New handles on genomic structural variation - p1143

doi:10.1038/ng1008-1143

Procedures for genotyping structural variants with SNP detection arrays now permit many of the larger and more common polymorphisms to be incorporated into association studies.

Abstract - | Full Text - New handles on genomic structural variation | PDF (76 KB) - New handles on genomic structural variation

Kidney disease and African ancestry - pp1145 - 1146

Martin R Pollak

doi:10.1038/ng1008-1145

Mapping by admixture linkage disequilibrium (MALD) leverages differences in disease frequencies among ancestry groups to map disease-susceptibility loci on the basis of genetic admixture. Two new studies use MALD to identify variation at the MYH9 locus as a major factor for the increased risk of nondiabetic kidney disease in African Americans.

Abstract - | Full Text - Kidney disease and African ancestry | PDF (196 KB) - Kidney disease and African ancestry

See also: Article by Kopp et al. | Article by Kao et al.

Pristionchus pacificus: an appropriate fondness for beetles - pp1146 - 1147

Jagan Srinivasan & Paul W Sternberg

doi:10.1038/ng1008-1146

The nematode Pristionchus pacificus associates with one particular beetle and eats its rotting corpse. The report of the genome sequence of P. pacificus, the fifth nematode to be sequenced and a useful secondary nematode genetic model system, highlights genes that may have influenced the route to parasitism.

Abstract - | Full Text - Pristionchus pacificus: an appropriate fondness for beetles | PDF (182 KB) - Pristionchus pacificus: an appropriate fondness for beetles

See also: Article by Dieterich et al.

Casting an eye on the Krebs cycle - pp1148 - 1149

Arnold Munnich

doi:10.1038/ng1008-1148

A new study identifies recessive, loss-of-function mutations in IDH3B, encoding a subunit of the NAD-specific isocitrate dehydrogenase, in individuals with retinitis pigmentosa. The lack of any obvious clinical signs in other tissues in these individuals forces a reassessment of the physiological role of this enzyme outside of the retina.

Abstract - | Full Text - Casting an eye on the Krebs cycle | PDF (139 KB) - Casting an eye on the Krebs cycle

See also: Letter by Hartong et al.

Kras and Hras—what is the difference? - pp1149 - 1150

Anton Berns

doi:10.1038/ng1008-1149

Kras, Hras or Nras mutations occur at varying frequencies across different tumors in humans for unknown reasons. A new study shows that, in mice, locus-specific regulatory elements determine whether mutations in Hras or Kras will predominate in lung and skin tumors.

Abstract - | Full Text - Kras and Hras—what is the difference? | PDF (139 KB) - Kras and Hras—what is the difference?

See also: Letter by To et al.

Research highlights - p1151

doi:10.1038/ng1008-1151

Full Text - Research highlights | PDF (72 KB) - Research highlights

Evidence for two independent prostate cancer risk–associated loci in the HNF1B gene at 17q12 - pp1153 - 1155

Jielin Sun, Siqun Lilly Zheng, Fredrik Wiklund, Sarah D Isaacs, Lina D Purcell, Zhengrong Gao, Fang-Chi Hsu, Seong-Tae Kim, Wennuan Liu, Yi Zhu, Pär Stattin, Hans-Olov Adami, Kathleen E Wiley, Latchezar Dimitrov, Jishan Sun, Tao Li, Aubrey R Turner, Tamara S Adams, Jan Adolfsson, Jan-Erik Johansson, James Lowey, Bruce J Trock, Alan W Partin, Patrick C Walsh, Jeffrey M Trent, David Duggan, John Carpten, Bao-Li Chang, Henrik Grönberg, William B Isaacs & Jianfeng Xu

doi:10.1038/ng.214

William Isaacs and colleagues report evidence for a second prostate cancer risk locus in the HNF1B gene at 17q12, 26 kb from the previously reported risk locus in this region. The two loci are separated by a recombination hot spot and contribute independently to prostate cancer risk.

