Nature Genetics

The ratio of human X chromosome to autosome diversity is positively correlated with genetic distance from genes.

Publication Date: 2010 Aug 29 PMID: 20802480
Authors: Hammer, M. F. - Woerner, A. E. - Mendez, F. L. - Watkins, J. C. - Cox, M. P. - Wall, J. D.
Journal: Nat Genet

The ratio of X-linked to autosomal diversity was estimated from an analysis of six human genome sequences and found to deviate from the expected value of 0.75. However, the direction of this deviation depends on whether a particular sequence is close to or far from the nearest gene. This pattern may be explained by stronger locally acting selection on X-linked genes compared with autosomal genes, combined with larger effective population sizes for females than for males.

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Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1.

Publication Date: 2010 Aug 29 PMID: 20802479
Authors: Anttila, V. - Stefansson, H. - Kallela, M. - Todt, U. - Terwindt, G. M. - Calafato, M. S. - Nyholt, D. R. - Dimas, A. S. - Freilinger, T. - Muller-Myhsok, B. - Artto, V. - Inouye, M. - Alakurtti, K. - Kaunisto, M. A. - Hamalainen, E. - de Vries, B. - Stam, A. H. - Weller, C. M. - Heinze, A. - Heinze-Kuhn, K. - Goebel, I. - Borck, G. - Gobel, H. - Steinberg, S. - Wolf, C. - Bjornsson, A. - Gudmundsson, G. - Kirchmann, M. - Hauge, A. - Werge, T. - Schoenen, J. - Eriksson, J. G. - Hagen, K. - Stovner, L. - Wichmann, H. E. - Meitinger, T. - Alexander, M. - Moebus, S. - Schreiber, S. - Aulchenko, Y. S. - Breteler, M. M. - Uitterlinden, A. G. - Hofman, A. - van Duijn, C. M. - Tikka-Kleemola, P. - Vepsalainen, S. - Lucae, S. - Tozzi, F. - Muglia, P. - Barrett, J. - Kaprio, J. - Farkkila, M. - Peltonen, L. - Stefansson, K. - Zwart, J. A. - Ferrari, M. D. - Olesen, J. - Daly, M. - Wessman, M. - van den Maagdenberg, A. M. - Dichgans, M. - Kubisch, C. - Dermitzakis, E. T. - Frants, R. R. - Palotie, A.
Journal: Nat Genet

Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 x 10(-9), odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 x 10(-11) (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 x 10(-5), permuted threshold for genome-wide significance 7.7 x 10(-5)). To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.

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Identity-by-descent filtering of exome sequence data identifies PIGV mutations in hyperphosphatasia mental retardation syndrome.

Publication Date: 2010 Aug 29 PMID: 20802478
Authors: Krawitz, P. M. - Schweiger, M. R. - Rodelsperger, C. - Marcelis, C. - Kolsch, U. - Meisel, C. - Stephani, F. - Kinoshita, T. - Murakami, Y. - Bauer, S. - Isau, M. - Fischer, A. - Dahl, A. - Kerick, M. - Hecht, J. - Kohler, S. - Jager, M. - Grunhagen, J. - de Condor, B. J. - Doelken, S. - Brunner, H. G. - Meinecke, P. - Passarge, E. - Thompson, M. D. - Cole, D. E. - Horn, D. - Roscioli, T. - Mundlos, S. - Robinson, P. N.
Journal: Nat Genet

Hyperphosphatasia mental retardation (HPMR) syndrome is an autosomal recessive form of mental retardation with distinct facial features and elevated serum alkaline phosphatase. We performed whole-exome sequencing in three siblings of a nonconsanguineous union with HPMR and performed computational inference of regions identical by descent in all siblings to establish PIGV, encoding a member of the GPI-anchor biosynthesis pathway, as the gene mutated in HPMR. We identified homozygous or compound heterozygous mutations in PIGV in three additional families.

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The genome of the domesticated apple (Malus x domestica Borkh.).

