Sunday, December 06, 2009

Finding the missing heritability   posted by ml @ 12/06/2009 09:31:00 PM

In a recent special issue of The Economist magazine, evolutionary psychologist Geoffrey Miller of the University of New Mexico writes that there is a "looming crisis in human genetics". Setting aside a number of mistakes Miller makes, a core truth he reports is that to date most genetic variants that have been associated with complex diseases such as diabetes and complex phenotypes such as height can account for only a small percentage of the estimated genetic contribution to population variation in these traits (~5% in total for the cases of type-2 diabetes and height). This residual unexplained variability has been dubbed the "missing heritability".

The missing heritability is an open and fascinating research question, not a crisis, although it has become fashionable to characterize it as such. First, it's important to realize that a primary goal of genetic studies of human disease is to identify the biological underpinnings of these diseases and thus advance work toward improved diagnoses, cures, and mechanisms of prevention. Important work has already been done towards these ends with many new and unexpected biological pathways now associated with diseases thanks to the recent successes of genome-wide association studies (GWAS). Thus, it may not be necessary to explain all of the missing heritability in order to make great strides towards these goals.

Second, the first generation of GWAS were not realistically expected to find loci of large effect as they focused on common variant; although the potential benefits of first-generation GWAS may have been oversold by some. Nonetheless, first-generation GWAS have explained a substantial fraction of the heritability of some traits, such as age-related macular degeneration.

Third, where should we look for the missing heritability? A recent review in Nature offers some suggestions:
Many explanations for this missing heritability have been suggested, including much larger numbers of variants of smaller effect yet to be found; rarer variants (possibly with larger effects) that are poorly detected by available genotyping arrays that focus on variants present in 5% or more of the population; structural variants poorly captured by existing arrays; low power to detect gene–gene interactions; and inadequate accounting for shared environment among relatives. Consensus is lacking, however, on approaches and priorities for research to examine what has been termed 'dark matter' of genome-wide association—dark matter in the sense that one is sure it exists, can detect its influence, but simply cannot 'see' it (yet). Here we examine potential sources of missing heritability and propose research strategies to illuminate the genetics of complex diseases.

A key consideration is the genetic architecture of each trait--the number, type, effect size and frequency of variants affecting a trait. Because the genetic architecture of a complex trait cannot be known a priori (although theory can suggest which architectures are more probable) it is an open question as to which approach to finding the missing heritability will yield the most success. Until more approaches are attempted, it is premature to predict a crisis. This does not mean, however, that success is guaranteed. It is possible that the genetic architecture of some complex traits is too complex to dissect practically with current methods. Rather than a crisis, we might instead expect more slow but steady progress in upcoming years. Some traits will be more amenable to new methods (as age-related macular degeneration was to fist-generation GWAS). Other traits will likely remain largely intractable.