Abstract - | Full Text - Evidence for two independent prostate cancer risk–associated loci in the HNF1B gene at 17q12 | PDF (189 KB) - Evidence for two independent prostate cancer risk–associated loci in the HNF1B gene at 17q12 | Supplementary information

Rheumatoid arthritis susceptibility loci at chromosomes 10p15, 12q13 and 22q13 - pp1156 - 1159

Anne Barton, Wendy Thomson, Xiayi Ke, Steve Eyre, Anne Hinks, John Bowes, Darren Plant, Laura J Gibbons, Wellcome Trust Case Control Consortium, YEAR Consortium, BIRAC Consortium, Anthony G Wilson, Deborah E Bax, Ann W Morgan, Paul Emery, Sophia Steer, Lynne Hocking, David M Reid, Paul Wordsworth, Pille Harrison & Jane Worthington

doi:10.1038/ng.218

Jane Worthington and colleagues report that three SNPs, located on chromosomes 10p15, 12q13 and 22q13, are associated with susceptibility to rheumatoid arthritis. These SNPs had previously been putatively associated with rheumatoid arthritis in the genome-wide association study conducted by the Wellcome Trust Case Control Consortium.

Abstract - | Full Text - Rheumatoid arthritis susceptibility loci at chromosomes 10p15, 12q13 and 22q13 | PDF (120 KB) - Rheumatoid arthritis susceptibility loci at chromosomes 10p15, 12q13 and 22q13 | Supplementary information

Common variants of FUT2 are associated with plasma vitamin B₁₂ levels - pp1160 - 1162

Aditi Hazra, Peter Kraft, Jacob Selhub, Edward L Giovannucci, Gilles Thomas, Robert N Hoover, Stephen J Chanock & David J Hunter

doi:10.1038/ng.210

David Hunter and colleagues report the discovery of associations between variants in FUT2 and plasma vitamin B12 levels. FUT2 encodes ,1,2-fucosyltransferase and is the classic human secretor locus that determines the secretion status of ABO blood group antigens.

Abstract - | Full Text - Common variants of FUT2 are associated with plasma vitamin B12 levels | PDF (176 KB) - Common variants of FUT2 are associated with plasma vitamin B12 levels | Supplementary information

MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity - pp1163 - 1165

Thomas Müller, Michael W Hess, Natalia Schiefermeier, Kristian Pfaller, Hannes L Ebner, Peter Heinz-Erian, Hannes Ponstingl, Joachim Partsch, Barbara Röllinghoff, Henrik Köhler, Thomas Berger, Henning Lenhartz, Barbara Schlenck, Roderick J Houwen, Christopher J Taylor, Heinz Zoller, Silvia Lechner, Olivier Goulet, Gerd Utermann, Frank M Ruemmele, Lukas A Huber & Andreas R Janecke

doi:10.1038/ng.225

Andreas Janecke and colleagues identify mutations in MYO5B, encoding the type Vb myosin motor protein, in individuals with microvillus inclusion disease, implicating myosin Vb as a key regulator of epithelial cell polarity.

Abstract - | Full Text - MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity | PDF (259 KB) - MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity | Supplementary information

Integrated detection and population-genetic analysis of SNPs and copy number variation - pp1166 - 1174

Steven A McCarroll, Finny G Kuruvilla, Joshua M Korn, Simon Cawley, James Nemesh, Alec Wysoker, Michael H Shapero, Paul I W de Bakker, Julian B Maller, Andrew Kirby, Amanda L Elliott, Melissa Parkin, Earl Hubbell, Teresa Webster, Rui Mei, James Veitch, Patrick J Collins, Robert Handsaker, Steve Lincoln, Marcia Nizzari, John Blume, Keith W Jones, Rich Rava, Mark J Daly, Stacey B Gabriel & David Altshuler

doi:10.1038/ng.238

David Altshuler and colleagues report the design of a hybrid SNP-CNV genotyping array (Affymetrix SNP 6.0 Array) allowing for integrated SNP and CNV detection. They describe its application to 270 HapMap samples to compile a high-resolution map of over 1,500 copy number polymorphisms, and related population-genetic analyses.

Abstract - | Full Text - Integrated detection and population-genetic analysis of SNPs and copy number variation | PDF (532 KB) - Integrated detection and population-genetic analysis of SNPs and copy number variation | Supplementary information

MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis - pp1175 - 1184

Jeffrey B Kopp, Michael W Smith, George W Nelson, Randall C Johnson, Barry I Freedman, Donald W Bowden, Taras Oleksyk, Louise M McKenzie, Hiroshi Kajiyama, Tejinder S Ahuja, Jeffrey S Berns, William Briggs, Monique E Cho, Richard A Dart, Paul L Kimmel, Stephen M Korbet, Donna M Michel, Michele H Mokrzycki, Jeffrey R Schelling, Eric Simon, Howard Trachtman, David Vlahov & Cheryl A Winkler

doi:10.1038/ng.226

Cheryl Winkler and colleagues use admixture mapping to identify risk variants in MYH9 associated with focal segmental glomerulosclerosis and end-stage renal disease in African Americans. The risk variants are more common in populations with West African ancestry and contribute to the excess burden of end-stage kidney diseases in these populations. A similar finding is reported in an accompanying paper by Linda Kao and colleagues.