Publication Date: 2010 Aug 29 PMID: 20802477
Authors: Velasco, R. - Zharkikh, A. - Affourtit, J. - Dhingra, A. - Cestaro, A. - Kalyanaraman, A. - Fontana, P. - Bhatnagar, S. K. - Troggio, M. - Pruss, D. - Salvi, S. - Pindo, M. - Baldi, P. - Castelletti, S. - Cavaiuolo, M. - Coppola, G. - Costa, F. - Cova, V. - Dal Ri, A. - Goremykin, V. - Komjanc, M. - Longhi, S. - Magnago, P. - Malacarne, G. - Malnoy, M. - Micheletti, D. - Moretto, M. - Perazzolli, M. - Si-Ammour, A. - Vezzulli, S. - Zini, E. - Eldredge, G. - Fitzgerald, L. M. - Gutin, N. - Lanchbury, J. - Macalma, T. - Mitchell, J. T. - Reid, J. - Wardell, B. - Kodira, C. - Chen, Z. - Desany, B. - Niazi, F. - Palmer, M. - Koepke, T. - Jiwan, D. - Schaeffer, S. - Krishnan, V. - Wu, C. - Chu, V. T. - King, S. T. - Vick, J. - Tao, Q. - Mraz, A. - Stormo, A. - Stormo, K. - Bogden, R. - Ederle, D. - Stella, A. - Vecchietti, A. - Kater, M. M. - Masiero, S. - Lasserre, P. - Lespinasse, Y. - Allan, A. C. - Bus, V. - Chagne, D. - Crowhurst, R. N. - Gleave, A. P. - Lavezzo, E. - Fawcett, J. A. - Proost, S. - Rouze, P. - Sterck, L. - Toppo, S. - Lazzari, B. - Hellens, R. P. - Durel, C. E. - Gutin, A. - Bumgarner, R. E. - Gardiner, S. E. - Skolnick, M. - Egholm, M. - Van de Peer, Y. - Salamini, F. - Viola, R.
Journal: Nat Genet

We report a high-quality draft genome sequence of the domesticated apple (Malus x domestica). We show that a relatively recent (>50 million years ago) genome-wide duplication (GWD) has resulted in the transition from nine ancestral chromosomes to 17 chromosomes in the Pyreae. Traces of older GWDs partly support the monophyly of the ancestral paleohexaploidy of eudicots. Phylogenetic reconstruction of Pyreae and the genus Malus, relative to major Rosaceae taxa, identified the progenitor of the cultivated apple as M. sieversii. Expansion of gene families reported to be involved in fruit development may explain formation of the pome, a Pyreae-specific false fruit that develops by proliferation of the basal part of the sepals, the receptacle. In apple, a subclade of MADS-box genes, normally involved in flower and fruit development, is expanded to include 15 members, as are other gene families involved in Rosaceae-specific metabolism, such as transport and assimilation of sorbitol.

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Research highlights.

Publication Date: 2010 Sep PMID: 20802476
Authors:
Journal: Nat Genet

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Variable evolutionary signatures at the heart of enhancers.

Publication Date: 2010 Sep PMID: 20802475
Authors: Hardison, R. C.
Journal: Nat Genet

What is the best way to identify regulatory DNA sequences such as enhancers, promoters, insulators and silencers? A new study shows that specific binding by a coactivator protein identifies enhancers that are invisible to common detection methods based on evolutionary constraint.

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Putting a finger on the switch.

Publication Date: 2010 Sep PMID: 20802474
Authors: Bieker, J. J.
Journal: Nat Genet

The transition from fetal to adult beta-like globin expression is a key step in the maturation of the red blood cell lineage. Two new studies show that the KLF1 zinc finger protein uses direct and indirect means to regulate the final switch from fetal to adult globin expression and that monoallelic loss of KLF1 expression leads to persistence of fetal hemoglobin.

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Infectious diseases not immune to genome-wide association.

Publication Date: 2010 Sep PMID: 20802473
Authors: de Bakker, P. I. - Telenti, A.
Journal: Nat Genet

Two genome-wide association studies for meningococcal disease and tuberculosis identify new loci associated with susceptibility to these infectious diseases. They highlight a role for the acquired and innate immune systems in host control of several human pathogens and demonstrate that denser genotyping platforms and population-specific reference panels are necessary for genetic studies in African populations.

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Cite site.

Publication Date: 2010 Sep PMID: 20802472
Authors:
Journal: Nat Genet

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A large and complex structural polymorphism at 16p12.1 underlies microdeletion disease risk.

