Volume 43 Issue 4, April 2011

A new study successfully applies complementary whole-genome sequencing and imputation approaches to establish robust disease associations in an isolated population. This strategy is poised to help elucidate the role of variants at the low end of the allele frequency spectrum in the genetic architecture of complex traits.

MicroRNAs (miRNAs) regulate expression of more than one half of the genes in the human genome. A study now reports a new method for selectively silencing whole families of miRNAs, thus providing a new paradigm for disease therapy.

New studies reveal that 20% of individuals with acute myeloid leukemia harbor somatic mutations in DNMT3A (encoding DNA methyltransferase 3A). Although these leukemias have some gene expression and DNA methylation changes, a direct link between mutant DNMT3A, epigenetic changes and pathogenesis remains to be established.

George Patrinos and colleagues report the first implementation of the microattribution approach to systematically document genetic variation associated with a disease, applied here to hemoglobinopathies and thalassemias. They developed a series of connected locus-specific databases that document genotype and phenotype information for genetic variation in 37 globin and erythroid protein genes in individuals with globin disorders, with reciprocal attribution to data contributors.

Richard Trembath and colleagues show that mutations in NOTCH2 cause Hajdu-Cheney syndrome, a multisystem disorder marked by severe and progressive bone loss. The mutations are predicted to result in elevated NOTCH2 signaling.

Cédric Le Caignec and colleagues show that truncating mutations in the last exon of NOTCH2 cause Hajdu-Cheney syndrome, a rare disorder marked by facial anomalies, osteoporosis and multiple organ defects. The mutations are predicted to result in an increase in NOTCH2 signaling.

Zhu Chen, Sai-Juan Chen and colleagues report exome sequencing of acute monocytic leukemia, a subtype of acute myeloid leukemia. They identified somatic mutations of DNMT3A, which encodes a DNA methyltransferase, in 20% of cases.

Hilma Holm et al. report a rare missense variant MYH6 that is associated with a high risk of sick sinus syndrome in Icelanders. This heart condition is found most often in elderly people and is the most frequent reason a heart pacemaker is implanted.

Ali Gharavi, Rick Lifton and colleagues report a genome-wide association study for IgA nephropathy, a major cause of kidney failure. They identify five susceptibility loci.

Carl Anderson and colleagues report a genome-wide association study identifying 13 new susceptibility loci for primary biliary cirrhosis, a chronic autoimmune liver disease.

Heribert Schunkert and colleagues report a meta-analysis of 14 genome-wide association studies of coronary disease (CAD) followed by replication in additional cohorts. They confirm 10 previously associated loci and identify 13 loci newly associated with CAD.

The Coronary Artery Disease Genetics Consortium report a meta-analysis of genome-wide association studies for coronary artery disease (CAD) in discovery and replication cohorts including both European and South Asian studies. They identify five loci newly associated with CAD.

Qing Wang and colleagues report a genome-wide association study for coronary artery disease (CAD) in a Chinese Han population. They identify a locus on chromosome 6p24.1 newly associated with CAD.

Mark O'Driscoll, Andrew Jackson and colleagues report the identification of mutations in ORC1 in individuals with microcephalic primordial dwarfism. ORC1 encodes the largest subunit of the origin recognition complex.

Andrew Jackson, Ernie Bongers and colleagues report the identification of mutations in five genes in individuals with Meier-Gorlin syndrome. The five genes, ORC1, ORC4, ORC6, CDT1 and CDC6, all encode components of the pre-replication complex.

Mark Samuels and colleagues report the identification of mutations in ORC4, which encodes a component of the origin recognition complex, in individuals with Meier-Gorlin syndrome. The features of this syndrome include small stature, small external ears and small or absent patellae.

Birgitte Lane and colleagues show that Ferguson-Smith disease, an autosomal dominant skin cancer condition characterized by the development of multiple self-healing tumors, is caused by a disease-specific spectrum of mutations in TGFBR1.

Sakari Kauppinen and colleagues report a method for silencing miRNA families in vivo. They find that seed-targeting 8-mer LNA oligonucleotides, termed tiny LNAs, can lead to long-term miRNA silencing in normal tissues and breast tumors in mice.

Francois Spitz and colleagues report GROMIT, a Sleeping Beauty transposon–based system for mapping genetic regulatory architecture in mouse. GROMIT is a regulatory sensor that responds to the activity of nearby enhancers.