Kári Stefánsson[a] (born 6 April 1949)[1] is an Icelandic neurologist and founder and CEO of Reykjavík-based biopharmaceutical company deCODE genetics. In Iceland he has pioneered the use of population-scale genetics to understand variation in the sequence of the human genome. His work has focused on how genomic diversity is generated and on the discovery of sequence variants impacting susceptibility to common diseases. This population approach has served as a model for national genome projects around the world and contributed to the realization of several aspects of precision medicine.[2][3]
Biography
Kari Stefansson was born in 1949 in Reykjavík, Iceland.[4] He was the second youngest of the five children of Sólveig Halldórsdóttir and Stefán Jónsson, a radio personality, writer and democratic socialist member of parliament.[5] He completed his secondary education at Reykjavik Junior College and received his M.D. in 1976 and his Dr. med. in 1986 from the University of Iceland. He was married to Valgerður Ólafsdóttir from 1970 until her death on 11 November 2021.[6] In June 2012, his daughter, Sólveig "Sóla" Káradóttir, married Dhani Harrison, son of the late George Harrison and his wife, Olivia Harrison.[7][8] Stefansson says that he owes much to his brother, who suffers from schizophrenia. He initially thought of becoming a writer, and attests to being a voracious reader. His favorite author is Isaac Bashevis Singer.[9]
Academic career
Following his internship at the National Hospital of Iceland, he went to the University of Chicago to work under Barry Arnason (coincidentally a Canadian of Icelandic descent). There he completed residencies in neurology and neuropathology, and in 1983 joined the faculty. In 1993 he was appointed professor of neurology, neuropathology and neuroscience at Harvard University and division chief of neuropathology at Boston's Beth Israel Hospital. While in Boston, he and his colleague Jeffrey Gulcher decided to return to Iceland to perform genetic studies to determine multiple sclerosis risk.[10] Stefansson resigned both positions in 1997 after founding deCODE and moving back to Reykjavík.[11] Since 2010, he has held a professorship in medicine at the University of Iceland.[12] He is a board-certified neurologist and neuropathologist in both Iceland and the US.[13]
From biology to genetics
Stefansson's academic work was focused on neurodegenerative disease.[14] The protein biology approach to this research involved trying to map complex processes using limited samples, mainly of brain tissue from deceased patients. Although publishing steadily, Stefansson was frustrated by the pace of progress and often by not knowing whether the proteins he was characterizing were involved in causing disease or the product of the disease process.[15] He and his colleagues came to question even the accepted definition of multiple sclerosis (MS) as an autoimmune disease.[16]
When he was recruited from Chicago to Harvard, Stefansson began to think that the genome might provide a better starting point than biology. Genes encode proteins, so identifying the genes and specific genetic variations that patients tended to share more often than healthy individuals should provide a foothold in the pathogenesis of disease.[17] In doing so they might point to biologically relevant targets for new drugs and predictive diagnostics.[18]
However, in the mid-1990s the tools for reading the sequence of the genome were primitive. Data was scarce and expensive to generate, and a major early focus of the Human Genome Project was to develop better methods.[19] In the meantime, one solution was to use genetics – how the genome is mixed and passed from one generation to the next – as a means of deriving more information from the available data.[20] Siblings share half their genomes; but cousins one eighth, second cousins one thirty-second, etc. Studying patients linked by extended genealogies should therefore make it possible to more efficiently find the inherited component of any phenotype or trait, even using low-resolution markers.
Back to Iceland
An important question was whether and where such extended genealogies might be found. It was not one that occurred to many leading geneticists to ask with regard to common diseases.[21] As an Icelander, Stefansson knew the country's passion for genealogy first hand and had grown up with and trained in its national health system. In 1995, he and his colleague and former graduate student, Jeffrey Gulcher, decided to go to Iceland to study multiple sclerosis. Working with doctors in the national health system they identified hundreds of patients and relatives who gave them blood samples to begin their research. As Icelanders they were almost by definition related, and due to the national pastime of genealogy those relationships could be established.
