Genes, disease and the mystery of the missing heritability

When the human genome was brought into the full light of day through the Human Genome Project, it was thought we could begin the task of uncovering the genetic bases of various diseases.

However, such genome-wide association (GWA) studies have so far seen limited success in achieving this goal. So say a cadre of top scientists writing in Nature Reviews Genetics.

GWA studies typically sequence the genomes of two groups of individuals: one with a particular disease, and one without. The object is to identify the variations in the respective genomes that might be associated with the disease.

Such studies were able to pick out variations, such as single nucleotide polymorphisms (SNPs), but they have found that many of these variations have a very small effect size - meaning possessing the variation associated with the disease only confers a relatively small increased chance of having the disease.

This also throws a spanner into the works when it comes to understanding heritability; an individual might inherit a gene associated with a disease, and still not have the disease.

In one article in Nature Reviews Genetics, seven experts give this perspectives on the problem of "missing heritability," offering a range of solutions for future studies.

Professor Evan Eichler, from the University of Washington School of Medicine, Seattle, suggests that we need to focus more attention on large structural variations, such as deletions, duplications and inversions, in order to better understand heritability.

Greg Gibson, professor in the School of Biology at the Georgia Institute of Technology in Atlanta, Georgia, thinks scientists might be looking for too much from GWAs today. "There is a missing genetic variance problem, which really relates to misplaced preconceptions."

He sees environmental factors as being are highly significant, and recommends more studies that focus on the interaction between environment and genes.

According to Professo Jason Moore from the Dartmouth Medical School in New Hampshire, the complexity in understanding the genetic basis of disease may come from a better understanding of epigenetic factors.

"The case of the missing heritability for common human diseases should not be a mystery to anyone given the inherent complexity of the relationship between genotype and phenotype," he writes.

"Consider, for example, the discovery of non-coding microRNAs that provide a new mechanism of translational regulation. Genetic variation influencing the expression of non-coding RNAs has the potential to add a previously unexpected layer of complexity to the genetic architecture of biological and clinical traits."

In the second paper, David Goldstein and Liz Cirulli argue that many of the high-risk genetic causes of disease may be caused by very rare variations, of precisely the kind that are often overlooked by broad-brush GWA studies.

They advocate the use of next generation sequencing technologies to sequence many new whole genomes - not just focusing on the known areas of variation - in order to reveal the more rare variants.

"Up until recently, this was a daunting task," they write. "However, new machines can currently sequence 55 billion bases in about 10 days; although this rate has been increasing with remarkable rapidity, the cost per accurate base call is still the most important parameter and needs improving. This impressive amount of data provides sufficient ‘coverage’ to identify most variants present in a given genome, and the increase in sequencing capacity is allowing more laboratories to sequence whole genomes."

Neither of the papers recommend a cessation to GWA studies, only that we can't expect these broad-brush studies to have the granularity to isolate all the factors that influence a particular disease.

Clearly, the age of genomics is still in its infancy, and there is yet a long way to go before we uncover all the secrets buried in our DNA.

The papers can be found here and here.