Research articles

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.

Kari Stefansson and colleagues report results of a genome-wide association study for urinary bladder cancer. The strongest association was with a variant on 8q24, located 30 kb upstream of MYC in a haplotype block distinct from previously reported 8q24 cancer risk variants.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

Gil McVean and colleagues examine recombination hot spots in the human genome, using new search methods and drawing on HapMap II to identify an extended family of hot spot–associated motifs. They report a common sequence motif estimated to be found in ∼40% of recombination hot spots.

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.

Mark Daly, Ramnik Xavier and colleagues report that a 20-kb deletion polymorphism upstream of IRGM is associated with altered IRGM expression and Crohn's disease. They also show that manipulation of IRGM levels in cells modulated the efficiency of autophagic responses to internalized bacteria, suggesting a mechanism by which the deletion variant might influence disease risk.

Pamela Sklar and colleagues report a genome-wide association study of bipolar disorder and identify variants in the genes encoding ankyrin-3 and the alpha-1C subunit of the L-type voltage-gated calcium channel as increasing risk.

Masato Kasuga and colleagues and Shiro Maeda and colleagues each report the independent identification of SNPs in KCNQ1 associated with type 2 diabetes in the Japanese population. Each group replicated the associations in other populations of East Asian and European descent.

Frank Baas and colleagues report mutations in three of the four subunits of the tRNA-splicing endonuclease complex in families with two subtypes of pontocerebellar hypoplasia. The findings implicate tRNA processing in neurological disorders.