Volume 41 Issue 11, November 2009

Four genome-wide association studies report associations to a range of clinically relevant hematological traits. The candidate genes identified include many that are known to be important in iron homeostasis and red blood cell maturation.

Two new studies report improved statistics to predict whether an individual participated in a genome-wide association study based on aggregate allele or genotype frequency information. They demonstrate that it may be possible to release summary statistics for a subset of genetic markers in a study while maintaining individual privacy.

Epigenetic marks, such as DNA methylation and histone modifications, undergo dynamic changes during cellular differentiation and development. A new study demonstrates that DNA methylation by Dnmt1 protects essential stem cell properties in both hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) by silencing differentiation programs that interfere with self-renewal and multipotency.

John Chambers and colleagues report the association of SNPs in TMPRSS6, which encodes a regulator of hepicidin synthesis, to hemoglobin levels.

Beben Benyamin and colleagues report a genome-wide association study to iron status, identifying variants in TMPRSS6 associated with serum iron, transferrin saturation and erythrocyte volume.

Dilys Parry and colleagues show that duplications of the T gene confer susceptibility to familial chordoma, a cancer of presumed notochordal origin. The T gene product, known as brachyury, is a transcription factor that plays an important role in notochord development.

Ingo Kurth and Christian Hübner report the identification of loss-of-function mutations in FAM134B, which encodes a novel cis-Golgi protein, in hereditary sensory and autonomic neuropathy type II.

Nicole Soranzo and colleagues report a meta-analysis of genome-wide association datasets identifying 22 associations to 8 clinically relevant hematological traits. They also identify a long-range haplotype at 12q24 that includes variants associated with platelet counts as well as coronary artery disease and shows evidence of a selective sweep in Europeans.

Santhi Ganesh and colleagues report meta-analyses of genome-wide association studies of six erythrocyte traits within the CHARGE consortium, with replication in cohorts of the HaemGen consortium. They report 23 loci associated with a range of clinically relevant red blood cell traits.

Fernando Rivadeneira and colleagues report findings from a large-scale meta-analysis of genome-wide association studies for bone mineral density. The loci identified in this study map to genes in signaling pathways relevant to bone metabolism and highlight the complex genetic architecture underlying osteoporosis.

Frank Rosenbauer and colleagues show that alternative functional programs of hematopoietic stem cells are governed by gradual differences in the cellular DNA methylation level.

Tomi Pastinen and colleagues report a genome-wide analysis of allelic expression variation in lymphoblastoid cell lines from HapMap individuals.

Jonathan Sebat and colleagues report the association of microduplication on chromosome 16p11.2 with schizophrenia, while the reciprocal microdeletion was associated with autism and developmental disorders.

Robert Graham and colleagues report results of a large-scale replication study for systemic lupus erythematosus (SLE) in individuals of European ancestry. Their findings expand the number of confirmed SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.

Xuejun Zhang and colleagues report results of a genome-wide association study of systemic lupus erythematosus (SLE) in a Chinese Han population. Their work identifies nine new SLE susceptibility loci and reveals overlap in the spectrum of risk alleles shared between Chinese Han and European populations.

Matthew Meyerson and colleagues report that SOX2, which encodes a transcription factor necessary for normal esophageal development, is an amplified lineage survival oncogene in lung and esophageal squamous cell carcinomas.

Charles Mullighan and colleagues report a recurrent rearrangement of CRLF2 in B-progenitor and Down syndrome-associated acute lymphoblastic leukemia. Their genetic and functional evidence indicates that CRLF2 cooperates with activated JAK2 to promote leukemogenesis.

Andrew Wilkie and colleagues report that activating paternal-effect mutations in FGFR3 and HRAS promote clonal expansion in the testis, leading to spermatocytic seminomas. The same mutation in FGFR3 leads to the lethal disorder thanatophoric dysplasia, revealing a shared genetic mechanism for congenital disorders and testicular tumors.

Kevin Jacobs and colleagues report a new test statistic for detection of membership of an individual within a genome-wide association study, based on reporting of study genotype frequencies.