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Systems models and biomarker studies both pose the problem of wrangling high information content. Such publications can be made easier to review and to use if they propose explicit alternative hypotheses and show experimental exclusion of each competing explanation. In practice, we will need to be able to identify and independently cite multiple hypotheses and related experiments within a published work.
Advances in analytical biochemistry have recently made it possible to obtain global snapshots of metabolism. A new study couples such technology with genome-wide genetic analysis to explore inherited variation in human metabolism.
Scapuloperoneal spinal muscular atrophy and Charcot-Marie-Tooth disease type 2C are inherited neurodegenerative diseases characterized by sensory defects and muscle weakness. Three new studies demonstrate that they are allelic disorders caused by mutations in the vanilloid transient receptor potential cation-channel gene TRPV4.
A new study now reports recurrent somatic mutation of EZH2, a histone methyltransferase that modifies H3K27, in diffuse large B-cell lymphoma (DLBCL). There is now evidence for both increased and decreased activity of enzymes controlling H3K27 methylation in cancer, suggesting that a precise balance of this methylation is critical for normal cell growth.
The MAGIC investigators report results of a large genome-wide association study meta-analysis to identify common variants influencing fasting glucose homeostasis. They further show that several of the newly discovered loci influencing glycemic traits are also associated with risk of type 2 diabetes.
Hilma Holm and colleagues report genome-wide association studies to electrocardiographic measures of heart rate, PR interval, QRS duration and QT interval.
Matthew Brown, John Reveille and colleagues report a genome-wide association study for ankylosing spondylitis. They identify four genetic loci outside of the MHC newly associated to AS susceptibility.
Francis McMahon and colleagues report a meta-analysis of genome-wide association data sets for major mood disorders, including bipolar disorder and major depressive disorder.
Richard Houlston and colleagues identify common variants at four loci associated with risk of chronic lymphocytic leukemia, including a coding variant in FARP2 on 2q37.3 and a noncoding variant in the region upstream of MYC on 8q24.21.
Richard Watanabe and colleagues of the MAGIC consortium report meta-analyses of genome-wide association studies to glucose levels two hours after an oral glucose challenge. They identify variants in GIPR associated with glucose and insulin responses.
John Chambers and colleagues report genome-wide association studies to several ECG measurements, identifying an association of SCN10A to PR interval. They find that Scn10a−/− mice show a shorter PR interval.
Arne Pfeufer and colleagues report a genome-wide association study of the electrocardiographic measurement of PR interval in seven population-based cohorts in the CHARGE consortium. They identify nine loci associated with PR interval and highlight candidate genes with a role in ion channels and cardiac development.
Michaela Auer-Grumbach and colleagues report that missense alterations in the N-terminal ankyrin domain of TRPV4 underlie three distinct autosomal dominant disorders of the peripheral nervous system. Alterations in other regions of TRPV4 have been shown to underlie a family of autosomal dominant skeletal dysplasias, underscoring the marked clinical heterogeneity associated with mutations in this channel.
Han-Xiang Deng, Teepu Siddique and colleagues report that scapuloperoneal spinal muscular atrophy and hereditary motor and sensory neuropathy type IIC are allelic disorders caused by mutations in TRPV4. Their functional studies indicate that the mutations result in increased calcium channel activity.
Charlotte Sumner and colleagues report that mutations in the ankyrin repeat region of TRPV4 cause Charcot-Marie-Tooth disease type 2C. Their functional studies indicate that the mutations result in increased channel activity.
Joseph Gleeson and colleagues show that Ahi1 is required in mice for retinal outer segment development and displays dosage-sensitive genetic interactions with Nphp1. They further show that a missense allele of AHI1 in humans modifies risk of retinal degeneration among individuals with nephronophthisis.
Marco Marra and colleagues identify somatic mutations in EZH2 in diffuse large B-cell lymphomas and follicular lymphomas. EZH2 is a histone methyltransferase that participates in trimethylation of H3 Lys27 (H3K27) as part of the PRC2 complex. The mutations alter a single tyrosine residue in the SET domain of EZH2 and reduce the ability of PRC2 to trimethylate H3K27 in vitro.