Publication Date: 2010 Sep PMID: 20729854
Authors: Antonacci, F. - Kidd, J. M. - Marques-Bonet, T. - Teague, B. - Ventura, M. - Girirajan, S. - Alkan, C. - Campbell, C. D. - Vives, L. - Malig, M. - Rosenfeld, J. A. - Ballif, B. C. - Shaffer, L. G. - Graves, T. A. - Wilson, R. K. - Schwartz, D. C. - Eichler, E. E.
Journal: Nat Genet

There is a complex relationship between the evolution of segmental duplications and rearrangements associated with human disease. We performed a detailed analysis of one region on chromosome 16p12.1 associated with neurocognitive disease and identified one of the largest structural inconsistencies in the human reference assembly. Various genomic analyses show that all examined humans are homozygously inverted relative to the reference genome for a 1.1-Mb region on 16p12.1. We determined that this assembly discrepancy stems from two common structural configurations with worldwide frequencies of 17.6% (S1) and 82.4% (S2). This polymorphism arose from the rapid integration of segmental duplications, precipitating two local inversions within the human lineage over the last 10 million years. The two human haplotypes differ by 333 kb of additional duplicated sequence present in S2 but not in S1. Notably, we show that the S2 configuration harbors directly oriented duplications, specifically predisposing this chromosome to disease-associated rearrangement.

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Genome-wide association study of esophageal squamous cell carcinoma in Chinese subjects identifies susceptibility loci at PLCE1 and C20orf54.

Publication Date: 2010 Sep PMID: 20729853
Authors: Wang, L. D. - Zhou, F. Y. - Li, X. M. - Sun, L. D. - Song, X. - Jin, Y. - Li, J. M. - Kong, G. Q. - Qi, H. - Cui, J. - Zhang, L. Q. - Yang, J. Z. - Li, J. L. - Li, X. C. - Ren, J. L. - Liu, Z. C. - Gao, W. J. - Yuan, L. - Wei, W. - Zhang, Y. R. - Wang, W. P. - Sheyhidin, I. - Li, F. - Chen, B. P. - Ren, S. W. - Liu, B. - Li, D. - Ku, J. W. - Fan, Z. M. - Zhou, S. L. - Guo, Z. G. - Zhao, X. K. - Liu, N. - Ai, Y. H. - Shen, F. F. - Cui, W. Y. - Song, S. - Guo, T. - Huang, J. - Yuan, C. - Huang, J. - Wu, Y. - Yue, W. B. - Feng, C. W. - Li, H. L. - Wang, Y. - Tian, J. Y. - Lu, Y. - Yuan, Y. - Zhu, W. L. - Liu, M. - Fu, W. J. - Yang, X. - Wang, H. J. - Han, S. L. - Chen, J. - Han, M. - Wang, H. Y. - Zhang, P. - Li, X. M. - Dong, J. C. - Xing, G. L. - Wang, R. - Guo, M. - Chang, Z. W. - Liu, H. L. - Guo, L. - Yuan, Z. Q. - Liu, H. - Lu, Q. - Yang, L. Q. - Zhu, F. G. - Yang, X. F. - Feng, X. S. - Wang, Z. - Li, Y. - Gao, S. G. - Qige, Q. - Bai, L. T. - Yang, W. J. - Lei, G. Y. - Shen, Z. Y. - Chen, L. Q. - Li, E. M. - Xu, L. Y. - Wu, Z. Y. - Cao, W. K. - Wang, J. P. - Bao, Z. Q. - Chen, J. L. - Ding, G. C. - Zhuang, X. - Zhou, Y. F. - Zheng, H. F. - Zhang, Z. - Zuo, X. B. - Dong, Z. M. - Fan, D. M. - He, X. - Wang, J. - Zhou, Q. - Zhang, Q. X. - Jiao, X. Y. - Lian, S. Y. - Ji, A. F. - Lu, X. M. - Wang, J. S. - Chang, F. B. - Lu, C. D. - Chen, Z. G. - Miao, J. J. - Fan, Z. L. - Lin, R. B. - Liu, T. J. - Wei, J. C. - Kong, Q. P. - Lan, Y. - Fan, Y. J. - Gao, F. S. - Wang, T. Y. - Xie, D. - Chen, S. Q. - Yang, W. C. - Hong, J. Y. - Wang, L. - Qiu, S. L. - Cai, Z. M. - Zhang, X. J.
Journal: Nat Genet

