Researchers from deCODE Genetics in Iceland have constructed a detailed picture of the country’s genomic profile, described in four linked papers published in Nature Genetics. In the main study, scientists used whole genome sequence data from 2,636 Icelanders combined with detailed genealogy and information from medical records to impute the DNA sequences of over 100,000 individuals – around a third of the entire population. This is the most comprehensive population-wide genome study to date; it has implications for improving our understanding of human genetic variation, evolution and genetic risk factors for disease.

Why Iceland?

Iceland has a small population (323,002 in 2013) that is relatively isolated with little immigration – all factors that lead toward genetic homogeneity. Genealogical records in Iceland are excellent and date back centuries, while the national electronic health records system allowed comprehensive data linkage. “It’s really the completeness of the information – the sequencing data, the clinical information, the phenotypical data, the drug reaction data – that lets you tie it all together” Dr Lisa Brooks of the US National Human Genome Research Institute commented in Wired.

Main findings

Researchers calculated that the most recent common ancestor of all Y chromosomes in the world today lived around 239,000 years ago, which is nearly 100,000 years more recent than other estimates. They found that both copies of at least one gene were missing in around 8% of the genotyped population – so-called ‘knockout’ humans. The team uncovered new genetic variants contributing to the risk of Alzheimer’s disease (ABCA7), atrial fibrillation (MYL4), thyroid disease (GNAS) and liver disease (ABCB4). In the study population there was also a high prevalence of a loss of function mutation in BRCA2 – a gene linked with hereditary breast and ovarian cancer syndrome. 

What are the implications?

Many have been enthused by the study’s use of genomic information to advance understanding of human health. Professor Mark Caulfield, chief scientist at Genomics England remarked to BBC News that: “We are on the cusp on the application of transformative genomic medicine at scale…The team in Iceland is to be congratulated as it has continued, over many years, to contribute to an understanding of the genetic information of disease by looking at the level of the population”.

Concerns and complexities

Nonetheless, there have been concerns about issues around consent, confidentiality and complexity of the data generated. Currently all information generated through the study is encrypted and anonymous and results are not being fed back to research participants.  Researchers estimate that there are around 2,000 men and women in Iceland who carry a BRCA2 mutation but are unaware of their gene carrier status. Kari Stefannson of deCODE Genetics, senior author of the study, told the BBC: “We could, in Iceland, at the push of a button find all women who carry mutations in the BRCA2 gene. It would be criminal not to take advantage of it and I am convinced that my fellow countrymen will begin to use it pretty soon”. Stefannson is reportedly in discussions with the Icelandic Medical School and Ministry of Health about how best to use clinically actionable data generated through the study. 

Finding a high risk cancer gene has potentially major implications for the health of an individual and their family. There are however technical limitations of whole genome sequencing for finding all classes of pathogenic BRCA2 variants. In addition, sequence data for over 100,000 individuals in this study were imputed and it is not known how closely imputed data correspond with actual sequence data. While BRCA2 mutations confer a high risk of breast and ovarian cancer when detected in the context of multi-case families, the association between mutation and disease is less clear in people with no family cancer history. An individual’s absolute cancer risk depends on their age at testing, family history and genetic and environmental modifiers of disease. Absolute cancer risk also affects the clinical utility and cost effectiveness of preventive strategies such as enhanced surveillance and prophylactic surgery.

Although individuals taking part in the study consented to having a blood sample taken for DNA analysis, it is likely that they did not consent to the return of secondary genomic findings such as carriage of BRCA2 mutations. Returning such findings therefore raises serious ethical questions, especially in relation to autonomy. Uncertainty about the accuracy of information fed back, and ambiguities about how to translate genomic information to clinical risk will heighten such concerns.  

Lessons for the future

This situation highlights the need for a clear strategy to deal with secondary genomic findings that is based upon knowledge of mutation prevalence, penetrance and the appropriate threshold for clinical action and incorporates a robust informed consent process for individuals undergoing whole genome sequencing. It will be important for future studies generating large-scale genomic datasets to consider carefully both the technical aspects of interpreting genome sequence data for human health as well as the associated ethical and public engagement challenges.