Nature Genetics. doi:10.1038/ng.484

Authors: Marielle Alders, Benjamin M Hogan, Evisa Gjini, Faranak Salehi, Lihadh Al-Gazali, Eric A Hennekam, Eva E Holmberg, Marcel M A M Mannens, Margot F Mulder, G Johan A Offerhaus, Trine E Prescott, Eelco J Schroor, Joke B G M Verheij, Merlijn Witte, Petra J Zwijnenburg, Mikka Vikkula, Stefan Schulte-Merker & Raoul C Hennekam

Lymphedema, lymphangiectasias, mental retardation and unusual facial characteristics define the autosomal recessive Hennekam syndrome. Homozygosity mapping identified a critical chromosomal region containing CCBE1, the human ortholog of a gene essential for lymphangiogenesis in zebrafish. Homozygous and compound heterozygous mutations in seven subjects paired with functional analysis in a zebrafish model identify CCBE1 as one of few genes causing primary generalized lymph-vessel dysplasia in humans.

Nature Genetics. doi:10.1038/ng.481

Authors: Marwan Shinawi, Christian P Schaaf, Samarth S Bhatt, Zhilian Xia, Ankita Patel, Sau Wai Cheung, Brendan Lanpher, Sandra Nagl, Heinrich Stephan Herding, Claudia Nevinny-Stickel, LaDonna L Immken, Gayle Simpson Patel, Jennifer Ruth German, Arthur L Beaudet & Pawel Stankiewicz

We report a recurrent 680-kb deletion within chromosome 15q13.3 in ten individuals, from four unrelated families, with neurodevelopmental phenotypes including developmental delay, mental retardation and seizures. This deletion likely resulted from nonallelic homologous recombination between low-copy repeats on the normal and inverted region of chromosome 15q13.3. Although this deletion also affects OTUD7A, accumulated data suggest that haploinsufficiency of CHRNA7 is causative for the majority of neurodevelopmental phenotypes in the 15q13.3 microdeletion syndrome.

Nature Genetics. doi:10.1038/ng.486

Authors: Rasmi Thomas, Richard Apps, Ying Qi, Xiaojiang Gao, Victoria Male, Colm O'hUigin, Geraldine O'Connor, Dongliang Ge, Jacques Fellay, Jeffrey N Martin, Joseph Margolick, James J Goedert, Susan Buchbinder, Gregory D Kirk, Maureen P Martin, Amalio Telenti, Steven G Deeks, Bruce D Walker, David Goldstein, Daniel W McVicar, Ashley Moffett & Mary Carrington

Nature Genetics. doi:10.1038/ng.499

Authors: Sarah B Ng, Kati J Buckingham, Choli Lee, Abigail W Bigham, Holly K Tabor, Karin M Dent, Chad D Huff, Paul T Shannon, Ethylin Wang Jabs, Deborah A Nickerson, Jay Shendure & Michael J Bamshad

Nature Genetics. doi:10.1038/ng.476

Authors: Benson C Lu, Cristina Cebrian, Xuan Chi, Satu Kuure, Richard Kuo, Carlton M Bates, Silvia Arber, John Hassell, Lesley MacNeil, Masato Hoshi, Sanjay Jain, Naoya Asai, Masahide Takahashi, Kai M Schmidt-Ott, Jonathan Barasch, Vivette D'Agati & Frank Costantini