We performed a genome-wide association study of esophageal squamous cell carcinoma (ESCC) by genotyping 1,077 individuals with ESCC and 1,733 control subjects of Chinese Han descent. We selected 18 promising SNPs for replication in an additional 7,673 cases of ESCC and 11,013 control subjects of Chinese Han descent and 303 cases of ESCC and 537 control subjects of Chinese Uygur-Kazakh descent. We identified two previously unknown susceptibility loci for ESCC: PLCE1 at 10q23 (P(Han combined for ESCC) = 7.46 x 10(-56), odds ratio (OR) = 1.43; P(Uygur-Kazakh for ESCC) = 5.70 x 10(-4), OR = 1.53) and C20orf54 at 20p13 (P(Han combined for ESCC) = 1.21 x 10(-11), OR = 0.86; P(Uygur-Kazakh for ESCC) = 7.88 x 10(-3), OR = 0.66). We also confirmed association in 2,766 cases of gastric cardia adenocarcinoma cases and the same 11,013 control subjects (PLCE1, P(Han for GCA) = 1.74 x 10(-39), OR = 1.55 and C20orf54, P(Han for GCA) = 3.02 x 10(-3), OR = 0.91). PLCE1 and C20orf54 have important biological implications for both ESCC and GCA. PLCE1 might regulate cell growth, differentiation, apoptosis and angiogenesis. C20orf54 is responsible for transporting riboflavin, and deficiency of riboflavin has been documented as a risk factor for ESCC and GCA.

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A shared susceptibility locus in PLCE1 at 10q23 for gastric adenocarcinoma and esophageal squamous cell carcinoma.

Publication Date: 2010 Sep PMID: 20729852
Authors: Abnet, C. C. - Freedman, N. D. - Hu, N. - Wang, Z. - Yu, K. - Shu, X. O. - Yuan, J. M. - Zheng, W. - Dawsey, S. M. - Dong, L. M. - Lee, M. P. - Ding, T. - Qiao, Y. L. - Gao, Y. T. - Koh, W. P. - Xiang, Y. B. - Tang, Z. Z. - Fan, J. H. - Wang, C. - Wheeler, W. - Gail, M. H. - Yeager, M. - Yuenger, J. - Hutchinson, A. - Jacobs, K. B. - Giffen, C. A. - Burdett, L. - Fraumeni, J. F. Jr - Tucker, M. A. - Chow, W. H. - Goldstein, A. M. - Chanock, S. J. - Taylor, P. R.
Journal: Nat Genet

We conducted a genome-wide association study of gastric cancer and esophageal squamous cell carcinoma (ESCC) in ethnic Chinese subjects in which we genotyped 551,152 SNPs. We report a combined analysis of 2,240 gastric cancer cases, 2,115 ESCC cases and 3,302 controls drawn from five studies. In logistic regression models adjusted for age, sex and study, multiple variants at 10q23 had genome-wide significance for gastric cancer and ESCC independently. A notable signal was rs2274223, a nonsynonymous SNP located in PLCE1, for gastric cancer (P = 8.40 x 10(-9); per-allele odds ratio (OR) = 1.31) and ESCC (P = 3.85 x 10(-9); OR = 1.34). The association with gastric cancer differed by anatomic subsite. For tumors in the cardia the association was stronger (P = 4.19 x 10(-15); OR = 1.57), and for those in the noncardia stomach it was absent (P = 0.44; OR = 1.05). Our findings at 10q23 could provide insight into the high incidence of both cancers in China.

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ChIP-Seq identification of weakly conserved heart enhancers.

Publication Date: 2010 Sep PMID: 20729851
Authors: Blow, M. J. - McCulley, D. J. - Li, Z. - Zhang, T. - Akiyama, J. A. - Holt, A. - Plajzer-Frick, I. - Shoukry, M. - Wright, C. - Chen, F. - Afzal, V. - Bristow, J. - Ren, B. - Black, B. L. - Rubin, E. M. - Visel, A. - Pennacchio, L. A.
Journal: Nat Genet

Accurate control of tissue-specific gene expression plays a pivotal role in heart development, but few cardiac transcriptional enhancers have thus far been identified. Extreme noncoding-sequence conservation has successfully predicted enhancers that are active in many tissues but has failed to identify substantial numbers of heart-specific enhancers. Here, we used ChIP-Seq with the enhancer-associated protein p300 from mouse embryonic day 11.5 heart tissue to identify over 3,000 candidate heart enhancers genome wide. Compared to enhancers active in othertissues we studied at this time point, most candidate heart enhancers were less deeply conserved in vertebrate evolution. Nevertheless, transgenic mouse assays of 130 candidate regions revealed that most function reproducibly as enhancers active in the heart, irrespective of their degree of evolutionary constraint. These results provide evidence for a large population of poorly conserved heart enhancers and suggest that the evolutionary conservation of embryonic enhancers can vary depending on tissue type.

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Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease.