When Stefansson and Gulcher returned to Boston, their grant proposal was turned down by the NIH, which had little experience of funding work using distantly related patients. But Stefansson saw potential in Iceland for using the same approach to find the genetic component of virtually any common disease.[22] This was beyond the scope of an academic laboratory, and he made contact with venture capital firms to find out if such an enterprise could be funded as a private company. In the summer of 1996 he raised $12 million from several American venture capital funds to found deCODE genetics.[23] He and Gulcher moved to Iceland to set up operations and resigned their positions at Harvard the following year.[24]
deCODE and the population approach
Stefansson conceived deCODE as an industrial-scale enterprise for human genetics. 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. Using bioinformatics and statistics, deCODE could then combine and mine all this data together for correlations between variation in the sequence and any disease or trait, in a nearly hypothesis-free manner.[25] The business model was to fund this effort through partnerships with pharmaceutical companies who would use the discoveries to develop new drugs.[26]
Iceland had the data sources required for this "population approach": a high-quality single-payer healthcare system; a relatively homogeneous population that would make finding disease variants less complex;[27] an educated citizenry that was willing to contribute DNA and medical and health information for research; and most uniquely, comprehensive national genealogies.[28]Mary Clare King, who had used family pedigrees to identify BRCA1 in breast cancer, was among the scientists who recognized the potential of these records. 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."[29]
From its inception, Stefansson's strategy was controversial. The genomics community was still far from generating a first human genome sequence; he was proposing a data system for mining hundreds of thousands of genomes. 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."[31] And deCODE was a private company that was taking an entire nation as a unit of study, with the unprecedented level of public engagement and participation that would entail.
What stirred the most controversy was Stefansson's proposal in 1997 to create a database of copies of medical records data from the national health service to correlate with genealogical and genomic data.[32] Supported by a large majority of the public and members of parliament, the Act on Health Sector Database authorizing the creation of such a database and its licensing for commercial use was passed in 1998. But it was fiercely opposed by a group of local academics and doctors as well as many international bioethicists.[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.[34]
Stefansson was attacked for the IHD and his broader approach.[35] He argued that far from supplanting traditional data sources or researchers, deCODE was creating a new scale of resources and opportunities including for the health service; benefitting the community by repatriating and employing Icelandic scientists in cutting-edge fields; and following international norms of consent while setting new standards in large-scale research, with oversight by public bioethics and data protection bodies and novel data and privacy protection protocols.[36] Critics at the time remained unconvinced. Stanford bioethicist Hank Greely concluded simply that "the Icelandic model is not a good precedent for similar research elsewhere."[37]
Scientific contributions
The feasibility of population genetics and national genome projects
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.[38] By the time Human Genome Project and Celera published their draft sequences of the human genome in 2001, his vision for population genetics had already taken shape and was yielding early discoveries of sequence variation linked to disease, human evolution and population history.[39][40] In 2002, deCODE used its capabilities in Iceland to publish a genetic map of the genome that was used to complete the final assembly of the reference human genome sequence.[41] By mid-decade, even former critics acknowledged that what Stefansson was building in Iceland through fully consented individual participation and datamining was indeed an important example to prospective genome projects in the UK, US, Canada, Sweden, Estonia and elsewhere, and to the foundation of new institutions like the Broad Institute.[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. An early partnership with local software developer Friðrik Skúlason created a computerized national genealogy database that linked all living Icelanders and included the majority of people who have ever lived in Iceland over the past eleven hundred years.[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.[45] The version used in research replaces names with encrypted personal identifiers overseen by Iceland's Data Protection Commission. This makes it possible to create pedigrees connecting the genetic and phenotypic data of any group of people in an anonymized manner. Stefansson and Gulcher published the structure of this data protection system for other genome projects to use.