Nature Genetics. doi:10.1038/ng.475

Authors: Sanwen Huang, Ruiqiang Li, Zhonghua Zhang, Li Li, Xingfang Gu, Wei Fan, William J Lucas, Xiaowu Wang, Bingyan Xie, Peixiang Ni, Yuanyuan Ren, Hongmei Zhu, Jun Li, Kui Lin, Weiwei Jin, Zhangjun Fei, Guangcun Li, Jack Staub, Andrzej Kilian, Edwin A G van der Vossen, Yang Wu, Jie Guo, Jun He, Zhiqi Jia, Yi Ren, Geng Tian, Yao Lu, Jue Ruan, Wubin Qian, Mingwei Wang, Quanfei Huang, Bo Li, Zhaoling Xuan, Jianjun Cao, Asan, Zhigang Wu, Juanbin Zhang, Qingle Cai, Yinqi Bai, Bowen Zhao, Yonghua Han, Ying Li, Xuefeng Li, Shenhao Wang, Qiuxiang Shi, Shiqiang Liu, Won Kyong Cho, Jae-Yean Kim, Yong Xu, Katarzyna Heller-Uszynska, Han Miao, Zhouchao Cheng, Shengping Zhang, Jian Wu, Yuhong Yang, Houxiang Kang, Man Li, Huiqing Liang, Xiaoli Ren, Zhongbin Shi, Ming Wen, Min Jian, Hailong Yang, Guojie Zhang, Zhentao Yang, Rui Chen, Shifang Liu, Jianwen Li, Lijia Ma, Hui Liu, Yan Zhou, Jing Zhao, Xiaodong Fang, Guoqing Li, Lin Fang, Yingrui Li, Dongyuan Liu, Hongkun Zheng, Yong Zhang, Nan Qin, Zhuo Li, Guohua Yang, Shuang Yang, Lars Bolund, Karsten Kristiansen, Hancheng Zheng, Shaochuan Li, Xiuqing Zhang, Huanming Yang, Jian Wang, Rifei Sun, Baoxi Zhang, Shuzhi Jiang, Jun Wang, Yongchen Du & Songgang Li

Nature Genetics. doi:10.1038/ng.477

Authors: Marc Monot, Nadine Honoré, Thierry Garnier, Nora Zidane, Diana Sherafi, Alberto Paniz-Mondolfi, Masanori Matsuoka, G Michael Taylor, Helen D Donoghue, Abi Bouwman, Simon Mays, Claire Watson, Diana Lockwood, Ali Khamispour, Yahya Dowlati, Shen Jianping, Thomas H Rea, Lucio Vera-Cabrera, Mariane M Stefani, Sayera Banu, Murdo Macdonald, Bishwa Raj Sapkota, John S Spencer, Jérôme Thomas, Keith Harshman, Pushpendra Singh, Philippe Busso, Alexandre Gattiker, Jacques Rougemont, Patrick J Brennan & Stewart T Cole

Nature Genetics. doi:10.1038/ng.490

Authors: Steven A McCarroll, James E Bradner, Hannu Turpeinen, Liisa Volin, Paul J Martin, Shannon D Chilewski, Joseph H Antin, Stephanie J Lee, Tapani Ruutu, Barry Storer, Edus H Warren, Bo Zhang, Lue Ping Zhao, David Ginsburg, Robert J Soiffer, Jukka Partanen, John A Hansen, Jerome Ritz, Aarno Palotie & David Altshuler

Transplantation and pregnancy, in which two diploid genomes reside in one body, can each lead to diseases in which immune cells from one individual target antigens encoded in the other's genome. One such disease, graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT, or bone marrow transplant), is common even after transplants between HLA-identical siblings, indicating that cryptic histocompatibility loci exist outside the HLA locus. The immune system of an individual whose genome is homozygous for a gene deletion could recognize epitopes encoded by that gene as alloantigens. Analyzing common gene deletions in three HSCT cohorts (1,345 HLA-identical sibling donor-recipient pairs), we found that risk of acute GVHD was greater (odds ratio (OR) = 2.5; 95% confidence interval (CI) 1.4–4.6) when donor and recipient were mismatched for homozygous deletion of UGT2B17, a gene expressed in GVHD-affected tissues and giving rise to multiple histocompatibility antigens. Human genome structural variation merits investigation as a potential mechanism in diseases of alloimmunity.