Publication Date: 2010 Sep PMID: 20711177
Authors: Hamza, T. H. - Zabetian, C. P. - Tenesa, A. - Laederach, A. - Montimurro, J. - Yearout, D. - Kay, D. M. - Doheny, K. F. - Paschall, J. - Pugh, E. - Kusel, V. I. - Collura, R. - Roberts, J. - Griffith, A. - Samii, A. - Scott, W. K. - Nutt, J. - Factor, S. A. - Payami, H.
Journal: Nat Genet

Parkinson's disease is a common disorder that leads to motor and cognitive disability. We performed a genome-wide association study of 2,000 individuals with Parkinson's disease (cases) and 1,986 unaffected controls from the NeuroGenetics Research Consortium (NGRC). We confirmed associations with SNCA and MAPT, replicated an association with GAK (using data from the NGRC and a previous study, P = 3.2 x 10(-9)) and detected a new association with the HLA region (using data from the NGRC only, P = 2.9 x 10(-8)), which replicated in two datasets (meta-analysis P = 1.9 x 10(-10)). The HLA association was uniform across all genetic and environmental risk strata and was strong in sporadic (P = 5.5 x 10(-10)) and late-onset (P = 2.4 x 10(-8)) disease. The association peak we found was at rs3129882, a noncoding variant in HLA-DRA. Two studies have previously suggested that rs3129882 influences expression of HLA-DR and HLA-DQ. The brains of individuals with Parkinson's disease show upregulation of DR antigens and the presence of DR-positive reactive microglia, and nonsteroidal anti-inflammatory drugs reduce Parkinson's disease risk. The genetic association with HLA supports the involvement of the immune system in Parkinson's disease and offers new targets for drug development.

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A genome-wide association study identifies four susceptibility loci for keloid in the Japanese population.

Publication Date: 2010 Sep PMID: 20711176
Authors: Nakashima, M. - Chung, S. - Takahashi, A. - Kamatani, N. - Kawaguchi, T. - Tsunoda, T. - Hosono, N. - Kubo, M. - Nakamura, Y. - Zembutsu, H.
Journal: Nat Genet

Keloid is a dermal fibroproliferative growth that results from dysfunction of the wound healing processes. Through a multistage genome-wide association study using 824 individuals with keloid (cases) and 3,205 unaffected controls in the Japanese population, we identified significant associations of keloid with four SNP loci in three chromosomal regions: 1q41, 3q22.3-23 and 15q21.3. The most significant association with keloid was observed at rs873549 (combined P = 5.89 x 10(-23), odds ratio (OR) = 1.77) on chromosome 1. Associations on chromosome 3 were observed at two separate linkage disequilibrium (LD) blocks: rs1511412 in the LD block including FOXL2 with P = 2.31 x 10(-13) (OR = 1.87) and rs940187 in another LD block with P = 1.80 x 10(-13) (OR = 1.98). Association of rs8032158 located in NEDD4 on chromosome 15 yielded P = 5.96 x 10(-13) (OR = 1.51). Our findings provide new insights into the pathophysiology of keloid formation.

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Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome.

Publication Date: 2010 Sep PMID: 20711175
Authors: Ng, S. B. - Bigham, A. W. - Buckingham, K. J. - Hannibal, M. C. - McMillin, M. J. - Gildersleeve, H. I. - Beck, A. E. - Tabor, H. K. - Cooper, G. M. - Mefford, H. C. - Lee, C. - Turner, E. H. - Smith, J. D. - Rieder, M. J. - Yoshiura, K. - Matsumoto, N. - Ohta, T. - Niikawa, N. - Nickerson, D. A. - Bamshad, M. J. - Shendure, J.
Journal: Nat Genet

We demonstrate the successful application of exome sequencing to discover a gene for an autosomal dominant disorder, Kabuki syndrome (OMIM%147920). We subjected the exomes of ten unrelated probands to massively parallel sequencing. After filtering against existing SNP databases, there was no compelling candidate gene containing previously unknown variants in all affected individuals. Less stringent filtering criteria allowed for the presence of modest genetic heterogeneity or missing data but also identified multiple candidate genes. However, genotypic and phenotypic stratification highlighted MLL2, which encodes a Trithorax-group histone methyltransferase: seven probands had newly identified nonsense or frameshift mutations in this gene. Follow-up Sanger sequencing detected MLL2 mutations in two of the three remaining individuals with Kabuki syndrome (cases) and in 26 of 43 additional cases. In families where parental DNA was available, the mutation was confirmed to be de novo (n = 12) or transmitted (n = 2) in concordance with phenotype. Our results strongly suggest that mutations in MLL2 are a major cause of Kabuki syndrome.

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Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy.

