneration (FTLD) is the second most common cause of presenile dementia. The predominant neuropathology is FTLD with TAR DNA-binding protein (TDP-43) inclusions (FTLD-TDP). FTLD-TDP is frequently familial, resulting from mutations in GRN (which encodes progranulin). We assembled an international collaboration to identify susceptibility loci for FTLD-TDP through a genome-wide association study of 515 individuals with FTLD-TDP. We found that FTLD-TDP associates with multiple SNPs mapping to a single linkage disequilibrium block on 7p21 that contains TMEM106B. Three SNPs retained genome-wide significance following Bonferroni correction (top SNP rs1990622, P = 1.08 x 10(-11); odds ratio, minor allele (C) 0.61, 95% CI 0.53-0.71). The association replicated in 89 FTLD-TDP cases (rs1990622; P = 2 x 10(-4)). TMEM106B variants may confer risk of FTLD-TDP by increasing TMEM106B expression. TMEM106B variants also contribute to genetic risk for FTLD-TDP in individuals with mutations in GRN. Our data implicate variants in TMEM106B as a strong risk factor for FTLD-TDP, suggesting an underlying pathogenic mechanism.

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Identification of DOK genes as lung tumor suppressors.

Publication Date: 2010 Mar PMID: 20139980
Authors: Berger, A. H. - Niki, M. - Morotti, A. - Taylor, B. S. - Socci, N. D. - Viale, A. - Brennan, C. - Szoke, J. - Motoi, N. - Rothman, P. B. - Teruya-Feldstein, J. - Gerald, W. L. - Ladanyi, M. - Pandolfi, P. P.
Journal: Nat Genet

Genome-wide analyses of human lung adenocarcinoma have identified regions of consistent copy-number gain or loss, but in many cases the oncogenes and tumor suppressors presumed to reside in these loci remain to be determined. Here we identify the downstream of tyrosine kinase (Dok) family members Dok1, Dok2 and Dok3 as lung tumor suppressors. Single, double or triple compound loss of these genes in mice results in lung cancer, with penetrance and latency dependent on the number of lost Dok alleles. Cancer development is preceded by an aberrant expansion and signaling profile of alveolar type II cells and bronchioalveolar stem cells. In human lung adenocarcinoma, we identify DOK2 as a target of copy-number loss and mRNA downregulation and find that DOK2 suppresses lung cancer cell proliferation in vitro and in vivo. Given the genomic localization of DOK2, we propose it as an 8p21.3 haploinsufficient human lung tumor suppressor.

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A basic helix-loop-helix transcription factor controls cell growth and size in root hairs.

Publication Date: 2010 Mar PMID: 20139979
Authors: Yi, K. - Menand, B. - Bell, E. - Dolan, L.
Journal: Nat Genet

Postmitotic cell growth defines cell shape and size during development. However, the mechanisms regulating postmitotic cell growth in plants remain unknown. Here we report the discovery of a basic helix-loop-helix (bHLH) transcription factor called RSL4 (ROOT HAIR DEFECTIVE 6-LIKE 4) that is sufficient to promote postmitotic cell growth in Arabidopsis thaliana root-hair cells. Loss of RSL4 function resulted in the development of very short root hairs. In contrast, constitutive RSL4 expression programmed constitutive growth, resulting in the formation of very long root hairs. Hair-cell growth signals, such as auxin and low phosphate availability, modulate hair cell extension by regulating RSL4 transcript and protein levels. RSL4 is thus a regulator of growth that integrates endogenous developmental and exogenous environmental signals that together control postmitotic growth in root hairs. The control of postmitotic growth by transcription factors may represent a general mechanism for regulating cell size across diverse organisms.

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Genome-wide association study of hematological and biochemical traits in a Japanese population.

Publication Date: 2010 Mar PMID: 20139978
Authors: Kamatani, Y. - Matsuda, K. - Okada, Y. - Kubo, M. - Hosono, N. - Daigo, Y. - Nakamura, Y. - Kamatani, N.
Journal: Nat Genet

We report genome-wide association studies for hematological and biochemical traits from approximately 14,700 Japanese individuals. We identified 60 associations for 8 hematological traits and 29 associations for 12 biochemical traits at genome-wide significance levels (P < 5 x 10(-8)). Of these, 46 associations were new to this study and 43 replicated previous reports. We compared these associated loci with those reported in similar GWAS in European populations. When the minor allele frequency was >10% in the Japanese population, 32 (94.1%) and 31 (91.2%) of the 34 hematological loci previously reported to be associated in a European population were replicated with P-values less than 0.05 and 0.01, respectively, and 31 (73.8%) and 27 (64.3%) of the 42 European biochemical loci were replicated.