Nature Genetics. doi:10.1038/ng.482

Authors: Kouichi Asano, Tomonaga Matsushita, Junji Umeno, Naoya Hosono, Atsushi Takahashi, Takahisa Kawaguchi, Takayuki Matsumoto, Toshiyuki Matsui, Yoichi Kakuta, Yoshitaka Kinouchi, Tooru Shimosegawa, Masayo Hosokawa, Yoshiaki Arimura, Yasuhisa Shinomura, Yutaka Kiyohara, Tatsuhiko Tsunoda, Naoyuki Kamatani, Mitsuo Iida, Yusuke Nakamura & Michiaki Kubo

Ulcerative colitis is one of the principal forms of inflammatory bowel disease with complex manifestations. Although previous studies have indicated that there is a genetic contribution to the pathogenesis of ulcerative colitis, the genes influencing susceptibility to the disease have not been fully determined. To identify genetic factors conferring risk of ulcerative colitis, here we conducted a two-stage genome-wide association study and subsequent replication study using 1,384 Japanese individuals with ulcerative colitis and 3,057 control subjects. In addition to the expected strong association with the major histocompatibility complex (MHC) region, we identified three new susceptibility loci: the immunoglobulin receptor gene FCGR2A (rs1801274, P = 1.56 × 10−12), a locus on chromosome 13q12 (rs17085007, P = 6.64 × 10−8) and the glycoprotein gene SLC26A3 (rs2108225, P = 9.50 × 10−8). rs1801274 is a nonsynonymous SNP of FCGR2A that is reported to have a critical effect on receptor binding affinity for IgG and to be associated with other autoimmune diseases. Our findings provide insight into the molecular pathogenesis of ulcerative colitis.

Nature Genetics. doi:10.1038/ng.483

Authors:

Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P < 1 × 10−5 were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 × 10−17), 16q22 (CDH1 and CDH3; P = 2.8 × 10−8) and 7q31 (LAMB1; P = 3.0 × 10−8). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis.

Nature Genetics. doi:10.1038/ng.489

Authors: Marcin Imielinski, Robert N Baldassano, Anne Griffiths, Richard K Russell, Vito Annese, Marla Dubinsky, Subra Kugathasan, Jonathan P Bradfield, Thomas D Walters, Patrick Sleiman, Cecilia E Kim, Aleixo Muise, Kai Wang, Joseph T Glessner, Shehzad Saeed, Haitao Zhang, Edward C Frackelton, Cuiping Hou, James H Flory, George Otieno, Rosetta M Chiavacci, Robert Grundmeier, Massimo Castro, Anna Latiano, Bruno Dallapiccola, Joanne Stempak, Debra J Abrams, Kent Taylor, Dermot McGovern, Melvin B Heyman, George D Ferry, Barbara Kirschner, Jessica Lee, Jonah Essers, Richard Grand, Michael Stephens, Arie Levine, David Piccoli, Johan Van Limbergen, Salvatore Cucchiara, Dimitri S Monos, Stephen L Guthery, Lee Denson, David C Wilson, Struan F A Grant, Mark Daly, Mark S Silverberg, Jack Satsangi & Hakon Hakonarson

Nature Genetics. doi:10.1038/ng.485

Authors: Wataru Satake, Yuko Nakabayashi, Ikuko Mizuta, Yushi Hirota, Chiyomi Ito, Michiaki Kubo, Takahisa Kawaguchi, Tatsuhiko Tsunoda, Masahiko Watanabe, Atsushi Takeda, Hiroyuki Tomiyama, Kenji Nakashima, Kazuko Hasegawa, Fumiya Obata, Takeo Yoshikawa, Hideshi Kawakami, Saburo Sakoda, Mitsutoshi Yamamoto, Nobutaka Hattori, Miho Murata, Yusuke Nakamura & Tatsushi Toda

To identify susceptibility variants for Parkinson's disease (PD), we performed a genome-wide association study (GWAS) and two replication studies in a total of 2,011 cases and 18,381 controls from Japan. We identified a new susceptibility locus on 1q32 (P = 1.52 × 10−12) and designated this as PARK16, and we also identified BST1 on 4p15 as a second new risk locus (P = 3.94 × 10−9). We also detected strong associations at SNCA on 4q22 (P = 7.35 × 10−17) and LRRK2 on 12q12 (P = 2.72 × 10−8), both of which are implicated in autosomal dominant forms of parkinsonism. By comparing results of a GWAS performed on individuals of European ancestry, we identified PARK16, SNCA and LRRK2 as shared risk loci for PD and BST1 and MAPT as loci showing population differences. Our results identify two new PD susceptibility loci, show involvement of autosomal dominant parkinsonism loci in typical PD and suggest that population differences contribute to genetic heterogeneity in PD.

