The GWA studies performed to date have only been designed to detect a particular subset of potential susceptibility effects – those attributable to common SNPs (or copy number variants (CNVs)) well-tagged by the particular variants represented on the various commodity genotyping arrays. Even with the latest wave of high-density arrays, an appreciable minority of common SNPs remains poorly-tagged, even in the European-descent populations which have been the focus of most studies (26
). In addition, there is limited coverage of low-frequency variants (27
) and, despite the advances in design represented by the new generation of “CNV-aware” chips, the capacity to genotype structural variants (a collective term for polymorphic duplications, deletions and inversions) across the allele frequency spectrum lags well behind that of SNPs (28
These considerations restrict the allele frequency range of the association signals that can be reliably detected. Since common variants of large effect seem to be few and far between, the consequence has also been to constrain the effect size spectrum of proven susceptibility variants (29
). Variants within TCF7L2
remain the basis for the strongest T2D-susceptibility signal in European-descent samples, all other associations displaying per-allele odds ratios between 1.1 and 1.2. Where available, robust estimates of the true effect sizes of many of these proven variants indicate that chance (the “winner’s curse”) often contributed to their initial detection, and that, by inference, many more loci of broadly similar size remain to be found. For some of the confirmed signals, it is probable that fine-mapping efforts will, in time, identify variants causal for the association which have effects larger than those of the tagged variants which led to their discovery (30
). In contrast, “winner’s curse” effects may mean that, for others, current measures of effect size overestimate the true state of affairs (31
How much of the genetic predisposition to T2D is explained by the known variants? Before we benchmark the known T2D-susceptibility variants against some measure of the overall genetic contribution to disease, it is important to acknowledge that estimates of heritability are, by their nature, population- and time-specific. Besides, we have little understanding of the extent to which epigenetic effects (such as the influence of maternal uterine environment on offspring diabetes) (32
) are capable of masquerading as apparent genetic predisposition, thereby inflating estimates of heritability. For dichotomous traits, the sibling relative risk (or λs
) is often used as a convenient measure of the extent of familial aggregation, though this encapsulates both shared environment and genetic effects. Thus, whilst the frequently-quoted sibling relative risk estimate of T2D in Europeans (~3) (1
) can only be considered to provide an upper bound for the total genetic influence, there seems little doubt that the combined effect attributable to known variants (a λs
of 1.07) falls well short of any credible assessment of the genetic contribution to T2D. Most probably, the 20 or so known variants explain only 5-10% of the inherited predisposition.
What could explain the missing heritability (or genetic “dark matter” as it has been termed)? Certainly, continued efforts to uncover more common causal variants, through GWA meta-analysis, and fine-mapping, should fill some of the gap. However, given the modest locus effect sizes likely to result from these future discovery efforts, the overall additional contribution to heritability is unlikely to be substantial. At the same time, efforts to use the GWA approach to identify common susceptibility variants in other ethnic groups should, as the recent revelations concerning KCNQ1
demonstrate, improve the proportion of genetic variance explicable in non-European descent populations (19
Common CNVs are also likely to be involved in disease-susceptibility (28
). In terms of the base pair numbers involved, the sequence diversity attributable to CNVs is roughly equivalent to that due to SNPs, so one might naively expect the overall contribution to disease predisposition made by SNPs and CNVs to be quite similar. However, growing evidence that common CNVs are typically well-tagged by adjacent SNPs (34
) suggests that many of the signals for which common CNVs are causal will already have been detected through SNP-based GWA studies. Ongoing efforts to explore global CNV associations for T2D and other common traits should clarify these issues.
Most evaluations of the joint effects of variants assume independence, so non-additivity (in the form of gene-gene and/or gene-environmental interactions) could be another factor contributing to the missing heritability. For the common T2D-susceptibility loci, little evidence of either has been observed (14
): this may in part reflect intrinsic low power to detect interaction effects, particularly when the causal variants have not yet been defined. However, it has been argued on population genetics grounds that gene-gene interaction (GGI) is unlikely to have a major effect (35
), and, in some scenarios, the variance explained under non-additivity can be LESS than that assumed if the effects are independent (36
For many researchers in the field, the most probable source of missing heritability lies in the putative contribution of low frequency and/or rare variants (both SNPs and CNVs) of intermediate penetrance. Variants with such characteristics will certainly show marked familial aggregation, though the penetrance would generally be insufficient to allow for detection using classical linkage approaches: at the same time, the risk allele frequency is below the threshold detected reliably through GWAs. As a result, where such variants exist, they are likely to have been refractory to the kinds of systematic genome-wide surveys that have been so successful for rare, penetrant variants (at one extreme) and common variants of modest effect (at the other) (30
). The arrival of “next-generation” sequencing technologies brings such variants into play and, in the coming years, it will become possible to examine the hypothesis that susceptibility to T2D (and other common traits) involves the action of multiple low-frequency variants.