Volume 44 Issue 3, March 2012

A new study refines the association signals for rheumatoid arthritis susceptibility in the major histocompatibility complex (MHC) region to five amino-acid positions encoded in three HLA genes, all within peptide-binding grooves. By adapting statistical methods from genome-wide association studies (GWAS) and using imputation from a large reference panel, they demonstrate the potential for this approach to identify functional variants in associated regions.

A new study reports a comprehensive survey of genetic diversity in natural populations of the nematode Caenorhabditis elegans. Their analyses suggest that recent chromosome-scale selective sweeps have reduced C. elegans genetic diversity worldwide and strongly structured genetic variation across its genome.

Mutations in CTC1, which encodes a key telomere component, have been identified as the cause of Coats plus syndrome. This discovery provides an important pathophysiological link between Coats plus and the clinically related telomere disorders dyskeratosis congenita, Revesz syndrome and Hoyeraal-Hreidarsson syndrome.

Gil McVean and Iain Mathieson report an analysis of the differential effects of population stratification on rare and common variants within association studies. They find that rare variants may show stronger stratification in some situations and that this is not corrected for by current structure methods, suggesting the need for the development of new statistical methods.

Naomi Wray, Peter Visscher and colleagues report analyses of the common variation that contributes to schizophrenia risk within three independent case-control datasets from the Psychiatric GWAS Consortium for schizophrenia. They estimate that 23% of the variation in liability to schizophrenia is captured by SNPs on current platforms.

Suzanne Baker and colleagues sequenced the whole genomes of seven pediatric brainstem glioblastomas and matched normal tissue. They found that 78% of diffuse intrinsic pontine gliomas and 22% of non-brainstem pediatric glioblastomas contained a mutation in H3F3A, encoding histone H3.3, or in the related HIST1H3B, encoding histone H3.1, causing a p.Lys27Met amino acid substitution in each protein.

Xue Zhang, Jing Yu Liu and colleagues report SLC20A2 mutations in familial idiopathic basal ganglia calcification (IBGC, also known as Fahr disease). These mutations impair the function of the type III phosphate transporter encoded by SLA20A2 and may disturb phosphate homeostasis in the body.

Christian Meyer and colleagues follow a previously reported GWAS for tuberculosis susceptibility with association analyses using 1000 Genomes Project imputation in two African studies and replication in Indonesian and Russian cohorts. They identify a new tuberculosis susceptibility locus on chromosome 11p13.

Kathryn Lunetta and colleagues report a meta-analysis of 22 genome-wide association studies for age at menopause. They identify 13 loci newly associated with age at natural menopause, including several candidate genes with roles in DNA repair and immune function.

Samuli Ripatti and colleagues report a genome-wide association study for human serum metabolites using NMR of serum samples from over 8,000 Finnish individuals. They identify 31 loci associated with at least one of 216 serum metabolic measures.

Eamonn Maher and colleagues report germline mutations in DIS3L2 causing the Perlman syndrome of overgrowth and susceptibility to Wilms tumor. DIS3L2 encodes a protein with exoribonuclease activity in the RNA exosome complex.

Leonid Kruglyak and colleagues report high-throughput selective sequencing of a worldwide collection of 200 wild C. elegans strains, providing a comprehensive characterization of genetic variation in this species. They find that chromosome-scale selective sweeps have acted to reduce genetic variation and shape the C. elegans population structure in recent history.

Soumya Raychaudhuri, Paul de Bakker and colleagues report fine mapping of the rheumatoid arthritis associations within the MHC by combining genome-wide SNP data and imputation of classical HLA alleles and SNPs across the MHC. They identify five amino acid positions in HLA-DRβ1, HLA-B and HLA-DPβ1 that together can explain most of the MHC association to seropositive rheumatoid arthritis.

Philippe Froguel, Ralf Jockers and colleagues report the functional characterization of 40 rare protein-coding variants of the MTNR1B gene (encoding melatonin receptor 1B, also known as MT₂). They find that functionally impaired MT₂ melatonin receptors confer higher risk to type 2 diabetes in Europeans.

Yukinori Okada and colleagues report a genome-wide association study for body mass index (BMI) in east Asians. They identify genetic variants associated with BMI near CDKAL1 and KLF9.

Xiao-Ou Shu and colleagues report a meta-analysis of genome-wide association studies for body mass index (BMI) in east Asians. They identify three new genetic loci associated with BMI.

Douglas Easton and colleagues report a genome-wide association analyses for breast cancer in ~70,000 cases and ~68,000 controls. They identify three new breast cancer susceptibility loci, two of which show association only with estrogen receptor–positive disease.

Julius Gudmundsson and colleagues report a genome-wide association study for circulating levels of thyroid-stimulating hormone in 27,758 individuals not known to have thyroid cancer. They follow with thyroid cancer association analyses and identify common variants at three loci newly associated with susceptibility to thyroid cancer.

Olivier Delattre and colleagues report a genome-wide association study of Ewing sarcoma. They identify common variants near TARDBP and EGR2 influencing susceptibility to this rare pediatric tumor.

Hugh Markus, Peter Donnelly and colleagues report a genome-wide association study for ischemic stroke. They identify a SNP in HDAC9, a histone deacetylase gene, that is associated with large vessel ischemic stroke and suggest subtype-specific associations to ischemic stroke.

Bjark Feenstra, Mads Melbye and colleagues report the association of three SNPs with infantile hypertrophic pyloric stenosis, a common digestive system disorder in newborns. The associated SNPs are located near MBNL1 and NKX2-5.

Yanick Crow and colleagues show that mutations in CTC1, which encodes a homolog of a yeast telomere maintenance protein, cause Coats plus, a highly pleiotropic disorder sharing phenotypic overlap with dyskeratosis congenita and other disorders of telomere maintenance.

Benoit Bruneau and colleagues show that Ezh2 stabilizes cardiac gene expression and prevents postnatal heart pathology by repressing the homeodomain transcription factor Six1 in differentiating cardiac progenitors. Their results suggest that epigenetic dysregulation in embryonic progenitor cells can predispose to adult disease.

Jeremy Green and colleagues determine that the mechanism establishing the pattern of rugae on the embryonic vertebrate palate is an activator-inhibitor reaction-diffusion mechanism rather than an alternative pattern signaling system, such as lateral inhibition.

Peter Donnelly and colleagues report sequencing of 62 pneumococcal isolates sampled from a CDC surveillance program. They characterize five independent instances of vaccine escape recombination through capsular switches, providing insight into the role of recombination in remodeling pneumococcal genomes under selective pressure and in the population dynamics of this pathogen.