Abstract - | Full Text - MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis | PDF (419 KB) - MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis | Supplementary information

See also: News and Views by Pollak | Article by Kao et al.

MYH9 is associated with nondiabetic end-stage renal disease in African Americans - pp1185 - 1192

W H Linda Kao, Michael J Klag, Lucy A Meoni, David Reich, Yvette Berthier-Schaad, Man Li, Josef Coresh, Nick Patterson, Arti Tandon, Neil R Powe, Nancy E Fink, John H Sadler, Matthew R Weir, Hanna E Abboud, Sharon G Adler, Jasmin Divers, Sudha K Iyengar, Barry I Freedman, Paul L Kimmel, William C Knowler, Orly F Kohn, Kristopher Kramp, David J Leehey, Susanne B Nicholas, Madeleine V Pahl, Jeffrey R Schelling, John R Sedor, Denyse Thornley-Brown, Cheryl A Winkler, Michael W Smith & Rulan S Parekh, on behalf of the Family Investigation of Nephropathy and Diabetes (FIND) Research Group

doi:10.1038/ng.232

Linda Kao and colleagues use admixture mapping to identify risk variants in MYH9 associated with nondiabetic end-stage renal disease in African Americans. The risk variants are more common in populations with West African ancestry and contribute to the excess burden of end-stage kidney diseases in these populations. A similar finding is reported in an accompanying paper by Cheryl Winkler and colleagues.

Abstract - | Full Text - MYH9 is associated with nondiabetic end-stage renal disease in African Americans | PDF (484 KB) - MYH9 is associated with nondiabetic end-stage renal disease in African Americans | Supplementary information

See also: News and Views by Pollak | Article by Kopp et al.

The Pristionchus pacificus genome provides a unique perspective on nematode lifestyle and parasitism - pp1193 - 1198

Christoph Dieterich, Sandra W Clifton, Lisa N Schuster, Asif Chinwalla, Kimberly Delehaunty, Iris Dinkelacker, Lucinda Fulton, Robert Fulton, Jennifer Godfrey, Pat Minx, Makedonka Mitreva, Waltraud Roeseler, Huiyu Tian, Hanh Witte, Shiaw-Pyng Yang, Richard K Wilson & Ralf J Sommer

doi:10.1038/ng.227

Ralf Sommer and colleagues present a draft genome sequence of the nematode Pristionchus pacificus, a species that lives in association with beetles and shows a major expansion of protein-coding genes. Comparative analysis with the genomes of the ecologically distinct nematodes C. elegans and B. malayi suggests insights into the association between their genome structures and differing lifestyles.

Abstract - | Full Text - The Pristionchus pacificus genome provides a unique perspective on nematode lifestyle and parasitism | PDF (307 KB) - The Pristionchus pacificus genome provides a unique perspective on nematode lifestyle and parasitism | Supplementary information

See also: News and Views by Srinivasan & Sternberg

Systematic assessment of copy number variant detection via genome-wide SNP genotyping - pp1199 - 1203

Gregory M Cooper, Troy Zerr, Jeffrey M Kidd, Evan E Eichler & Deborah A Nickerson

doi:10.1038/ng.236

Evan Eichler and colleagues present an analysis of how well current commercial SNP platforms accurately capture copy number variants (CNVs). Although they were able accurately predict from Illumina Human 1M genotype data many sites identified in their recent study assessing CNVs in nine human individuals with a fosmid paired-end sequence approach, they find that commonly used platforms offer limited coverage for a large fraction of CNVs.

