Volume 44 Issue 5, May 2012

Three teams have applied whole-exome and proteome methods to identify a new cofactor of human RNA polymerase II that is required for the recovery of transcription on damaged templates. The identification of this new factor raises questions about the causal relationships between molecular mechanisms of transcription regulation and excision repair and developmental and neurological disease and nonmalignant skin photosensitivity.

A new study reports the mapping of gene expression in primary immune cell subsets, showing the presence of cell type–specific cis and trans expression quantitative trait loci (eQTLs). The identification of cell type–specific trans-regulated networks can inform functional studies of susceptibility loci identified from genome-wide association studies for human complex diseases.

Eli Stahl, Robert Plenge and colleagues report the application of a polygenic analysis, using a Bayesian inference framework, to rheumatoid arthritis GWAS datasets. They find that polygenic risk scores are associated with rheumatoid arthritis case-control status and estimate the total variance explained by common variants in these GWAS. They show comparable estimates for applications to GWAS for celiac disease, myocardial infarction and coronary artery disease and type 2 diabetes.

Fernando Rivadeneira and colleagues in the Genetic Factors for Osteoporosis Consortium report a large-scale meta-analysis identifying new loci associated with bone mineral density (BMD) and risk of fracture. Thirty-two new loci are found to be associated with BMD, and 6 loci confer higher risk for low-trauma bone fracture.

Expression quantitative trait loci (eQTLs) are the genetic units of gene expression variation. Julian Knight and colleagues report an analysis of cell type–specific eQTLs from positively purified primary monocytes and B cells. Among the trans-acting eQTLs identified, they report new master regulators of gene expression, as well as autoimmune disease associations to specific HLA alleles.

Yuta Kochi and colleagues report a meta-analysis of genome-wide association studies for rheumatoid arthritis in a Japanese population. They identify nine loci newly associated with rheumatoid arthritis in this population and consider overlap of associations with previous studies in European populations.

Yoshihiro Onouchi and colleagues report the results of a genome-wide association study of Kawasaki disease. They identify three new risk loci, all mapping near genes previously implicated in adult-onset autoimmune diseases.

Jer-Yuarn Wu, Fuu-Jen Tsai, Yuan-Tsong Chen and colleagues report a genome-wide association study of Kawasaki disease. They show that common variants near BLK and CD40 influence susceptibility to this acute childhood vasculitis.

Struan Grant and colleagues perform a meta-analysis of genome-wide association studies to identify loci influencing childhood obesity. They discover variants near OLFM4 and HOXB5 associated with this trait and show that these loci are also associated with increased body mass index in adults.

Vincent Jaddoe and colleagues report a genome-wide association study for infant head circumference. They identify variants in SBNO1 and near HMGA2 that are associated with this phenotype.

M. Arfan Ikram and colleagues report a genome-wide association study for intracranial volume and brain volume. They report two loci associated with intracranial volume.

Sudha Seshadri and colleagues report a genome-wide association study for hippocampal volume. The authors identify loci at 12q14 and 12q24 associated with this phenotype.

Paul Thompson and colleagues report a genome-wide association study for hippocampal, intracranial and total brain volume. They identify a locus at 12q24 associated with hippocampal volume and a locus at 12q14 associated with intracranial volume.

Lisa Strug and colleagues report a genome-wide association study for meconium ileus in individuals with cystic fibrosis. Conventional genome-wide approaches identified variants in SLC26A9 and SLC6A14 associated with meconium ileus. The authors also performed a hypothesis-driven genome-wide association study (HD-GWAS) that upweighted 3,814 SNPs within 10 kb of 155 genes expressed in the apical plasma membrane. The HD-GWAS identified variants near SLC9A3 associated with meconium ileus.

Patrick Tan, Bin Tean Teh, Steve Rozen and colleagues report recurrent somatic mutations in the cell-adhesion gene FAT4 and the chromatin-remodeling gene ARID1A in gastric adenocarcinomas. Their data suggest that FAT4 functions as a tumor suppressor by maintaining proper cell adhesion and preventing malignant cell migration.

Kevin Campbell and colleagues identify mutations in ISPD as a cause of Walker-Warburg syndrome (WWS) using a complementation assay in fibroblasts derived from affected individuals and targeted sequencing. They find that loss-of-function mutations in ISPD disrupt dystroglycan O-mannosylation, suggesting a new disease mechanism.

Hans van Bokhoven and colleagues report mutations in the ISPD gene as a cause of Walker-Warburg syndrome. Knockdown of ispd in zebrafish causes hydrocephalus, reduced eye size, muscle degeneration and α-dystroglycan hypoglycosylation.

Tomoo Ogi and colleagues report mutations of UVSSA causing a third complementation group of the UV-sensitive syndrome. UVSSA deficiency results in defective transcription-coupled nucleotide-excision repair and failure to resolve stalled RNA polymerase IIo at DNA damage sites.

Kiyoji Tanaka and colleagues report mutations of UVSSA causing a third complementation group of UV-sensitive syndrome. UVSSA deficiency results in defective transcription-coupled nucleotide-excision repair and failure to resolve stalled RNA polymerase IIo at DNA damage sites.

Jurgen Marteijn, Wim Vermeulen and colleagues report proteomic identification of UVSSA in a UV-induced protein complex implicated in UV-sensitive syndrome. They show that knockdown of UVSSA impairs trancription-coupled nucleotide-excision repair.

Eric Schadt and colleagues report a Bayesian method to predict individual SNP genotypes based on RNA expression data. Using simulations and empirical data sets, they show that it is possible to infer a genotypic barcode specific to an individual, although the identification of an individual as a participant in a study is limited by factors such as the availability of large-scale expression quantitative trait loci (eQTLs) and expression data sets.