[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. Participation entails not only written informed consent but also filling out health questionnaires; undergoing detailed clinical examination and measurements; and giving blood for the isolation of DNA; all of this takes place at a special clinic and requires the commitment by participants of several hours to complete.[47] The IHD was never built, its scientific and business rationale largely superseded by the response of Icelanders to contribute their data one by one.[48] By 2003, with some 95% of people asked to participate agreeing to do so, more than 100,000 were taking part in the study of one or more of three-dozen diseases.[49] By 2007, this had grown to 130,000;[50] and by 2018 to more than 160,000. This is roughly 70% of all adult citizens, 60,000 of whom have had their whole genomes sequenced.[51]
At each successive stage of technology for reading the genome – from microsatellite markers to SNPs to whole-genome sequencing – this participation is unique as a proportion of the population and has also consistently comprised one of the largest collections of genomic data in the world in absolute terms.[52] Using the genealogies deCODE can impute the sequence data of the entire population, yielding a single encrypted, minable dataset of more than 300,000 whole genomes.[53]
Discoveries and publications
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. Myles Axton, the longtime editor of Nature Genetics, noted at deCODE's 20th anniversary celebration that this leadership had put deCODE and Iceland "in the forefront of a revolution that has delivered much of what was promised in the mapping of the human genome."[54]
These discoveries, tools and observations have been shared with the scientific community in hundreds of scientific publications. Stefansson guides and oversees all research at deCODE and is senior author on its papers, with project and group leaders the first authors and co-authors drawn from the hundreds of local and international institutions and organizations with whom deCODE has collaborations.[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]
The generation of human diversity and mechanisms of evolution
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. They have provided a detailed view of how the genome uses recombination, de novo mutation and gene conversion to promote and generate its own diversity but within certain bounds.
In 2002, deCODE published its first recombination map of the human genome. It was constructed with 5000 microsatellite markers and highlighted 104 corrections to the Human Genome Project's draft assembly of the genome, immediately increasing the accuracy of the draft from 93 to 99%. But from an evolutionary biology perspective it demonstrated in new detail the non-random location of recombinations - the reshuffling of the genome that goes into the making of eggs and sperm - and that women recombine 1.6 times more than men.[57]
They then showed that older women recombine more than younger women; that higher recombination correlates with higher fertility;[58] and that a large inversion on chromosome 17 is at present under positive evolutionary selection in European populations, with carriers having higher recombination and fertility rates than non-carriers.[59] A second recombination map published in 2010 utilized 300,000 SNPs and revealed different recombination hotspots between women and men, as well as novel genetic variations that affect recombination rate, and that do so differently in European and African populations.[60]
This map also showed that while women are responsible for most recombination, men generate the bulk of de novo mutations. 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.[61] A detailed analysis of the different types and distribution of maternal and paternal de novo mutations was published in 2017,[62] and a subsequent paper demonstrated how de novo mutations in parents can be passed on.[63]
A third source of genomic diversity, gene conversions, are difficult to detect except by looking at very large genealogies. 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.[64] In 2019, deCODE utilized the genealogies, the large number of whole genome sequences (WGS) that it had completed in the preceding years, and genotyping data on the majority of the population, to publish a third recombination map of the genome. This is the first created using WGS data, and like the previous maps has been made openly available to the global scientific community.[65]
Contributions to population history and genetic anthropology include pioneering work on the mutation rate and mechanisms in mitochondria and the Y chromosome;[66] comparing ancient to contemporary DNA;[67] characterization of the respective Norse and Celtic roots of mitochondria and Y chromosomes in the Icelandic population;[68] observations of the phenomenon of genetic drift, as an isolated population diverges from it source populations over time;[69] the relationship between kinship and fertility;[70] the impact of population structure on disease associated variants and vice versa,[71] and a population-wide catalogue of human knockouts, people missing certain genes.[72]
In 2018, deCODE used its capabilities to reconstruct the genome of Hans Jonatan, one of the first Icelanders of African descent. He immigrated to Iceland in 1802 and his genome was reconstructed from fragments of the genomes of 180 of his nearly 800 living descendants, traceable through Íslendingabok.[73]
