Mining the human phenome using allelic scores that index biological intermediates

J. Kaprio ja M-L. Lokki työryhmien jäseniä.It is common practice in genome-wide association studies (GWAS) to focus on the relationship between disease risk and genetic variants one marker at a time. When relevant genes are identified it is often possible to implicate biological intermediates and pathways likely to be involved in disease aetiology. However, single genetic variants typically explain small amounts of disease risk. Our idea is to construct allelic scores that explain greater proportions of the variance in biological intermediates, and subsequently use these scores to data mine GWAS. To investigate the approach's properties, we indexed three biological intermediates where the results of large GWAS meta-analyses were available: body mass index, C-reactive protein and low density lipoprotein levels. We generated allelic scores in the Avon Longitudinal Study of Parents and Children, and in publicly available data from the first Wellcome Trust Case Control Consortium. We compared the explanatory ability of allelic scores in terms of their capacity to proxy for the intermediate of interest, and the extent to which they associated with disease. We found that allelic scores derived from known variants and allelic scores derived from hundreds of thousands of genetic markers explained significant portions of the variance in biological intermediates of interest, and many of these scores showed expected correlations with disease. Genome-wide allelic scores however tended to lack specificity suggesting that they should be used with caution and perhaps only to proxy biological intermediates for which there are no known individual variants. Power calculations confirm the feasibility of extending our strategy to the analysis of tens of thousands of molecular phenotypes in large genome-wide meta-analyses. We conclude that our method represents a simple way in which potentially tens of thousands of molecular phenotypes could be screened for causal relationships with disease without having to expensively measure these variables in individual disease collections.Peer reviewe

Genetic approaches in preeclampsia

Preeclampsia (PE) is a serious hypertensive disorder that affects up to 8% of all pregnancies annually. An established risk factor for PE is family history, clearly demonstrating an underlying genetic component to the disorder. To date, numerous genetic studies, using both the candidate gene and genome-wide approach, have been undertaken to tease out the genetic basis of PE and understand its origins. Such studies have identified some promising candidate genes such as STOX1 and ACVR2A. Nevertheless, researchers face ongoing challenges of replicating these genetic associations in different populations and performing the functional validation of identified genetic variants to determine their causality in the disorder. This chapter will review the genetic approaches used in the study of PE, discuss their limitations and possible confounders, and describe current strategies

It's Getting Better All the Time: Comparative Perspectives from Oceania and West Africa on Genetic Analysis and Archaeology

Technological advances are making genetic data collection and analysis feasible on a scale unimaginable only a few years ago. Early genetic research using mitochondrial DNA and the Y chromosome provided important insights for macroscale modeling of regional and continent-wide population movements, but the capacity to study the entire genome now opens an era of finer-grained,mesoscale studies of regional and local population histories that are more compatible with the scale of archaeological analysis. The utility of integrating both types of data is illustrated by a case study from Oceania, where genetic studies were used to evaluate two models for the geographic origins of the populations that colonized Polynesia beginning ca. 3000 BP, bringing with them the distinctive Lapita cultural assemblage. A second case study considers the application of genetic studies to an understanding of Fulbe history, especially that of the pastoral Fulbe. Both archaeological and genetic data are underdeveloped for the key Fulbe homeland regions of Mauritania and Senegal, but recent research in the Middle Senegal Valley permits some conjectures on the history of Fulbe nomadic pastoralism. The article concludes with suggestions for a multidisciplinary research agenda to expand and upgrade the quality of relevant archaeological data, incorporate biodistance studies of human skeletal material, and improve and expand genetic sampling using more historically sensitive collection protocols