Nature Genetics. doi:10.1038/ng.487

Authors: Javier Simón-Sánchez, Claudia Schulte, Jose M Bras, Manu Sharma, J Raphael Gibbs, Daniela Berg, Coro Paisan-Ruiz, Peter Lichtner, Sonja W Scholz, Dena G Hernandez, Rejko Krüger, Monica Federoff, Christine Klein, Alison Goate, Joel Perlmutter, Michael Bonin, Michael A Nalls, Thomas Illig, Christian Gieger, Henry Houlden, Michael Steffens, Michael S Okun, Brad A Racette, Mark R Cookson, Kelly D Foote, Hubert H Fernandez, Bryan J Traynor, Stefan Schreiber, Sampath Arepalli, Ryan Zonozi, Katrina Gwinn, Marcel van der Brug, Grisel Lopez, Stephen J Chanock, Arthur Schatzkin, Yikyung Park, Albert Hollenbeck, Jianjun Gao, Xuemei Huang, Nick W Wood, Delia Lorenz, Günther Deuschl, Honglei Chen, Olaf Riess, John A Hardy, Andrew B Singleton & Thomas Gasser

We performed a genome-wide association study (GWAS) in 1,713 individuals of European ancestry with Parkinson's disease (PD) and 3,978 controls. After replication in 3,361 cases and 4,573 controls, we observed two strong association signals, one in the gene encoding α-synuclein (SNCA; rs2736990, OR = 1.23, P = 2.24 × 10−16) and another at the MAPT locus (rs393152, OR = 0.77, P = 1.95 × 10−16). We exchanged data with colleagues performing a GWAS in Japanese PD cases. Association to PD at SNCA was replicated in the Japanese GWAS, confirming this as a major risk locus across populations. We replicated the effect of a new locus detected in the Japanese cohort (PARK16, rs823128, OR = 0.66, P = 7.29 × 10−8) and provide supporting evidence that common variation around LRRK2 modulates risk for PD (rs1491923, OR = 1.14, P = 1.55 × 10−5). These data demonstrate an unequivocal role for common genetic variants in the etiology of typical PD and suggest population-specific genetic heterogeneity in this disease.

Nature Genetics. doi:10.1038/ng.480

Authors: Hiba Mahdi, Benjamin A Fisher, Henrik Källberg, Darren Plant, Vivianne Malmström, Johan Rönnelid, Peter Charles, Bo Ding, Lars Alfredsson, Leonid Padyukov, Deborah P M Symmons, Patrick J Venables, Lars Klareskog & Karin Lundberg

Gene-environment associations are important in rheumatoid arthritis (RA) susceptibility, with an association existing between smoking, HLA- DRB1 'shared epitope' alleles, PTPN22 and antibodies to cyclic citrullinated peptides(CCP). Here, we test the hypothesis that a subset of the anti-CCP response, with specific autoimmunity to citrullinated α-enolase, accounts for an important portion of these associations. In 1,497 individuals from three RA cohorts, antibodies to the immunodominant citrullinated α-enolase CEP-1 epitope were detected in 43–63% of the anti-CCP–positive individuals, and this subset was preferentially linked to HLA-DRB1*04. In a case-control analysis of 1,000 affected individuals and 872 controls, the combined effect of shared epitope, PTPN22 and smoking showed the strongest association with the anti-CEP-1–positive subset (odds ratio (OR) of 37, compared to an OR of 2 for the corresponding anti-CEP-1–negative, anti-CCP–positive subset). We conclude that citrullinated α-enolase is a specific citrullinated autoantigen that links smoking to genetic risk factors in the development of RA.

