Wellcome Trust Centre for Human Genetics

About: Wellcome Trust Centre for Human Genetics is a facility organization based out in Oxford, United Kingdom. It is known for research contribution in the topics: Population & Genome-wide association study. The organization has 2122 authors who have published 4269 publications receiving 433899 citations.

TCF7L2: the biggest story in diabetes genetics since HLA?

Abstract: Much has been made over the past decade of the potential for genetics to advance our understanding of the pathogenesis of type 2 diabetes and to ‘revolutionise’ management of this condition [1]. Others have argued that these claims are premature [2]; indeed, some have questioned the contribution of genetic predisposition to the pathogenesis of common forms of type 2 diabetes [3]. In the case of relatively uncommon monogenic and syndromic forms of diabetes, such as maturity onset diabetes of the young (MODY) and neonatal diabetes, identification of rare causal mutations has delivered both knowledge and clinical translation [4, 5]. In contrast, progress in unravelling the genetic architecture of more typical, common, multifactorial type 2 diabetes has been painfully slow [6]. The reasons have been well-rehearsed [7]. The complex web of susceptibility factors—genetic, environmental, social—that contributes to individual risk of developing type 2 diabetes means that most predisposing genetic variants will have only a modest marginal impact on disease risk. The majority of genetic studies performed to date have simply had insufficient power to uncover these reliably [7]. The few type 2 diabetes-susceptibility variants convincingly demonstrated—notably the P12A variant in PPARG and E23K in KCNJ11 [8, 9]—have only modest effects on disease risk (odds ratios ~1.2), far too small to offer (either individually or in combination) clinically useful predictive testing. Since these variants lie within genes whose products are already known to be therapeutic targets, these particular discoveries have also had limited capacity to deliver novel pathophysiological insights. Among those working on the genetics of type 2 diabetes, there was growing apprehension that these two genes might be providing a representative view of the genetic architecture of type 2 diabetes. However, recent revelations concerning a novel type 2 diabetes-susceptibility gene (encoding the transcription factor, TCF7L2 [‘7-like 2’]) show that this is definitely not the case. As two papers in this issue of Diabetologia demonstrate [10, 11], common variants in this gene have a marked and reproducible effect on type 2 diabetes risk, identifying sizeable groups of individuals who differ up to twofold in their risk of developing type 2 diabetes, purely as a result of variation at a single nucleotide position within TCF7L2. These studies in Dutch [10] and Indian [11] samples are the latest in a series of reports confirming the powerful effect of TCF7L2 variation on type 2 diabetes-risk which have followed the initial publication from Iceland in early 2006 [12]. Researchers at Decode Genetics seeking the cause of a previously-identified linkage signal on chromosome 10q [13] found strong associations between type 2 diabetes status and TCF7L2 variants that they were able to replicate in samples from the USA and Denmark. The effect size in this initial report appeared substantial (each additional copy of the risk allele was associated with an odds ratio of ~1.5), and the strength of the association was impressive (p ~ 10−18 overall). Since the initial report in early 2006, the freezers of diabetes researchers worldwide have been raided and many tens of thousands of samples typed for these same variants. These studies have, without exception, confirmed those original findings. In UK samples for example, the same TCF7L2 susceptibility variants were associated with a per-allele odds ratio of ~1.4 [14]. As in the original report, there was clear evidence of a gene dosage effect, such that the 10% of individuals with two copies of the susceptibility allele were at almost twice the risk of developing diabetes as those with none. In participants from the Diabetes Prevention Program, the same TCF7L2 variants were associated with increased rates of progression from IGT to diabetes (with a hazard ratio of 1.55 between homozygote groups) [15]. Further replications have appeared from analyses in subjects of Amish [16], Finnish [17], French [18] and US [19, 20] origin. Little wonder that one colleague was moved to describe TCF7L2 as ‘the biggest story in diabetes genetics since HLA’. The speed of confirmation and reproducibility of the findings has certainly been unprecedented. All very well, you may say, that must be great for the geneticists, but what does all of this mean for our understanding of diabetes? And what difference will this make to the clinical management of this condition? In truth, it is far too early to offer an authoritative answer to such questions, but here are three immediate lessons.

Ultrafast search of all deposited bacterial and viral genomic data.

Abstract: Exponentially increasing amounts of unprocessed bacterial and viral genomic sequence data are stored in the global archives. The ability to query these data for sequence search terms would facilitate both basic research and applications such as real-time genomic epidemiology and surveillance. However, this is not possible with current methods. To solve this problem, we combine knowledge of microbial population genomics with computational methods devised for web search to produce a searchable data structure named BItsliced Genomic Signature Index (BIGSI). We indexed the entire global corpus of 447,833 bacterial and viral whole-genome sequence datasets using four orders of magnitude less storage than previous methods. We applied our BIGSI search function to rapidly find resistance genes MCR-1, MCR-2, and MCR-3, determine the host-range of 2,827 plasmids, and quantify antibiotic resistance in archived datasets. Our index can grow incrementally as new (unprocessed or assembled) sequence datasets are deposited and can scale to millions of datasets. The global set of bacterial and viral sequences can be rapidly searched using a data structure inspired by web-search algorithms.

Growing evidence for diabetes susceptibility genes from genome scan data.

Abstract: Genome-wide scans for linkage have provided one of the dominant approaches adopted by researchers in their efforts to identify genes responsible for the inherited component of type 2 diabetes susceptibility. Around 20 genome scans have now been completed, in a wide variety of populations. Integration of data from these diverse scans has proven far from trivial, but the contours of genome-wide linkage topography are steadily emerging from the fog of data. Identification of the calpain- 10 gene as the probable basis for the chromosome 2q linkage seen in Mexican Americans has provided validation of this positional cloning approach. This report provides an update on recent type 2 diabetes genome scan data, focusing on several chromosomal regions where the evidence for linkage has considerably strengthened in the past year. The current and future value of genome-wide linkage information in the search for type 2 diabetes susceptibility effects is also discussed.

PCSK6 is associated with handedness in individuals with dyslexia

Abstract: Approximately 90% of humans are right-handed Handedness is a heritable trait, yet the genetic basis is not well understood Here we report a genome-wide association study for a quantitative measure of relative hand skill in individuals with dyslexia [reading disability (RD)] The most highly associated marker, rs11855415 (P = 47 × 10-7), is located within PCSK6 Two independent cohorts with RD show the same trend, with the minor allele conferring greater relative right-hand skill Meta-analysis of all three RD samples is genome-wide significant (n = 744, P = 20 × 10-8) Conversely, in the general population (n = 2666), we observe a trend towards reduced laterality of hand skill for the minor allele (P = 00020) These results provide molecular evidence that cerebral asymmetry and dyslexia are linked Furthermore, PCSK6 is a protease that cleaves the left–right axis determining protein NODAL Functional studies of PCSK6 promise insights into mechanisms underlying cerebral lateralization and dyslexia