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Genetic Susceptibility to Common Complex Disorders Time:12/9/2009 11:51:03 PM Count:

As our understanding of genetics and associated disorders has developed, many genetic tests performing functions - from predicting certain genetic predispositions and identifying rare monogenetic disorders, to ancestry and other 'novelty' tests - have been introduced to the healthcare market. Many geneticists are concerned about the regulation of these tests, which are performed by the NHS, the private sector, or distributed directly to consumers. Experts are calling for more transparent evaluation of these tests before marketing , improved technical quality and diagnostic accuracy, and a clearly defined clinical utility, where applicable not to mention the need for continuous assessment of the ethical, social and legal consequences of genetic testing.

The availability of inexpensive, fast and accurate genome sequencing technology has lead to so-called genome-wide association (GWA) studies becoming one of the most popular approaches to the genetic study of complex disorders such as diabetes, cancer and heart disease. GWA studies involve examining the entire genome, without a specific hypothesis in mind, merely looking for replicable associations between genetic variation and a given disorder. While this has lead to many new genetic variants that raise the risk of inheriting a particular complex disorder being identified, variants identified in this way often only account for a small proportion of the heritable component of such disorders. But does 'missing heritability' suggest that the genetic component of common complex disorders has been overestimated?

A panel of speakers set about answering this question at the Progress Educational Trust (PET) conference - 'Does Genetics Matter? Help Hype and the New Horizon of Epigenetics' - held at Clifford Chance on Wednesday 18 November 2009.

Professor Steve Humphries, Director of the Centre for Cardiovascular Genetics at University College London and chair of the session, set the agenda against the backdrop of the recently insolvent Icelandic firm, deCODE, which raised privacy fears among customers for whom it held genetic data. Meanwhile, competing genomics company 23andMe reportedly put up its prices, which Professor Humphries took as a potential sign of the 'struggling consumer genetics industry', casting further doubt over whether this emergent field is ready to enter the clinic.

But determining clinical value, at this stage, is difficult. Professor Steve Jones, Head of Genetics, Evolution and Environment at University College London, said that, on the whole, we know little about genes - and the public knows even less. He explained that among the surprises stemming from the sequencing of the human genome was the discovery that a mere 25,000 genes account for all the variation seen among humanity. This notion, he said, tells us we don't know much about how the human genome works. Given our current level of understanding, it would be foolish to expect to explain complex common diseases in terms of their genetics. Professor Jones reiterated the concerns he expressed in an earlier Daily Telegraph article about spending large sums of money on identifying genetic variants with little or no predictive value.

Professor Jones referred briefly to the eugenics movement of the early 1900's, whose members sought to banish intellectual 'simplicity' and other socially undesirable traits by restricting breeding. Our improved understanding today of the rudiments of genetics refutes the assumption of the eugenics movement that complex human traits are governed by simple genetics. And yet, he said, a narrative of genetic determinism still rages in today's media reporting of genetics and elsewhere. He recalled that a recent Google search for the phrase 'Scientists find the gene for...' returned some 36,000 potential hits (despite there being only 25,000 genes in the human genome).

Modern research shows us that, for most human traits, there is huge genotypic variation behind phenotypic variation, he said, with each individual gene having only a small effect on the overall phenotype. To illustrate his point, Professor Jones used the example of human height. Scientists have long been trying to understand the genetics of human height and genomic searches have lead to the discovery of a number of associated genetic variants. Nevertheless, different studies have identified different variants and it is likely that the total number of genes identified so far only accounts for approximately 3 per cent of variation.

The 1948 Framingham Heart Study provides another example. It was a project that sought to identify the common genetic factors contributing to cardiovascular disease by following its development over a lengthy period in a large group of participants. Over the years, this study has lead to a significant number of risk variants attributable to cardiovascular disease being identified. But Professor Jones questioned the value of these discoveries when the likely interventions, such as quitting smoking, exercise and healthy diet, are of benefit to everyone, regardless of risk. He suggested that a better approach might be to target many low risk groups of people, rather than a few high risk individuals.

Professor Mark McCarthy, from the Oxford Centre for Diabetes, Endocrinology and Metabolism, cast further doubt on the usefulness of genetic tests for diabetes. He told the audience that, at present, it would be easier to identify a predisposition to the condition by reference to a patient's family history and lifestyle choices, rather than genetics. Yet, he acknowledged that the predictive value of genetics is therapeutically important where there is limited biological understanding. Although, at present, we do not all have the genetic information needed to accurately predict most disorders, we will have new ways of treating and preventing disease in the future.

Realising this goal requires embracing competing methodologies. Professor McCarthy questioned GWA studies, which restrict research to certain common gene variants, but it is important to acknowledge that rare gene variants are also making a significant contribution. To date, 40 genetic variants have been found that influence diabetes, but these account for perhaps less than 10 per cent of the genetic contribution to the disease. Furthermore, we understand little of the biology of these gene variants, meaning there is little scope for clinical translation. Furthermore, the majority have been identified within populations of European origin meaning further studies will be needed to establish whether they have predictive value among other non-European populations.

In conclusion, Professor McCarthy stressed that what we know about the genetics of diabetes was really just the tip of the iceberg. He predicted that further research into understanding the biology of certain risk variants and identifying risk factors of intermediate predictive power and prevalence, would help provide a more complete view of the condition and lead to improved treatment and prevention.