First Paragraph - | Full Text - Systematic assessment of copy number variant detection via genome-wide SNP genotyping | PDF (243 KB) - Systematic assessment of copy number variant detection via genome-wide SNP genotyping | Supplementary information

A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia - pp1204 - 1210

Maria Chiara Di Bernardo, Dalemari Crowther-Swanepoel, Peter Broderick, Emily Webb, Gabrielle Sellick, Ruth Wild, Kate Sullivan, Jayaram Vijayakrishnan, Yufei Wang, Alan M Pittman, Nicola J Sunter, Andrew G Hall, Martin J S Dyer, Estella Matutes, Claire Dearden, Tryfonia Mainou-Fowler, Graham H Jackson, Geoffrey Summerfield, Robert J Harris, Andrew R Pettitt, Peter Hillmen, David J Allsup, James R Bailey, Guy Pratt, Chris Pepper, Chris Fegan, James M Allan, Daniel Catovsky & Richard S Houlston

doi:10.1038/ng.219

Richard Houlston and colleagues identify variants at six loci associated with risk of chronic lymphocytic leukemia. These findings confirm that common, low-penetrance susceptibility alleles contribute to this hematological malignancy and provide new insights into disease etiology.

First Paragraph - | Full Text - A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia | PDF (329 KB) - A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia | Supplementary information

Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease - pp1211 - 1215

Subra Kugathasan, Robert N Baldassano, Jonathan P Bradfield, Patrick M A Sleiman, Marcin Imielinski, Stephen L Guthery, Salvatore Cucchiara, Cecilia E Kim, Edward C Frackelton, Kiran Annaiah, Joseph T Glessner, Erin Santa, Tara Willson, Andrew W Eckert, Erin Bonkowski, Julie L Shaner, Ryan M Smith, F George Otieno, Nicholas Peterson, Debra J Abrams, Rosetta M Chiavacci, Robert Grundmeier, Petar Mamula, Gitit Tomer, David A Piccoli, Dimitri S Monos, Vito Annese, Lee A Denson, Struan F A Grant & Hakon Hakonarson

doi:10.1038/ng.203

Hakon Hakonarson and colleagues report the identification of two new susceptibility loci for inflammatory bowel disease (IBD). One variant is near a gene encoding tumor necrosis factor receptor subfamily member 6B and is associated with increased levels of this protein in serum from individuals with IBD.

First Paragraph - | Full Text - Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease | PDF (421 KB) - Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease | Supplementary information

Common variants at CD40 and other loci confer risk of rheumatoid arthritis - pp1216 - 1223

Soumya Raychaudhuri, Elaine F Remmers, Annette T Lee, Rachel Hackett, Candace Guiducci, Noël P Burtt, Lauren Gianniny, Benjamin D Korman, Leonid Padyukov, Fina A S Kurreeman, Monica Chang, Joseph J Catanese, Bo Ding, Sandra Wong, Annette H M van der Helm-van Mil, Benjamin M Neale, Jonathan Coblyn, Jing Cui, Paul P Tak, Gert Jan Wolbink, J Bart A Crusius, Irene E van der Horst-Bruinsma, Lindsey A Criswell, Christopher I Amos, Michael F Seldin, Daniel L Kastner, Kristin G Ardlie, Lars Alfredsson, Karen H Costenbader, David Altshuler, Tom W J Huizinga, Nancy A Shadick, Michael E Weinblatt, Niek de Vries, Jane Worthington, Mark Seielstad, Rene E M Toes, Elizabeth W Karlson, Ann B Begovich, Lars Klareskog, Peter K Gregersen, Mark J Daly & Robert M Plenge

doi:10.1038/ng.233

Robert Plenge and colleagues report the results of a meta-analysis of published genome-wide association studies that led to the identification of two previously unknown variants associated with rheumatoid arthritis.

First Paragraph - | Full Text - Common variants at CD40 and other loci confer risk of rheumatoid arthritis | PDF (472 KB) - Common variants at CD40 and other loci confer risk of rheumatoid arthritis | Supplementary information

Functional SNPs in CD244 increase the risk of rheumatoid arthritis in a Japanese population - pp1224 - 1229

Akari Suzuki, Ryo Yamada, Yuta Kochi, Tetsuji Sawada, Yukinori Okada, Koichi Matsuda, Yoichiro Kamatani, Mikako Mori, Kenichi Shimane, Yasuhiko Hirabayashi, Atsushi Takahashi, Tatsuhiko Tsunoda, Akihiko Miyatake, Michiaki Kubo, Naoyuki Kamatani, Yusuke Nakamura & Kazuhiko Yamamoto

doi:10.1038/ng.205

Kazuhiko Yamamoto and colleagues report an association of two SNPs in CD244 with increased risk of rheumatoid arthritis. These variants promote increased expression of CD244 in luciferase reporter assays.