Publication Date: 2010 Sep PMID: 20711174
Authors: Hor, H. - Kutalik, Z. - Dauvilliers, Y. - Valsesia, A. - Lammers, G. J. - Donjacour, C. E. - Iranzo, A. - Santamaria, J. - Peraita Adrados, R. - Vicario, J. L. - Overeem, S. - Arnulf, I. - Theodorou, I. - Jennum, P. - Knudsen, S. - Bassetti, C. - Mathis, J. - Lecendreux, M. - Mayer, G. - Geisler, P. - Beneto, A. - Petit, B. - Pfister, C. - Burki, J. V. - Didelot, G. - Billiard, M. - Ercilla, G. - Verduijn, W. - Claas, F. H. - Vollenwider, P. - Waeber, G. - Waterworth, D. M. - Mooser, V. - Heinzer, R. - Beckmann, J. S. - Bergmann, S. - Tafti, M.
Journal: Nat Genet

Narcolepsy is a rare sleep disorder with the strongest human leukocyte antigen (HLA) association ever reported. Since the associated HLA-DRB1*1501-DQB1*0602 haplotype is common in the general population (15-25%), it has been suggested that it is almost necessary but not sufficient for developing narcolepsy. To further define the genetic basis of narcolepsy risk, we performed a genome-wide association study (GWAS) in 562 European individuals with narcolepsy (cases) and 702 ethnically matched controls, with independent replication in 370 cases and 495 controls, all heterozygous for DRB1*1501-DQB1*0602. We found association with a protective variant near HLA-DQA2 (rs2858884; P < 3 x 10(-8)). Further analysis revealed that rs2858884 is strongly linked to DRB1*03-DQB1*02 (P < 4 x 10(-43)) and DRB1*1301-DQB1*0603 (P < 3 x 10(-7)). Cases almost never carried a trans DRB1*1301-DQB1*0603 haplotype (odds ratio = 0.02; P < 6 x 10(-14)). This unexpected protective HLA haplotype suggests a virtually causal involvement of the HLA region in narcolepsy susceptibility.

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Genome-wide association analyses identifies a susceptibility locus for tuberculosis on chromosome 18q11.2.

Publication Date: 2010 Sep PMID: 20694014
Authors: Thye, T. - Vannberg, F. O. - Wong, S. H. - Owusu-Dabo, E. - Osei, I. - Gyapong, J. - Sirugo, G. - Sisay-Joof, F. - Enimil, A. - Chinbuah, M. A. - Floyd, S. - Warndorff, D. K. - Sichali, L. - Malema, S. - Crampin, A. C. - Ngwira, B. - Teo, Y. Y. - Small, K. - Rockett, K. - Kwiatkowski, D. - Fine, P. E. - Hill, P. C. - Newport, M. - Lienhardt, C. - Adegbola, R. A. - Corrah, T. - Ziegler, A. - Morris, A. P. - Meyer, C. G. - Horstmann, R. D. - Hill, A. V.
Journal: Nat Genet

We combined two tuberculosis genome-wide association studies from Ghana and The Gambia with subsequent replication in a combined 11,425 individuals. rs4331426, located in a gene-poor region on chromosome 18q11.2, was associated with disease (combined P = 6.8 x 10(-9), odds ratio = 1.19, 95% CI = 1.13-1.27). Our study demonstrates that genome-wide association studies can identify new susceptibility loci for infectious diseases, even in African populations, in which levels of linkage disequilibrium are particularly low.

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Genome-wide association study identifies variants in the CFH region associated with host susceptibility to meningococcal disease.

Publication Date: 2010 Sep PMID: 20694013
Authors: Davila, S. - Wright, V. J. - Khor, C. C. - Sim, K. S. - Binder, A. - Breunis, W. B. - Inwald, D. - Nadel, S. - Betts, H. - Carrol, E. D. - de Groot, R. - Hermans, P. W. - Hazelzet, J. - Emonts, M. - Lim, C. C. - Kuijpers, T. W. - Martinon-Torres, F. - Salas, A. - Zenz, W. - Levin, M. - Hibberd, M. L.
Journal: Nat Genet

Meningococcal disease is an infection caused by Neisseria meningitidis. Genetic factors contribute to host susceptibility and progression to disease, but the genes responsible for disease development are largely unknown. We report here a genome-wide association study for host susceptibility to meningococcal disease using 475 individuals with meningococcal disease (cases) and 4,703 population controls from the UK. We performed, in Western European and South European cohorts (consisting of 968 cases and 1,376 controls), two replication studies for the most significant SNPs. A cluster of complement factor SNPs replicated independently in both cohorts, including SNPs within complement factor H (CFH) (rs1065489 (p.936D
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Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia.