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Common variants near TERC are associated with mean telomere length.

Publication Date: 2010 Mar PMID: 20139977
Authors: Codd, V. - Mangino, M. - van der Harst, P. - Braund, P. S. - Kaiser, M. - Beveridge, A. J. - Rafelt, S. - Moore, J. - Nelson, C. - Soranzo, N. - Zhai, G. - Valdes, A. M. - Blackburn, H. - Leach, I. M. - de Boer, R. A. - Goodall, A. H. - Ouwehand, W. - van Veldhuisen, D. J. - van Gilst, W. H. - Navis, G. - Burton, P. R. - Tobin, M. D. - Hall, A. S. - Thompson, J. R. - Spector, T. - Samani, N. J.
Journal: Nat Genet

We conducted genome-wide association analyses of mean leukocyte telomere length in 2,917 individuals, with follow-up replication in 9,492 individuals. We identified an association with telomere length on 3q26 (rs12696304, combined P = 3.72 x 10(-14)) at a locus that includes TERC, which encodes the telomerase RNA component. Each copy of the minor allele of rs12696304 was associated with an approximately 75-base-pair reduction in mean telomere length, equivalent to approximately 3.6 years of age-related telomere-length attrition.

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Mutations in PNKP cause microcephaly, seizures and defects in DNA repair.

Publication Date: 2010 Mar PMID: 20118933
Authors: Shen, J. - Gilmore, E. C. - Marshall, C. A. - Haddadin, M. - Reynolds, J. J. - Eyaid, W. - Bodell, A. - Barry, B. - Gleason, D. - Allen, K. - Ganesh, V. S. - Chang, B. S. - Grix, A. - Hill, R. S. - Topcu, M. - Caldecott, K. W. - Barkovich, A. J. - Walsh, C. A.
Journal: Nat Genet

Maintenance of DNA integrity is crucial for all cell types, but neurons are particularly sensitive to mutations in DNA repair genes, which lead to both abnormal development and neurodegeneration. We describe a previously unknown autosomal recessive disease characterized by microcephaly, early-onset, intractable seizures and developmental delay (denoted MCSZ). Using genome-wide linkage analysis in consanguineous families, we mapped the disease locus to chromosome 19q13.33 and identified multiple mutations in PNKP (polynucleotide kinase 3'-phosphatase) that result in severe neurological disease; in contrast, a splicing mutation is associated with more moderate symptoms. Unexpectedly, although the cells of individuals carrying this mutation are sensitive to radiation and other DNA-damaging agents, no such individual has yet developed cancer or immunodeficiency. Unlike other DNA repair defects that affect humans, PNKP mutations universally cause severe seizures. The neurological abnormalities in individuals with MCSZ may reflect a role for PNKP in several DNA repair pathways.

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A map of open chromatin in human pancreatic islets.

Publication Date: 2010 Mar PMID: 20118932
Authors: Gaulton, K. J. - Nammo, T. - Pasquali, L. - Simon, J. M. - Giresi, P. G. - Fogarty, M. P. - Panhuis, T. M. - Mieczkowski, P. - Secchi, A. - Bosco, D. - Berney, T. - Montanya, E. - Mohlke, K. L. - Lieb, J. D. - Ferrer, J.
Journal: Nat Genet

Tissue-specific transcriptional regulation is central to human disease. To identify regulatory DNA active in human pancreatic islets, we profiled chromatin by formaldehyde-assisted isolation of regulatory elements coupled with high-throughput sequencing (FAIRE-seq). We identified approximately 80,000 open chromatin sites. Comparison of FAIRE-seq data from islets to that from five non-islet cell lines revealed approximately 3,300 physically linked clusters of islet-selective open chromatin sites, which typically encompassed single genes that have islet-specific expression. We mapped sequence variants to open chromatin sites and found that rs7903146, a TCF7L2 intronic variant strongly associated with type 2 diabetes, is located in islet-selective open chromatin. We found that human islet samples heterozygous for rs7903146 showed allelic imbalance in islet FAIRE signals and that the variant alters enhancer activity, indicating that genetic variation at this locus acts in cis with local chromatin and regulatory changes. These findings illuminate the tissue-specific organization of cis-regulatory elements and show that FAIRE-seq can guide the identification of regulatory variants underlying disease susceptibility.

