Genome-wide association studies, field synopses, and the development of the knowledge base on genetic variation and human diseases

Abstract

Genome-wide association studies (GWAS) have led to a rapid increase in available data on common genetic variants and phenotypes and numerous discoveries of new loci associated with susceptibility to common complex diseases. Integrating the evidence from GWAS and candidate gene studies depends on concerted efforts in data production, online publication, database development, and continuously updated data synthesis. Here the authors summarize current experience and challenges on these fronts, which were discussed at a 2008 multidisciplinary workshop sponsored by the Human Genome Epidemiology Network. Comprehensive field synopses that integrate many reported gene-disease associations have been systematically developed for several fields, including Alzheimer's disease, schizophrenia, bladder cancer, coronary heart disease, preterm birth, and DNA repair genes in various cancers. The authors summarize insights from these field synopses and discuss remaining unresolved issues -- especially in the light of evidence from GWAS, for which they summarize empirical P-value and effect-size data on 223 discovered associations for binary outcomes (142 with P < 10(-7)). They also present a vision of collaboration that builds reliable cumulative evidence for genetic associations with common complex diseases and a transparent, distributed, authoritative knowledge base on genetic variation and human health. As a next step in the evolution of Human Genome Epidemiology reviews, the authors invite investigators to submit field synopses for possible publication in the American Journal of Epidemiology.

Figure 1.

A) Levels of statistical significance for associations of genetic loci with P values of 10⁻⁵ or lower identified through genome-wide association studies (GWAS) and entered in the National Human Genome Research Institute catalog of GWAS as of October 14, 2008 (38, 39); data are limited to those loci that have binary outcome phenotypes (n = 223). For details on selection of loci in the catalog, see Hindorff et al. (38) and Manolio et al. (39). B) Odds ratios (per allele) for the 223 associations. C) Odds ratios for the 142 of the 233 associations that had P values less than 10⁻⁷. Not shown are the 5, 13, and 7 outliers that had values outside of the depicted range in the 3 panels, respectively.

Figure 2.

A vision for collaboration among disease- and gene-specific investigators, systematic reviewers, and online publishers. HuGENet, Human Genome Epidemiology Network; HVP, Human Variome Project; P³G, Public Population Project in Genomics.