Publication Date: 2010 Sep PMID: 20694012
Authors: Niemeyer, C. M. - Kang, M. W. - Shin, D. H. - Furlan, I. - Erlacher, M. - Bunin, N. J. - Bunda, S. - Finklestein, J. Z. - Sakamoto, K. M. - Gorr, T. A. - Mehta, P. - Schmid, I. - Kropshofer, G. - Corbacioglu, S. - Lang, P. J. - Klein, C. - Schlegel, P. G. - Heinzmann, A. - Schneider, M. - Stary, J. - van den Heuvel-Eibrink, M. M. - Hasle, H. - Locatelli, F. - Sakai, D. - Archambeault, S. - Chen, L. - Russell, R. C. - Sybingco, S. S. - Ohh, M. - Braun, B. S. - Flotho, C. - Loh, M. L.
Journal: Nat Genet

CBL encodes a member of the Cbl family of proteins, which functions as an E3 ubiquitin ligase. We describe a dominant developmental disorder resulting from germline missense CBL mutations, which is characterized by impaired growth, developmental delay, cryptorchidism and a predisposition to juvenile myelomonocytic leukemia (JMML). Some individuals experienced spontaneous regression of their JMML but developed vasculitis later in life. Importantly, JMML specimens from affected children show loss of the normal CBL allele through acquired isodisomy. Consistent with these genetic data, the common p.371Y>H altered Cbl protein induces cytokine-independent growth and constitutive phosphorylation of ERK, AKT and S6 only in hematopoietic cells in which normal Cbl expression is reduced by RNA interference. We conclude that germline CBL mutations have developmental, tumorigenic and functional consequences that resemble disorders that are caused by hyperactive Ras/Raf/MEK/ERK signaling and include neurofibromatosis type 1, Noonan syndrome, Costello syndrome, cardiofaciocutaneous syndrome and Legius syndrome.

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Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency.

Publication Date: 2010 Sep PMID: 20694011
Authors: Ferreira, R. C. - Pan-Hammarstrom, Q. - Graham, R. R. - Gateva, V. - Fontan, G. - Lee, A. T. - Ortmann, W. - Urcelay, E. - Fernandez-Arquero, M. - Nunez, C. - Jorgensen, G. - Ludviksson, B. R. - Koskinen, S. - Haimila, K. - Clark, H. F. - Klareskog, L. - Gregersen, P. K. - Behrens, T. W. - Hammarstrom, L.
Journal: Nat Genet

To understand the genetic predisposition to selective immunoglobulin A deficiency (IgAD), we performed a genome-wide association study in 430 affected individuals (cases) from Sweden and Iceland and 1,090 ethnically matched controls, and we performed replication studies in two independent European cohorts. In addition to the known association of HLA with IgAD, we identified association with a nonsynonymous variant in IFIH1 (rs1990760G>A, P = 7.3 x 10(-10)) which was previously associated with type 1 diabetes and systemic lupus erythematosus. Variants in CLEC16A, another known autoimmunity locus, showed suggestive evidence for association (rs6498142C>G, P = 1.8 x 10(-7)), and 29 additional loci were identified with P < 5 x 10(-5). A survey in IgAD of 118 validated non-HLA autoimmunity loci indicated a significant enrichment for association with autoimmunity loci as compared to non-autoimmunity loci (P = 9.0 x 10(-4)) or random SNPs across the genome (P < 0.0001). These findings support the hypothesis that autoimmune mechanisms may contribute to the pathogenesis of IgAD.

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Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin.

Publication Date: 2010 Sep PMID: 20676099
Authors: Borg, J. - Papadopoulos, P. - Georgitsi, M. - Gutierrez, L. - Grech, G. - Fanis, P. - Phylactides, M. - Verkerk, A. J. - van der Spek, P. J. - Scerri, C. A. - Cassar, W. - Galdies, R. - van Ijcken, W. - Ozgur, Z. - Gillemans, N. - Hou, J. - Bugeja, M. - Grosveld, F. G. - von Lindern, M. - Felice, A. E. - Patrinos, G. P. - Philipsen, S.
Journal: Nat Genet

Hereditary persistence of fetal hemoglobin (HPFH) is characterized by persistent high levels of fetal hemoglobin (HbF) in adults. Several contributory factors, both genetic and environmental, have been identified but others remain elusive. HPFH was found in 10 of 27 members from a Maltese family. We used a genome-wide SNP scan followed by linkage analysis to identify a candidate region on chromosome 19p13.12-13. Sequencing revealed a nonsense mutation in the KLF1 gene, p.K288X, which ablated the DNA-binding domain of this key erythroid transcriptional regulator. Only family members with HPFH were heterozygous carriers of this mutation. Expression profiling on primary erythroid progenitors showed that KLF1 target genes were downregulated in samples from individuals with HPFH. Functional assays suggested that, in addition to its established role in regulating adult globin expression, KLF1 is a key activator of the BCL11A gene, which encodes a suppressor of HbF expression. These observations provide a rationale for the effects of KLF1 haploinsufficiency on HbF levels.