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Population resequencing reveals local adaptation of Arabidopsis lyrata to serpentine soils.

Publication Date: 2010 Mar PMID: 20101244
Authors: Turner, T. L. - Bourne, E. C. - Von Wettberg, E. J. - Hu, T. T. - Nuzhdin, S. V.
Journal: Nat Genet

A powerful way to map functional genomic variation and reveal the genetic basis of local adaptation is to associate allele frequency across the genome with environmental conditions. Serpentine soils, characterized by high heavy-metal content and low calcium-to-magnesium ratios, are a classic context for studying adaptation of plants to local soil conditions. To investigate whether Arabidopsis lyrata is locally adapted to serpentine soil, and to map the polymorphisms responsible for such adaptation, we pooled DNA from individuals from serpentine and nonserpentine soils and sequenced each 'gene pool' with the Illumina Genome Analyzer. The polymorphisms that are most strongly associated with soil type are enriched at heavy-metal detoxification and calcium and magnesium transport loci, providing numerous candidate mutations for serpentine adaptation. Sequencing of three candidate loci in the European subspecies of A. lyrata indicates parallel differentiation of the same polymorphism at one locus, confirming ecological adaptation, and different polymorphisms at two other loci, which may indicate convergent evolution.

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A genome-wide association study identifies pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33.

Publication Date: 2010 Mar PMID: 20101243
Authors: Petersen, G. M. - Amundadottir, L. - Fuchs, C. S. - Kraft, P. - Stolzenberg-Solomon, R. Z. - Jacobs, K. B. - Arslan, A. A. - Bueno-de-Mesquita, H. B. - Gallinger, S. - Gross, M. - Helzlsouer, K. - Holly, E. A. - Jacobs, E. J. - Klein, A. P. - LaCroix, A. - Li, D. - Mandelson, M. T. - Olson, S. H. - Risch, H. A. - Zheng, W. - Albanes, D. - Bamlet, W. R. - Berg, C. D. - Boutron-Ruault, M. C. - Buring, J. E. - Bracci, P. M. - Canzian, F. - Clipp, S. - Cotterchio, M. - de Andrade, M. - Duell, E. J. - Gaziano, J. M. - Giovannucci, E. L. - Goggins, M. - Hallmans, G. - Hankinson, S. E. - Hassan, M. - Howard, B. - Hunter, D. J. - Hutchinson, A. - Jenab, M. - Kaaks, R. - Kooperberg, C. - Krogh, V. - Kurtz, R. C. - Lynch, S. M. - McWilliams, R. R. - Mendelsohn, J. B. - Michaud, D. S. - Parikh, H. - Patel, A. V. - Peeters, P. H. - Rajkovic, A. - Riboli, E. - Rodriguez, L. - Seminara, D. - Shu, X. O. - Thomas, G. - Tjonneland, A. - Tobias, G. S. - Trichopoulos, D. - Van Den Eeden, S. K. - Virtamo, J. - Wactawski-Wende, J. - Wang, Z. - Wolpin, B. M. - Yu, H. - Yu, K. - Zeleniuch-Jacquotte, A. - Fraumeni, J. F. Jr - Hoover, R. N. - Hartge, P. - Chanock, S. J.
Journal: Nat Genet

We conducted a genome-wide association study of pancreatic cancer in 3,851 affected individuals (cases) and 3,934 unaffected controls drawn from 12 prospective cohort studies and 8 case-control studies. Based on a logistic regression model for genotype trend effect that was adjusted for study, age, sex, self-described ancestry and five principal components, we identified eight SNPs that map to three loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Two correlated SNPs, rs9543325 (P = 3.27 x 10(-11), per-allele odds ratio (OR) 1.26, 95% CI 1.18-1.35) and rs9564966 (P = 5.86 x 10(-8), per-allele OR 1.21, 95% CI 1.13-1.30), map to a nongenic region on chromosome 13q22.1. Five SNPs on 1q32.1 map to NR5A2, and the strongest signal was at rs3790844 (P = 2.45 x 10(-10), per-allele OR 0.77, 95% CI 0.71-0.84). A single SNP, rs401681 (P = 3.66 x 10(-7), per-allele OR 1.19, 95% CI 1.11-1.27), maps to the CLPTM1L-TERT locus on 5p15.33, which is associated with multiple cancers. Our study has identified common susceptibility loci for pancreatic cancer that warrant follow-up studies.

