翻译：Genome-wide association studies: potential next steps on a genetic journey

                          Genome-wide association studies: potential next steps on a genetic journey

                          全基因组关联研究：基因之旅的潜在下一步
       Genome-wide association studies have successfully identified numerous loci at which common variants
influence disease risk or quantitative traits. Despite these successes, the variants identified by these studies
have generally explained only a small fraction of the heritable component of disease risk, and have not pin-
pointed with certainty the causal variant(s) at the associated loci. Furthermore, the mechanisms of action by
which associated loci influence disease or quantitative phenotypes are often unclear, because we do not
know through which gene(s) the associated variants exert their effects or because these gene(s) are of
unknown function or have no clear connection to known disease biology. Thus, the initial set of genome-
wide association studies serve as a starting point for future genetic and functional studies. We outline poss-
ible next steps that may help accelerate progress from genetic studies to the biological knowledge that can
guide the development of predictive, preventive, or therapeutic measures.

      全基因组关联研究已经成功地确定了许多常见变异影响疾病风险或数量性状的位点。尽管取得了这些成功，但这些研究确定的变异通常只解释了疾病风险的一小部分可遗传成分，并没有确切地指出相关位点上的因果变异。此外，相关位点影响疾病或数量表型的作用机制往往不清楚，因为我们不知道相关变异通过哪些基因发挥作用，或者因为这些基因具有未知的功能或与已知的疾病生物学没有明确的联系。因此，最初的全基因组关联研究是未来遗传和功能研究的起点。我们概述了下一步可能的步骤，这些步骤可能有助于加快从基因研究到生物学知识的进展，这些知识可以指导预测性、预防性或治疗性措施的发展。

INTRODUCTION

绪论
The first successful wave of genome-wide association (GWA) studies has, over the last year, identified common variants associated with numerous common polygenic diseases and quantitative traits. As illustrated in several reviews in this
special issue, these GWA studies have mapped many novel, convincingly associated loci [for example, at least 32 for
Crohn’s disease (1), 14 for prostate cancer (2), 15 for type 2 diabetes (3) and 40 for height (4–6)]. These discoveries
have more often than not implicated previously unsuspected genes, highlighting the power of unbiased genetic screens to
uncover novel biology. However, these loci in combination typically explain only a fraction of the inherited contribution
to risk, raising the question of how best to find the variation responsible for the remainder. As discussed in several of the
articles in this issue, the successful GWA studies were often poorly powered to discover most of the loci that they ident-
ified, indicating that more loci with equivalent effect sizes can be discovered simply by increasing sample size. In
addition, most GWA studies have been completed in European-derived populations, suggesting that performing
GWA studies in non-European samples will also be important (7). However, it is not clear how much of the remaining
relevant variation will be uncovered by these steps. 

在过去的一年里，第一波成功的全基因组关联(GWA)研究已经确定了与许多常见的多基因疾病和数量性状相关的常见变异。正如在本期特刊的几篇综述中所说明的那样，这些GWA研究绘制了许多新的、令人信服的相关位点[例如，至少32个克罗恩病(1个)，14个前列腺癌(2个)，15个2型糖尿病(3个)和40个身高(4-6个)]。这些发现往往牵涉到以前未被怀疑的基因，突显了无偏见的基因筛查在发现新生物学方面的力量。然而，这些基因座结合在一起通常只能解释遗传风险贡献的一小部分，这就提出了一个问题，即如何最好地找到导致其余风险的变异。正如本期几篇文章中所讨论的那样，成功的GWA研究往往不能很好地发现他们所确定的大多数位点，这表明只需增加样本量就可以发现更多具有相同效应大小的位点。此外，大多数GWA研究都是在欧洲派生的人群中完成的，这表明在非欧洲样本中进行GWA研究也将是重要的(7)。然而，目前尚不清楚这些步骤将揭示多少剩余的相关变异。

In most cases, the associated loci themselves demand additional exploration. The causal variant is usually not ident-
ified by GWA studies (see Finding Additional Associated Loci and Variants section) and in some cases the causal variant may
be more strongly associated (and explain more of the risk) than the marker detected in the initial GWA. Furthermore, the
associated loci remain essentially unexplored for independent causal alleles, which may account for additional genetic risk.
Finally, it is possible that new approaches (such as genome- wide resequencing) designed at detecting variants not well
assayed in current GWA studies will be required to define more fully the inherited basis of common disease.

在大多数情况下，相关的位置本身需要额外的探索。GWA研究通常不能识别因果变体(参见查找其他相关位点和变体部分)，在某些情况下，因果变体可能比在初始GWA中检测到的标记具有更强的关联性(并解释更多的风险)。此外，相关的基因座基本上还没有发现独立的因果等位基因，这可能是额外的遗传风险的原因。最后，有可能需要设计新的方法(如全基因组重测序)来检测在当前GWA研究中没有很好分析的变异，以更全面地定义常见疾病的遗传基础。

One of the main goals of genetic studies of complex traits is to flag pathways relevant to disease that could reveal novel
therapeutic targets. However, for most associated loci, there is substantial ignorance regarding the mechanisms by which
genetic variation could influence phenotype: the identity of the gene(s) affected by the susceptibility variant(s) at each
locus is often uncertain, and the mechanisms by which the causal variants (also often unknown) influence phenotype is
usually unclear. This lack of knowledge is a substantial impediment to the understanding needed to make progress towards
new therapies or preventive measures. This obstacle highlights the need to pinpoint the causal variants and the genes affected
by those variants, as well as for informative functional and computational studies to move from gene identification to possible mechanisms that could guide translational progress.

复杂性状的遗传学研究的主要目标之一是标记与疾病相关的路径，以揭示新的治疗目标。然而，对于大多数相关的基因位点，人们对遗传变异影响表型的机制基本上是忽视的：每个基因位点上受易感变异影响的基因的同一性通常是不确定的，而因果变异(通常也是未知的)影响表型的机制通常不清楚。这种知识的缺乏严重阻碍了在新疗法或预防措施方面取得进展所需的理解。这一障碍突显了确定因果变体和受这些变体影响的基因的必要性，以及从基因识别转移到可能的机制来指导翻译进展的信息性功能和计算研究的必要性。

Clearly, this first wave of GWA studies represents a starting point on the journey to elucidating and understanding the
genetic basis of complex traits and common disease and translating this knowledge into clinically useful insights. In this
review, we describe some possible next steps. Specifically, we outline possible approaches in three areas: finding
additional loci that contain causal variants, refining the location and phenotypic consequences of causal variants and
progressing from known loci and variants to functional mech- anisms. We do not address the ability to translate genetic dis-
coveries into predictive tests, as finding additional causal variation is a necessary precursor to making genotype-based
predictors more accurate and useful.

显然，GWA的第一波研究代表了阐明和理解复杂性状和常见疾病的遗传基础，并将这些知识转化为临床有用见解的旅程的起点。在这篇综述中，我们描述了一些可能的后续步骤。具体地说，我们在三个方面概述了可能的方法：寻找包含因果变异的额外基因座，提炼因果变异的位置和表型结果，以及从已知的基因座和变异到功能机制的进展。我们没有讨论将基因发现转化为预测性测试的能力，因为发现额外的因果变异是使基于基因型的预测者更准确和更有用的必要先兆。