Meta-analysis identifies common variants associated with body mass index in east Asians

Multiple genetic loci associated with obesity or body mass index (BMI) have been identified through genome-wide association studies conducted predominantly in populations of European ancestry. We performed a meta-analysis of associations between BMI and approximately 2.4 million SNPs in 27,715 east Asians, which was followed by in silico and de novo replication studies in 37,691 and 17,642 additional east Asians, respectively. We identified ten BMI-associated loci at genome-wide significance (P < 5.0 × 10(-8)), including seven previously identified loci (FTO, SEC16B, MC4R, GIPR-QPCTL, ADCY3-DNAJC27, BDNF and MAP2K5) and three novel loci in or near the CDKAL1, PCSK1 and GP2 genes. Three additional loci nearly reached the genome-wide significance threshold, including two previously identified loci in the GNPDA2 and TFAP2B genes and a newly identified signal near PAX6, all of which were associated with BMI with P < 5.0 × 10(-7). Findings from this study may shed light on new pathways involved in obesity and demonstrate the value of conducting genetic studies in non-European populations.     

Detectable clonal mosaicism and its relationship to aging and cancer

In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.     

Histone deacetylases: Focus on the nervous system

Neurodegenerative disease strikes millions worldwide and there is mounting evidence suggesting that underlying the onset and progression of these debilitating diseases is inappropriate neuronal apoptosis. Recent reports have implicated a family of proteins known as histone deacetylases (HDACs) in various neuronal processes including the neuronal death program. Initial headway in this field has been made largely through the use of broad-spectrum HDAC inhibitors. In fact, pharmacological inhibition of HDAC activity has been shown to protect neurons in several models of neurodegeneration. The observation that HDAC inhibitors can have opposing effects in different paradigms of neurodegeneration suggests that individual members of the HDAC protein family may play distinct roles that could depend on the specific cell type under study. The purpose of this review is to detail work involving the use of HDAC inhibitors within the context of neurodegeneration and examine the roles of individual HDAC members in the nervous system with specific focus on neuronal cell death. Received 25 January 2007; received after revision 3 April 2007; accepted 26 April 2007     

Population genomics of human gene expression

Genetic variation influences gene expression, and this variation in gene expression can be efficiently mapped to specific genomic regions and variants. Here we have used gene expression profiling of Epstein-Barr virus-transformed lymphoblastoid cell lines of all 270 individuals genotyped in the HapMap Consortium to elucidate the detailed features of genetic variation underlying gene expression variation. We find that gene expression is heritable and that differentiation between populations is in agreement with earlier small-scale studies. A detailed association analysis of over 2.2 million common SNPs per population (5% frequency in HapMap) with gene expression identified at least 1,348 genes with association signals in cis and at least 180 in trans. Replication in at least one independent population was achieved for 37% of cis signals and 15% of trans signals, respectively. Our results strongly support an abundance of cis-regulatory variation in the human genome. Detection of trans effects is limited but suggests that regulatory variation may be the key primary effect contributing to phenotypic variation in humans. We also explore several methodologies that improve the current state of analysis of gene expression variation.     

A common genetic risk factor for colorectal and prostate cancer

Variants on chromosome 8q24 contribute risk for prostate cancer; here, we tested whether they also modulate risk for colorectal cancer. We studied 1,807 affected individuals and 5,511 controls and found that one variant, rs6983267, is also significantly associated with colorectal cancer (odds ratio = 1.22; P = 4.4 x 10(-6)) and that the apportionment of risk among the variants differs significantly between the two cancers. Comprehensive testing in the region uncovered variants capturing significant additional risk. Our results show that variants at 8q24 have different effects on cancer development that depend on the tissue type.     

Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible

Nephrotic syndrome, a malfunction of the kidney glomerular filter, leads to proteinuria, edema and, in steroid-resistant nephrotic syndrome, end-stage kidney disease. Using positional cloning, we identified mutations in the phospholipase C epsilon gene (PLCE1) as causing early-onset nephrotic syndrome with end-stage kidney disease. Kidney histology of affected individuals showed diffuse mesangial sclerosis (DMS). Using immunofluorescence, we found PLCepsilon1 expression in developing and mature glomerular podocytes and showed that DMS represents an arrest of normal glomerular development. We identified IQ motif-containing GTPase-activating protein 1 as a new interaction partner of PLCepsilon1. Two siblings with a missense mutation in an exon encoding the PLCepsilon1 catalytic domain showed histology characteristic of focal segmental glomerulosclerosis. Notably, two other affected individuals responded to therapy, making this the first report of a molecular cause of nephrotic syndrome that may resolve after therapy. These findings, together with the zebrafish model of human nephrotic syndrome generated by plce1 knockdown, open new inroads into pathophysiology and treatment mechanisms of nephrotic syndrome.     

Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection

Aicardi-Goutières syndrome (AGS) is an autosomal recessive neurological disorder, the clinical and immunological features of which parallel those of congenital viral infection. Here we define the composition of the human ribonuclease H2 enzyme complex and show that AGS can result from mutations in the genes encoding any one of its three subunits. Our findings demonstrate a role for ribonuclease H in human neurological disease and suggest an unanticipated relationship between ribonuclease H2 and the antiviral immune response that warrants further investigation.     

Active formation of 'chaos terrain' over shallow subsurface water on Europa

Europa, the innermost icy satellite of Jupiter, has a tortured young surface and sustains a liquid water ocean below an ice shell of highly debated thickness. Quasi-circular areas of ice disruption called chaos terrains are unique to Europa, and both their formation and the ice-shell thickness depend on Europa's thermal state. No model so far has been able to explain why features such as Conamara Chaos stand above surrounding terrain and contain matrix domes. Melt-through of a thin (few-kilometre) shell is thermodynamically improbable and cannot raise the ice. The buoyancy of material rising as either plumes of warm, pure ice called diapirs or convective cells in a thick (>10 kilometres) shell is insufficient to produce the observed chaos heights, and no single plume can create matrix domes. Here we report an analysis of archival data from Europa, guided by processes observed within Earth's subglacial volcanoes and ice shelves. The data suggest that chaos terrains form above liquid water lenses perched within the ice shell as shallow as 3?kilometres. Our results suggest that ice-water interactions and freeze-out give rise to the diverse morphologies and topography of chaos terrains. The sunken topography of Thera Macula indicates that Europa is actively resurfacing over a lens comparable in volume to the Great Lakes in North America.     

Heterodimeric JAK-STAT activation as a mechanism of persistence to JAK2 inhibitor therapy

The identification of somatic activating mutations in JAK2 (refs?1–4) and in the thrombopoietin receptor gene (MPL) in most patients with myeloproliferative neoplasm (MPN) led to the clinical development of JAK2 kinase inhibitors. JAK2 inhibitor therapy improves MPN-associated splenomegaly and systemic symptoms but does not significantly decrease or eliminate the MPN clone in most patients with MPN. We therefore sought to characterize mechanisms by which MPN cells persist despite chronic inhibition of JAK2. Here we show that JAK2 inhibitor persistence is associated with reactivation of JAK–STAT signalling and with heterodimerization between activated JAK2 and JAK1 or TYK2, consistent with activation of JAK2 in trans by other JAK kinases. Further, this phenomenon is reversible: JAK2 inhibitor withdrawal is associated with resensitization to JAK2 kinase inhibitors and with reversible changes in JAK2 expression. We saw increased JAK2 heterodimerization and sustained JAK2 activation in cell lines, in murine models and in patients treated with JAK2 inhibitors. RNA interference and pharmacological studies show that JAK2-inhibitor-persistent cells remain dependent on JAK2 protein expression. Consequently, therapies that result in JAK2 degradation retain efficacy in persistent cells and may provide additional benefit to patients with JAK2-dependent malignancies treated with JAK2 inhibitors.