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Genome-wide association study identifies five new susceptibility loci for prostate cancer in the Japanese population.

Publication Date: 2010 Sep PMID: 20676098
Authors: Takata, R. - Akamatsu, S. - Kubo, M. - Takahashi, A. - Hosono, N. - Kawaguchi, T. - Tsunoda, T. - Inazawa, J. - Kamatani, N. - Ogawa, O. - Fujioka, T. - Nakamura, Y. - Nakagawa, H.
Journal: Nat Genet

Prostate cancer is one of the most common malignancies in males throughout the world, and its incidence is increasing in Asian countries. We carried out a genome-wide association study and replication study using 4,584 Japanese men with prostate cancer and 8,801 control subjects. From the thirty-one associated SNPs reported in previous genome-wide association studies in European populations, we confirmed the association of nine SNPs at P < 1.0 x 10(-7) and ten SNPs at P < 0.05 in the Japanese population. The remaining 12 SNPs showed no association (P > 0.05). In addition, we report here five new loci for prostate cancer susceptibility, at 5p15 (lambda-corrected probability P(GC) = 3.9 x 10(-18)), GPRC6A/RFX6 (P(GC) = 1.6 x 10(-12)), 13q22 (P(GC) = 2.8 x 10(-9)), C2orf43 (P(GC) = 7.5 x 10(-8)) and FOXP4 (P(GC) = 7.6 x 10(-8)). These findings advance our understanding of the genetic basis of prostate carcinogenesis and also highlight the genetic heterogeneity of prostate cancer susceptibility among different ethnic populations.

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KLF1 regulates BCL11A expression and gamma- to beta-globin gene switching.

Publication Date: 2010 Sep PMID: 20676097
Authors: Zhou, D. - Liu, K. - Sun, C. W. - Pawlik, K. M. - Townes, T. M.
Journal: Nat Genet

We show that knockdown of KLF1 in human and mouse adult erythroid progenitors markedly reduces BCL11A levels and increases human gamma-globin/beta-globin expression ratios. These results suggest that KLF1 controls globin gene switching by directly activating beta-globin and indirectly repressing gamma-globin gene expression. Controlled knockdown of KLF1 in adult erythroid progenitors may provide a method to activate fetal hemoglobin expression in individuals with beta-thalassemia or sickle cell disease.

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Genome-wide association study identifies 1p36.22 as a new susceptibility locus for hepatocellular carcinoma in chronic hepatitis B virus carriers.

Publication Date: 2010 Sep PMID: 20676096
Authors: Zhang, H. - Zhai, Y. - Hu, Z. - Wu, C. - Qian, J. - Jia, W. - Ma, F. - Huang, W. - Yu, L. - Yue, W. - Wang, Z. - Li, P. - Zhang, Y. - Liang, R. - Wei, Z. - Cui, Y. - Xie, W. - Cai, M. - Yu, X. - Yuan, Y. - Xia, X. - Zhang, X. - Yang, H. - Qiu, W. - Yang, J. - Gong, F. - Chen, M. - Shen, H. - Lin, D. - Zeng, Y. X. - He, F. - Zhou, G.
Journal: Nat Genet

To identify susceptibility variants for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we conducted a genome-wide association study by genotyping 440,794 SNPs in 355 chronic HBV carriers with HCC and 360 chronic HBV carriers without HCC, all of Chinese ancestry. We identified one intronic SNP (rs17401966) in KIF1B on chromosome 1p36.22 that was highly associated with HBV-related HCC and confirmed this association in five additional independent samples, consisting of 1,962 individuals with HCC, 1,430 control subjects and 159 family trios. Across the six studies, the association with rs17401966 was highly statistically significant (joint odds ratio = 0.61, P = 1.7 x 10(-18)). In addition to KIF1B, the association region tagged two other plausible causative genes, UBE4B and PGD. Our findings provide evidence that the 1p36.22 locus confers susceptibility to HBV-related HCC, and suggest that KIF1B-, UBE4B- or PGD-related pathways might be involved in the pathogenesis of this malignancy.

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