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Prevalent positive epistasis in Escherichia coli and Saccharomyces cerevisiae metabolic networks.

Publication Date: 2010 Mar PMID: 20101242
Authors: He, X. - Qian, W. - Wang, Z. - Li, Y. - Zhang, J.
Journal: Nat Genet

Epistasis refers to the interaction between genes. Although high-throughput epistasis data from model organisms are being generated and used to construct genetic networks, the extent to which genetic epistasis reflects biologically meaningful interactions remains unclear. We have addressed this question through in silico mapping of positive and negative epistatic interactions amongst biochemical reactions within the metabolic networks of Escherichia coli and Saccharomyces cerevisiae using flux balance analysis. We found that negative epistasis occurs mainly between nonessential reactions with overlapping functions, whereas positive epistasis usually involves essential reactions, is highly abundant and, unexpectedly, often occurs between reactions without overlapping functions. We offer mechanistic explanations of these findings and experimentally validate them for 61 S. cerevisiae gene pairs.

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Genome-wide association mapping identifies multiple loci for a canine SLE-related disease complex.

Publication Date: 2010 Mar PMID: 20101241
Authors: Wilbe, M. - Jokinen, P. - Truve, K. - Seppala, E. H. - Karlsson, E. K. - Biagi, T. - Hughes, A. - Bannasch, D. - Andersson, G. - Hansson-Hamlin, H. - Lohi, H. - Lindblad-Toh, K.
Journal: Nat Genet

The unique canine breed structure makes dogs an excellent model for studying genetic diseases. Within a dog breed, linkage disequilibrium is extensive, enabling genome-wide association (GWA) with only around 15,000 SNPs and fewer individuals than in human studies. Incidences of specific diseases are elevated in different breeds, indicating that a few genetic risk factors might have accumulated through drift or selective breeding. In this study, a GWA study with 81 affected dogs (cases) and 57 controls from the Nova Scotia duck tolling retriever breed identified five loci associated with a canine systemic lupus erythematosus (SLE)-related disease complex that includes both antinuclear antibody (ANA)-positive immune-mediated rheumatic disease (IMRD) and steroid-responsive meningitis-arteritis (SRMA). Fine mapping with twice as many dogs validated these loci. Our results indicate that the homogeneity of strong genetic risk factors within dog breeds allows multigenic disorders to be mapped with fewer than 100 cases and 100 controls, making dogs an excellent model in which to identify pathways involved in human complex diseases.

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Plasmodium falciparum genome-wide scans for positive selection, recombination hot spots and resistance to antimalarial drugs.

Publication Date: 2010 Mar PMID: 20101240
Authors: Mu, J. - Myers, R. A. - Jiang, H. - Liu, S. - Ricklefs, S. - Waisberg, M. - Chotivanich, K. - Wilairatana, P. - Krudsood, S. - White, N. J. - Udomsangpetch, R. - Cui, L. - Ho, M. - Ou, F. - Li, H. - Song, J. - Li, G. - Wang, X. - Seila, S. - Sokunthea, S. - Socheat, D. - Sturdevant, D. E. - Porcella, S. F. - Fairhurst, R. M. - Wellems, T. E. - Awadalla, P. - Su, X. Z.
Journal: Nat Genet

Antimalarial drugs impose strong selective pressure on Plasmodium falciparum parasites and leave signatures of selection in the parasite genome; screening for genes under selection may suggest potential drug or immune targets. Genome-wide association studies (GWAS) of parasite traits have been hampered by the lack of high-throughput genotyping methods, inadequate knowledge of parasite population history and time-consuming adaptations of parasites to in vitro culture. Here we report the first Plasmodium GWAS, which included 189 culture-adapted P. falciparum parasites genotyped using a custom-built Affymetrix molecular inversion probe 3K malaria panel array with a coverage of approximately 1 SNP per 7 kb. Population structure, variation in recombination rate and loci under recent positive selection were detected. Parasite half-maximum inhibitory concentrations for seven antimalarial drugs were obtained and used in GWAS to identify genes associated with drug responses. This study provides valuable tools and insight into the P. falciparum genome.

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