Is the NIH policy for sharing GWAS data running the risk of being counterproductive?

Through their current policy on data sharing, the National Institutes of Health (NIH) are inadvertently placing a serious and potentially insuperable burden upon non-US researchers who perform patient-based genomics studies in collaboration with US institutions. Because this policy could adversely affect future transnational scientific collaborations, we explore some of its likely consequences and suggest possible courses of remedial action wherever feasible

Likelihood ratio and posterior odds in forensic genetics: Two sides of the same coin

It has become widely accepted in forensics that, owing to a lack of sensible priors, the evidential value of matching DNA profiles in trace donor identification or kinship analysis is most sensibly communicated in the form of a likelihood ratio (LR). This restraint does not abate the fact that the posterior odds (PO) would be the preferred basis for returning a verdict. A completely different situation holds for Forensic DNA Phenotyping (FDP), which is aimed at predicting externally visible characteristics (EVCs) of a trace donor from DNA left behind at the crime scene. FDP is intended to provide leads to the police investigation helping them to find unknown trace donors that are unidentifiable by DNA profiling. The statistical models underlying FDP typically yield posterior odds (PO) for an individual possessing a certain EVC. This apparent discrepancy has led to confusion as to when LR or PO is the appropriate outcome of forensic DNA analysis to be communicated to the investigating authorities. We thus set out to clarify the distinction between LR and PO in the context of forensic DNA profiling and FDP from a statistical point of view. In so doing, we also addressed the influence of population affiliation on LR and PO. In contrast to the well-known population dependency of the LR in DNA profiling, the PO as obtained in FDP may be widely population-independent. The actual degree of independence, however, is a matter of (i) how much of the causality of the respective EVC is captured by the genetic markers used for FDP and (ii) by the extent to which non-genetic such as environmental causal factors of the same EVC are distributed equally throughout populations. The fact that an LR should be communicated in cases of DNA profiling whereas the PO are suitable for FDP does not conflict with theory, but rather reflects the immanent differences between these two forensic applications of DNA information

IMHOTEP A composite score integrating popular tools for predicting the functional consequences of non-synonymous sequence variants

The in silico prediction of the functional consequences of mutations is an important goal of human pathogenetics. However, bioinformatic tools that classify mutations according to their functionality employ different algorithms so that predictions may vary markedly between tools. We therefore integrated nine popular prediction tools (PolyPhen-2, SNPs&GO, MutPred, SIFT, MutationTaster2, Mutation Assessor and FATHMM as well as conservation-based Grantham Score and PhyloP) into a single predictor. The optimal combination of these tools was selected by means of a wide range of statistical modeling techniques, drawing upon 10 029 disease-causing single nucleotide variants (SNVs) from Human Gene Mutation Database and 10 002 putatively ‘benign’ non-synonymous SNVs from UCSC. Predictive performance was found to be markedly improved by model-based integration, whilst maximum predictive capability was obtained with either random forest, decision tree or logistic regression analysis. A combination of PolyPhen-2, SNPs&GO, MutPred, MutationTaster2 and FATHMM was found to perform as well as all tools combined. Comparison of our approach with other integrative approaches such as Condel, CoVEC, CAROL, CADD, MetaSVM and MetaLR using an independent validation dataset, revealed the superiority of our newly proposed integrative approach. An online implementation of this approach, IMHOTEP (‘Integrating Molecular Heuristics and Other Tools for Effect Prediction’), is provided at http://www.uni-kiel.de/medinfo/cgi-bin/predictor/

Efficacy assessment of SNP sets for genome-wide disease association studies

The power of a genome-wide disease association study depends critically upon the properties of the marker set used, particularly the number and physical spacing of markers, and the level of inter-marker association due to linkage disequilibrium. Extending our previously devised theoretical framework for the entropy-based selection of genetic markers, we have developed a local measure of the efficacy of a marker set, relative to including a maximally polymorphic single nucleotide polymorphism (SNP) at the map position of interest. Using this quantitative criterion, we evaluated five currently available SNP sets, namely Affymetrix 100K and 500K, and Illumina 100K, 300K and 550K in the CEU, YRI and JPT + CHB HapMap populations. At 50% relative efficacy, the commercial marker sets cover between 19 and 68% of the human genome, depending upon the population under study. An optimal technology-independent 500K marker set constructed from HapMap for Caucasians, in contrast, would achieve 73% coverage at the same relative efficacy

