The past decade has witnessed growing interest in genetic predisposition to common diseases, and along with rapid advancements in high-throughput genotyping technology, has resulted in a tremendous amount of published epidemiological evidence on gene-disease associations. Reported genetic associations with common diseases have become numerous and are mostly of small magnitude . With this growth in evidence has come an increasing need to collate and summarize the evidence in order to identify true genetic associations among the large volume of false positives . Convincing evidence of true association therefore requires careful control over potential biases and chance effects. Control over bias is important both in study design  and in considering the selective availability of data on associations that have been examined . Because most genetic associations are small, large sample sizes are necessary for their detection, especially when many genetic variants are investigated simultaneously, as in genome-wide association studies. Furthermore, replication of findings in independent data sets is now widely regarded as a prerequisite for convincing evidence of association. Thus, multiple studies from several independent groups exist.
Systematic reviews and meta-analyses have become a common approach to summarize gene-disease associations . However, as apparently inconsistent results and interpretations of syntheses of evidence on the same genetic association have been reported , it is useful to lay out issues in the methods and conduct of these types of research studies. The Human Genome Epidemiology Network (HuGENet) has developed “HuGE reviews” (typically systematic reviews) as the cornerstone of an online resource containing the cumulative and changing information on epidemiologic aspects of human genes . Many of these contain meta-analyses, or statistical syntheses of the findings from multiple studies. In this article, we describe some key components of the methodology for undertaking systematic reviews and meta-analyses of genetic association studies. Detailed discussions of these issues and further recommendations can be found in the HuGE Review Handbook  (see also Box 1). Additional detailed guidance on conducting systematic reviews is available in the Cochrane Handbook for Systematic Reviews of Interventions  and The Handbook of Research Synthesis .
Box 1: Development of This Guidance
The guidance in this paper stems primarily from the Human Genome Epidemiology Network (HuGENet) HuGE Review Handbook. This document arose from a two-day discussion workshop held in Cambridge, United Kingdom, on November 2–3, 2004. In attendance were 27 participants with expertise in genetic epidemiology, clinical medicine, public health, meta-analysis, systematic review methods, searching, and statistical methods. The discussions built on previous iterations of guidance from the HuGENet Executive Committee. Speakers at the workshop were asked to comment on current methods, on empirical evidence currently available to guide methods, and on current uncertainties. A writing committee was appointed to produce the Handbook, under the editorship of Julian Little and Julian Higgins. The Handbook was influenced heavily by the Cochrane Handbook for Systematic Reviews of Interventions, which has a long history of evolution and is also based on empirical evidence where available.
The guidance has been updated for this paper to reflect developments in technology and methodology. Gurdeep Sagoo was invited to join to bring a new perspective, given his experience of undertaking HuGE systematic reviews. Passages about genome-wide association studies were added at the request of the current journal editors and are based on the consensus of the authors. The development of the guidance benefits from being the broad consensus (in 2004 to 2006) of numerous individuals with an interest in systematic reviews, but does not claim to be authoritative or to reflect the current views of all people listed below.
Writing Group for the HuGE Review Handbook
Molly Bray, Julian Higgins, John Ioannidis, Muin Khoury, Julian Little, Teri Manolio, Liam Smeeth, Jonathan Sterne.
Participants at the 2004 Workshop
Betsy Anagnostelis, Adam Butterworth, John Danesh, Carol Dezateux, Doug Easton, John Gallacher, Marta Gwinn, Julian Higgins, John Ioannidis, Muin Khoury, Sarah Lewis, Julian Little, Teri Manolio, David Melzer, Cosetta Minelli, Paul Pharoah, Georgia Salanti, Simon Sanderson, Liam Smeeth, Lesley Smith, Jonathan Sterne, Donna Stroup, Emanuela Taioli, John Thompson, Simon Thompson, Neil Walker, Ron Zimmern.