Nature Genetics. doi:10.1038/ng.479

Authors: Soumya Raychaudhuri, Brian P Thomson, Elaine F Remmers, Stephen Eyre, Anne Hinks, Candace Guiducci, Joseph J Catanese, Gang Xie, Eli A Stahl, Robert Chen, Lars Alfredsson, Christopher I Amos, Kristin G Ardlie, Anne Barton, John Bowes, Noel P Burtt, Monica Chang, Jonathan Coblyn, Karen H Costenbader, Lindsey A Criswell, J Bart A Crusius, Jing Cui, Phillip L De Jager, Bo Ding, Paul Emery, Edward Flynn, Pille Harrison, Lynne J Hocking, Tom W J Huizinga, Daniel L Kastner, Xiayi Ke, Fina A S Kurreeman, Annette T Lee, Xiangdong Liu, Yonghong Li, Paul Martin, Ann W Morgan, Leonid Padyukov, David M Reid, Mark Seielstad, Michael F Seldin, Nancy A Shadick, Sophia Steer, Paul P Tak, Wendy Thomson, Annette H M van der Helm-van Mil, Irene E van der Horst-Bruinsma, Michael E Weinblatt, Anthony G Wilson, Gert Jan Wolbink, Paul Wordsworth, David Altshuler, Elizabeth W Karlson, Rene E M Toes, Niek de Vries, Ann B Begovich, Katherine A Siminovitch, Jane Worthington, Lars Klareskog, Peter K Gregersen, Mark J Daly & Robert M Plenge

To discover new rheumatoid arthritis (RA) risk loci, we systematically examined 370 SNPs from 179 independent loci with P < 0.001 in a published meta-analysis of RA genome-wide association studies (GWAS) of 3,393 cases and 12,462 controls. We used Gene Relationships Across Implicated Loci (GRAIL), a computational method that applies statistical text mining to PubMed abstracts, to score these 179 loci for functional relationships to genes in 16 established RA disease loci. We identified 22 loci with a significant degree of functional connectivity. We genotyped 22 representative SNPs in an independent set of 7,957 cases and 11,958 matched controls. Three were convincingly validated: CD2-CD58 (rs11586238, P = 1 × 10−6 replication, P = 1 × 10−9 overall), CD28 (rs1980422, P = 5 × 10−6 replication, P = 1 × 10−9 overall) and PRDM1 (rs548234, P = 1 × 10−5 replication, P = 2 × 10−8 overall). An additional four were replicated (P < 0.0023): TAGAP (rs394581, P = 0.0002 replication, P = 4 × 10−7 overall), PTPRC (rs10919563, P = 0.0003 replication, P = 7 × 10−7 overall), TRAF6-RAG1 (rs540386, P = 0.0008 replication, P = 4 × 10−6 overall) and FCGR2A (rs12746613, P = 0.0022 replication, P = 2 × 10−5 overall). Many of these loci are also associated to other immunologic diseases.

Nature Genetics. doi:10.1038/ng.478

Authors: Colin J D Ross, Hagit Katzov-Eckert, Marie-Pierre Dubé, Beth Brooks, S Rod Rassekh, Amina Barhdadi, Yassamin Feroz-Zada, Henk Visscher, Andrew M K Brown, Michael J Rieder, Paul C Rogers, Michael S Phillips, Bruce C Carleton & Michael R Hayden

Cisplatin is a widely used and effective chemotherapeutic agent, although its use is restricted by the high incidence of irreversible ototoxicity associated with it. In children, cisplatin ototoxicity is a serious and pervasive problem, affecting more than 60% of those receiving cisplatin and compromising language and cognitive development. Candidate gene studies have previously reported associations of cisplatin ototoxicity with genetic variants in the genes encoding glutathione S-transferases and megalin. We report association analyses for 220 drug-metabolism genes in genetic susceptibility to cisplatin-induced hearing loss in children. We genotyped 1,949 SNPs in these candidate genes in an initial cohort of 54 children treated in pediatric oncology units, with replication in a second cohort of 112 children recruited through a national surveillance network for adverse drug reactions in Canada. We identified genetic variants in TPMT (rs12201199, P value = 0.00022, OR = 17.0, 95% CI 2.3–125.9) and COMT (rs9332377, P value = 0.00018, OR = 5.5, 95% CI 1.9–15.9) associated with cisplatin-induced hearing loss in children.

Nature Genetics. doi:10.1038/ng.471

Authors: Akiko Doi, In-Hyun Park, Bo Wen, Peter Murakami, Martin J Aryee, Rafael Irizarry, Brian Herb, Christine Ladd-Acosta, Junsung Rho, Sabine Loewer, Justine Miller, Thorsten Schlaeger, George Q Daley & Andrew P Feinberg