Biomaterialbanken - Rechtliche Rahmenbedingungen

Der Aufbau und Betrieb von großen Biomaterialbanken wird zunehmend wichtiger: Materialbanken, die Proben langfristig für medizinisch-wissenschaftliche Analysen verfügbar machen, bieten ein großes Potential für die Klärung drängender Fragen der medizinischen Forschung. Dies gilt besonders, wenn die Proben mit Daten zum Erkrankungsverlauf der jeweiligen Patienten zusammengeführt werden. Die zunehmende Vernetzung in der biomedizinischen Forschung führt auch zum Aufbau übergreifender Daten- und Probensammlungen. Dabei stellt sich eine Vielzahl von rechtlichen und organisatorischen Fragen, für die in Deutschland bisher eine eindeutige Regelung fehlte. Die TMF hat diese Fragen aufgegriffen und in einem interdisziplinären Projekt viele Aspekte geklärt, die den Forschern nun in Form von Handlungsleitfäden und Mustertexten an die Hand gegeben werden. Der vorliegende zweite Band der TMF-Schriftenreihe beleuchtet aus juristischer Sicht die rechtlichen Rahmenbedingungen für den Aufbau und Betrieb von Biomaterialbanken: umfassendes Rechtsgutachten; Zusammenstellung der Rechtsvorschriften; Musterverträge können von der TMF zur Verfügung gestellt werden

Chromosomal evolution of the PKD1 gene family in primates

Correction to Kirsch S, Pasantes J, Wolf A, Bogdanova N, Münch C, Pennekamp P, Krawczak M, Dworniczak B, Schempp W: Chromosomal evolution of the PKD1 gene family in primates. BMC Evolutionary Biology 2008, 8:263 (doi:10.1186/1471-2148-8-263

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

Some individuals with a particular disease-causing mutation or genotype fail to express most if not all features of the disease in question, a phenomenon that is known as ‘reduced (or incomplete) penetrance’. Reduced penetrance is not uncommon; indeed, there are many known examples of ‘disease-causing mutations’ that fail to cause disease in at least a proportion of the individuals who carry them. Reduced penetrance may therefore explain not only why genetic diseases are occasionally transmitted through unaffected parents, but also why healthy individuals can harbour quite large numbers of potentially disadvantageous variants in their genomes without suffering any obvious ill effects. Reduced penetrance can be a function of the specific mutation(s) involved or of allele dosage. It may also result from differential allelic expression, copy number variation or the modulating influence of additional genetic variants in cis or in trans. The penetrance of some pathogenic genotypes is known to be age- and/or sex-dependent. Variable penetrance may also reflect the action of unlinked modifier genes, epigenetic changes or environmental factors. At least in some cases, complete penetrance appears to require the presence of one or more genetic variants at other loci. In this review, we summarize the evidence for reduced penetrance being a widespread phenomenon in human genetics and explore some of the molecular mechanisms that may help to explain this enigmatic characteristic of human inherited disease

'Sifting the significance from the data' - the impact of high-throughput genomic technologies on human genetics and health care.

This report is of a round-table discussion held in Cardiff in September 2009 for Cesagen, a research centre within the Genomics Network of the UK's Economic and Social Research Council. The meeting was arranged to explore ideas as to the likely future course of human genomics. The achievements of genomics research were reviewed, and the likely constraints on the pace of future progress were explored. New knowledge is transforming biology and our understanding of evolution and human disease. The difficulties we face now concern the interpretation rather than the generation of new sequence data. Our understanding of gene-environment interaction is held back by our current primitive tools for measuring environmental factors, and in addition, there may be fundamental constraints on what can be known about these complex interactions.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

The case of GWAS of obesity: does body weight control play by the rules?

As yet, genome-wide association studies (GWAS) have not added much to our understanding of the mechanisms of body weight control and of the etiology of obesity. This shortcoming is widely attributed to the complexity of the issues. The appeal of this explanation notwithstanding, we surmise that (i) an oversimplification of the phenotype (namely by the use of crude anthropometric traits) and (ii) a lack of sound concepts of body weight control and, thus, a lack of a clear research focus have impeded better insights most. The idea of searching for polygenetic mechanisms underlying common forms of obesity was born out of the impressive findings made for monogenetic forms of extreme obesity. In the case of common obesity, however, observational studies on normal weight and overweight subjects never provided any strong evidence for a tight internal control of body weight. In addition, empirical studies of weight changes in normal weight and overweight subjects revealed an intra- individual variance that was similar to inter-individual variance suggesting the absence of tight control of body weight. Not least, this lack of coerciveness is reflected by the present obesity epidemic. Finally, data on detailed body composition highlight that body weight is too heterogeneous a phenotype to be controlled as a single entity. In summary GWAS of obesity using crude anthropometric traits have likely been misled by popular heritability estimates that may have been inflated in the first place. To facilitate more robust and useful insights into the mechanisms of internal control of human body weight and, consequently, the genetic basis of obesity, we argue in favor of a broad discussion between scientists from the areas of integrative physiologic and of genomics. This discussion should aim at better conceived studies employing biologically more meaningful phenotypes based on in depth body composition analysis. To advance the scientific community—including the editors of our top journals—needs a re-launch of future GWAS of obesity