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Association studies in current cardiovascular genetics – functional variants, tags or both?

Journal of Human Hypertension volume 21, pages 425–426 (2007)Cite this article

Cardiovascular genetics has undergone a significant transformation in the recent years. Completion of the Human Genome Project, comparative genomics in silico, new statistical strategies and plummeting costs of high-throughput genotyping have all contributed to an explosion of genetic association studies. However, perhaps the most important contributions to the recent progress in cardiovascular genetics come from availability of information on the architecture of variation in the human genome provided by the HapMap project.1

Access to information of the haplostructure of human DNA and evidence for transferability of tags across populations2 has launched an era of tagging to track maximum genetic information from a locus using a minimal number of single nucleotide polymorphisms (SNPs). In consequence, cardiovascular genetics has evolved from analyses of single markers to tag-based investigations in which an association signal is easier to capture and may be unambiguously mapped to a specific haploblock. This advantage of tag-based strategy in association studies is unfortunately counterbalanced by high linkage disequilibria among SNPs when it comes to identification of the casual variant in the implicated genomic regions. Fine mapping and statistical approaches may be of limited utility in the final dissection of the association that maps to a large block of tightly linked SNPs. Identification of the driver of the detected association and providing mechanistic explanations behind the findings is facilitated by functional cardiovascular genetics. Analysis of correlation between SNPs and measures of gene expression at the transcriptional and translational level in the relevant cardiovascular cells/tissues is commonly used to verify whether the implicated variants may be functionally important. Although relatively straightforward in concept, this SNP–mRNA–protein correlation analysis often requires availability of relevant human tissue. As an alternative to time-consuming collection of human biological material, new bioinformatics tools allow investigation of putative SNP functions on the screen of a computer. Current in silico modelling can predict how exonic non-synonymous SNP affect the structure and the ultimate function of the encoded protein.3 It is now also possible to annotate functions to SNPs located outside exons of cardiovascular candidate genes.4 Location of polymorphisms within evolutionarily conserved sequence may serve as a surrogate of potential functionality, in particular when supported by additional biologically relevant features such as predicted interactions with transcriptional regulators. Indeed, the recent in silico analysis of SNPs located within the 5′-flanking region of β2-adrenergic receptor gene5 provided functional context to their association with blood pressure.6 Other markers of regulatory potential such as location within CpG islands, DNAse I hypersensitive sites or microRNA target sites can be annotated to SNPs in silico4 and used in exploration of their functional relevance. Thus, information on SNP functions obtained in vitro, in vivo or in silico may now be used either in studies on mechanistic models of the detected association or at the preexperimental stage – in selection of polymorphisms for genotyping.

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  1. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK

    M Tomaszewski, F J Charchar & N J Samani

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  1. M Tomaszewski
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Correspondence to M Tomaszewski.

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Tomaszewski, M., Charchar, F. & Samani, N. Association studies in current cardiovascular genetics – functional variants, tags or both?. J Hum Hypertens 21, 425–426 (2007). https://doi.org/10.1038/sj.jhh.1002197

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