Gene mapping often fails to predict disease

Whole genome sequencing as a method of predicting disease risks isn’t as informative as thought, a study of thousands of identical twins has found.

It doesn’t provide informative guidance to most people about their risk for most common diseases, say Johns Hopkins investigators, and negative results can lead to complacency.

Whole genomic sequencing catalogs all of the genes that a person inherits from each parent. It identifies the several million

differences between any two individuals’ genomes and links them to known or suspected contributions to the risk of certain diseases.

But, says the team, their research casts doubt on whether whole genome sequencing can reliably predict the majority of future medical problems that will be encountered by most people who take the tests.

“We believe that genomic tests will not be substitutes for current disease prevention strategies,” says oncology professor Bert Vogelstein.

“Prudent screening, early diagnosis and prevention strategies, such as not smoking and removing early cancers, will be the keys to cutting disease death rates.”

The team used data recorded on thousands of identical twins entered into registries in Sweden, Denmark, Finland, Norway and the National Academy of Science’s National Research World War II Veterans Twins Registry.

“Identical twins share the same genome, and if the genome were the determining factor for common diseases, then the prevalence of a specific disease in an individual whose twin has that disease can be used to determine how well whole genome sequencing could predict an individual’s disease risk,” says Vogelstein.

They collected information on the incidence of 24 diseases among the twin-pair groups, including cancer, as well as autoimmune, cardiovascular, genitourinary, neurological and obesity-associated diseases.

They used mathematical models to calculate the capacity of whole genome sequencing to predict the risk of each disease.

And the analysis showed that whole genome sequencing could alert most individuals to an increased risk of at least one disease – but for most people would provide negative test results for the majority of diseases studied, failing to forewarn them of diseases they could ultimately develop.

“As many as two percent of women undergoing whole genome sequencing could receive a positive test result for ovarian cancer, alerting them that they have at least a one-in-ten chance of developing that cancer over their lifetime,” says professor Kenneth Kinzler.

“The other 98 percent of women who receive a negative test for ovarian cancer will not be guaranteed a lifetime free of ovarian cancer because their risk of developing it is very similar to that of the general population. So, a negative test is not a ‘free pass’ to discount the chance of acquiring any particular disease.”

The results specifically show that whole-genome-based tests are not very informative for predicting cancer in most individuals without a strong family history of the disease. However, they could identify, theoretically, more than three-quarters of patients at risk of developing coronary heart disease in men, thyroid autoimmunity, type 1 diabetes and Alzheimer’s disease.

“In families with strong histories of cancer, whole genome sequencing can still be very informative for identifying inherited genes that increase cancer risk,” says professor Victor Velculescu.

“But hereditary cancers are rare. Most cancers arise from mutations acquired through environmental exposures, lifestyle choices and random mistakes in genes that occur when cells divide.”