Unlike the prevailing academic model of scientists undertaking discrete projects in their separate labs, he proposed to gather and generate as much genealogical, medical and genomic data as he could from across the population.
As she told the New Yorker, "to be able to trace the genealogy of an entire nation for a thousand years...and obtain samples of blood and tissue from healthy living people...could become one of the treasures of modern medicine.
Genes linked to rarer syndromes had been identified in isolated families in Sardinia, Newfoundland, Finland and elsewhere, and a BRCA2 variant had been found in Iceland, but he wanted to look at the most common public health problems.
[30] The Wall Street Journal called the venture a "big gamble," citing noted scientists that "to date, there's no scientific proof that researchers can decipher the genetics of a complex disease among the population of Iceland – or any country.
[33] Opponents of the Iceland Health Sector Database (IHD) objected to the use of public data by a private enterprise and to presumed consent as the model for the use of medical records in research.
They argued that the project put individuals' data privacy at risk, would stifle scientific freedom, and they generally disapproved of the new venture-funded model of biomedical innovation that deCODE represented.
"[37] As the architect, scientific leader and very public face of deCODE, one of Stefansson's fundamental contributions has been to demonstrate that genomics can be done at national scale, and to provide a realized example of how to do it.
[42][43] One pillar of the success of Stefansson's strategy has been his ability to convince tens of thousands of people to volunteer to take part in deCODE's research, and to connect and analyze their data using the genealogies.
[44] In 2003, one version of this database, called Íslendingabók, was made freely available online to anyone with an Icelandic national identity number, and is used by thousands of citizens every day.
[46] The primary means of recruitment for deCODE research has been through collaboration with physicians across the health service who construct lists of patients with different diseases who are then invited to take part.
[53] Leading his deCODE colleagues to continually build and re-query these population datasets, Stefansson has made a steady stream of contributions to the understanding of how variation in the sequence of the genome is generated and its impact on health and disease.
[55] A large number of these are noteworthy contributions to the field and Stefansson and several of his deCODE colleagues are consistently ranked among the most highly cited scientists in genetics and molecular biology.
[56] In more than a dozen major papers published over nearly twenty years, Stefansson and his colleagues used their holistic view of an entire population to build a novel picture of the human genome as a system for transmitting information.
In a much discussed paper from 2012 they demonstrated that the number of such mutations — variants that appear in the genomes of children but are not inherited from either parent — increases with paternal age and constitute a major source of rare diseases of childhood.
deCODE combined genomic and genealogical data on some 150,000 people to demonstrate that this process is, like crossover recombination, more common in women; is age dependent; and that male and female gene conversions tend to be complementary in type, so that they hold each other in check.
[76] Stefansson and his team have used the breadth of the company's datasets and links between diseases and traits to discover new risk variants for mental illness, but also to refine the understanding of the perturbations that define these conditions and the nature of cognition itself.
[103] Among their noteworthy recent discoveries is a rare variant in the ASGR1 gene that confers substantial protection from coronary artery disease, the leading cause of death in the developed world.
[105] Another very large study, analyzing clinical and whole-genome sequence data from some 300,000 people, found more than a dozen relatively rare variants corresponding to elevated cholesterol levels.
[108] The deCODE team has made contributions to the understanding of genetic variation influencing a range of other diseases and traits including glaucoma;[109] menarche;[110] essential tremor;[111] tuberculosis susceptibility;[112] height;[113] gene expression;[114] hair, eye and skin pigmentation;[115] aortic valve stenosis;[116] rhinosinusitis;[117] and dozens of others.
[120] One factor underlying its success and driving participation in Iceland is clearly national pride, turning the country's small size and historical isolation into a unique advantage in an important field.
[123] deCODEme included polygenic risk scores built principally on its discoveries to gauge individual predisposition to dozens of common diseases, an approach followed by 23andMe and others.
[124] Stefansson also oversaw deCODE bringing to market clinical tests for polygenic risk of type 2 diabetes, heart attack, prostate cancer, and atrial fibrillation and stroke.
[125] Marketing of these products and deCODEme ceased with the company's financial troubles in 2011, but recent high-profile studies from Massachusetts General Hospital have revived interest in the medical value polygenic risk testing.
Since then it has operated as a wholly owned but quite independent subsidiary, applying its capabilities across Amgen's drug development pipeline while maintaining local control over its data and science.
[140] Introducing Stefansson for the William Allan Award lecture at the 2017 American Society of Human Genetics annual conference, Mark Daly, then co-director of the Broad Institute, said: "it is impossible to overlook a pervasive paradigm involving biobanks recruited with full population engagement, historical medical registry data, investments in large-scale genetic data collection and statistical methodology, and collaborative follow-up across academic and industry boundaries.
[156] Projects funded either largely or partially by pharmaceutical companies to inform drug target discovery include FinnGen (partly led by Mark Daly), Regeneron/Geisinger,[157] and Genomics Medicine Ireland.
[160] His work has been recognized by patient and research organizations such as the American Alzheimer's Society and by major international publications and bodies including Time,[161] Newsweek,[162] Forbes,[163] BusinessWeek[164] and the World Economic Forum.
[166] In 2019, he was elected a foreign associate of the US National Academy of Sciences, and received the International KFJ Award from Rigshospitalet, one of the oldest and most prestigious medical institutions in Denmark.
[169][170] In his 2002 novel Jar City, Arnaldur Indriðason mixes critical and humorous references to deCODE and Stefansson by creating a vaguely sinister genetics institute based in Reykjavík headed by a scrupulously polite, petite brunette named Karitas.
In the 2006 film version directed by Baltasar Kormákur, Stefansson (who is 6'5" and with gray hair) plays himself, adding a moment of vérité but losing the satirical irony of his namesake.