First Paragraph - | Full Text - Functional SNPs in CD244 increase the risk of rheumatoid arthritis in a Japanese population | PDF (476 KB) - Functional SNPs in CD244 increase the risk of rheumatoid arthritis in a Japanese population | Supplementary information

Insights from retinitis pigmentosa into the roles of isocitrate dehydrogenases in the Krebs cycle - pp1230 - 1234

Dyonne T Hartong, Mayura Dange, Terri L McGee, Eliot L Berson, Thaddeus P Dryja & Roberta F Colman

doi:10.1038/ng.223

Thaddeus Dryja and colleagues identify homozygous loss-of-function mutations in IDH3B, encoding the beta subunit of the NAD-specific isocitrate dehydrogenase enzyme, in two families with retinitis pigmentosa. The absence of obvious clinical phenotypes outside of the retina suggests that the NADP-specific form of this enzyme can compensate for the absence of the NAD-specific form in most human tissues.

First Paragraph - | Full Text - Insights from retinitis pigmentosa into the roles of isocitrate dehydrogenases in the Krebs cycle | PDF (308 KB) - Insights from retinitis pigmentosa into the roles of isocitrate dehydrogenases in the Krebs cycle | Supplementary information

See also: News and Views by Munnich

A canine DNM1 mutation is highly associated with the syndrome of exercise-induced collapse - pp1235 - 1239

Edward E Patterson, Katie M Minor, Anna V Tchernatynskaia, Susan M Taylor, G Diane Shelton, Kari J Ekenstedt & James R Mickelson

doi:10.1038/ng.224

Edward Patterson and colleagues report that a missense mutation in the gene encoding dynamin 1 (DNM1) is associated with exercise-induced collapsed in Labrador retriever dogs. This is the first documented mutation in DNM1 in mammals and suggests a critical role for dynamin 1 in maintaining proper neurotransmission under conditions of high synaptic activity.

First Paragraph - | Full Text - A canine DNM1 mutation is highly associated with the syndrome of exercise-induced collapse | PDF (433 KB) - A canine DNM1 mutation is highly associated with the syndrome of exercise-induced collapse | Supplementary information

Kras regulatory elements and exon 4A determine mutation specificity in lung cancer - pp1240 - 1244

Minh D To, Christine E Wong, Anthony N Karnezis, Reyno Del Rosario, Roberto Di Lauro & Allan Balmain

doi:10.1038/ng.211

Ras family genes are common targets for somatic mutations in human cancer: KRAS is frequently mutated in lung carcinomas, whereas HRAS mutations are common in skin tumors. Allan Balmain and colleagues use genetic engineering of ras genes in mice to show that specificity for ras mutations is determined by local regulatory elements, and that Kras 4A is the major oncogenic isoform of Kras.

First Paragraph - | Full Text - Kras regulatory elements and exon 4A determine mutation specificity in lung cancer | PDF (615 KB) - Kras regulatory elements and exon 4A determine mutation specificity in lung cancer | Supplementary information

See also: News and Views by Berns

A robust statistical method for case-control association testing with copy number variation - pp1245 - 1252

Chris Barnes, Vincent Plagnol, Tomas Fitzgerald, Richard Redon, Jonathan Marchini, David Clayton & Matthew E Hurles

doi:10.1038/ng.206

Matt Hurles and colleagues present a general statistical framework for copy number variation (CNV) association tests in a case-control study design. They show that existing strategies for CNV association with binary disease phenotypes are complicated by differential errors and poor clustering quality. Here they report new methods, robust to these factors, which apply likelihood ratio testing to constrained Gaussian mixture models of quantitative CNV signals in cases and controls. Their methods are assay and platform independent, and implemented in freely available CNVtools software.

Abstract - | Full Text - A robust statistical method for case-control association testing with copy number variation | PDF (527 KB) - A robust statistical method for case-control association testing with copy number variation | Supplementary information

Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs - pp1253 - 1260

Joshua M Korn, Finny G Kuruvilla, Steven A McCarroll, Alec Wysoker, James Nemesh, Simon Cawley, Earl Hubbell, Jim Veitch, Patrick J Collins, Katayoon Darvishi, Charles Lee, Marcia M Nizzari, Stacey B Gabriel, Shaun Purcell, Mark J Daly & David Altshuler

doi:10.1038/ng.237

David Altshuler and colleagues describe analysis for integrating genotype calling of SNPs, common copy number polymorphisms and rare CNVs, implemented in a suite of software programs collectively named Birdsuite.

Abstract - | Full Text - Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs | PDF (622 KB) - Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs | Supplementary information