The genetics of common diseases and traits
Stefansson is probably best known for the contribution he and his deCODE colleagues have made to the discovery of genetic variations linked to risk of disease and to a range of other traits. The population approach — the scale and breadth of resources and the focus on cross-mining disparate datasets — has been key to this productivity. It makes it possible to use both broad and rigorous definitions of phenotypes, rapidly test ideas, and for deCODE scientists to follow where the data leads rather than their own hypotheses.[74] This has led to a range of discoveries that link diseases and at times use the genetics even to redefine phenotypes in unusual ways, and Stefansson has spent significant time explaining these discoveries and their utility to the scientific and lay media. Typically, discoveries made in Iceland are published alongside validation in outside populations. Conversely, deCODE has often used its resources to validate discoveries made elsewhere. Among the more noteworthy of these discoveries are, by disease and trait:
Alzheimer's disease
A variant in the APP gene was discovered in 2012 that protects carriers against Alzheimer's disease (AD) and protects the elderly from cognitive decline. It has been widely cited and used to inform the development of BACE1 inhibitors as potential treatments.[75] Stefansson and the deCODE team have also discovered variants in the TREM2 and ABCA7 genes that increase risk of AD.[76]
Schizophrenia, other psychiatric disorders, cognition
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. Studies in the early 2000s mapped the involvement of the Neuregulin 1 gene in schizophrenia, leading to substantial research in this novel pathway.[77] Over the next fifteen years they used standard GWAS and reduced fecundity as an intermediate phenotype to home in on SNPs and copy number variations (CNVs) linked to risk of schizophrenia and other disorders;[78] they demonstrated that genetic risk factors for schizophrenia and autism confer cognitive abnormalities even in control subjects;[79] they linked schizophrenia, bipolar disorder with both creativity and risk of addiction;[80] they identified genetic variants associated with educational attainment and childhood cognition;[81] and demonstrated that these variants are currently under negative evolutionary selection.[82] In addressing common psychiatric disorders and cognitive processes and traits across a population, this body of work has contributed to the present understanding of these conditions not as discrete phenotypes but as related through the disruption of fundamental cognitive functions.
Cancer
Stefansson and his colleagues have made numerous pioneering discoveries of genome variants conferring risk of many common cancers. They have played a role in shaping the now commonly accepted new paradigm for understanding cancer: that it should be defined at least as much in molecular terms as in where it occurs in the body. deCODE published holistic evidence of this in a familial aggregation of all cancers diagnosed in anyone in Iceland over fifty years, as well as other aggregation studies.[83] These have demonstrated through basic genetics that while certain site cancers clustered in families, others cluster in a non-site specific way, pointing to common molecular causes. They discovered the chromosome 8q24 locus as harboring risk variants for many types of cancer,[84] and variants in the TERT, TP53 and LG24 genes as risk factors for multiple cancers.[85]
deCODE has discovered a number of sequence variants linked to risk of prostate cancer (as well as a protective variant),[86] breast cancer,[87] melanoma and basal cell carcinoma,[88] thyroid cancer,[89] urinary bladder cancer,[90] ovarian cancer,[91] renal cell cancer,[92] gastric cancer,[93] testicular cancer,[94] lung cancer,[95] and clonal hematopoiesis.[96] Three studies over nearly a decade demonstrated the power of the population datasets in Iceland by showing that both common and rare variants linked to increased nicotine addiction and the number of cigarettes smoked per day were also a risk factor for lung cancer and peripheral artery disease; that is, that a genetic predisposition to smoking was at the same time a risk factor for smoking-related disease.[97]
Cardiovascular disease
Stefansson and his cardiovascular research team have worked with collaborators around the world to discover common and rare variants associated with risk of atrial fibrillation,[98] coronary artery disease (CAD),[99] stroke,[100] peripheral artery disease,[101] sick sinus syndrome,[102] and aortic and intracranial aneurysm.[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.[104] This finding is being used in drug discovery and development at Amgen.[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. However the genetic links to CAD risk provided a new view of how cholesterol is linked to heart disease. They reported that measuring non-HDL cholesterol better captures risk than measuring LDL cholesterol, which is current standard practice.[106]
Diabetes and other traits and conditions
deCODE discovered the link between type 2 diabetes (T2D) and variants in the TCF7L2 gene,[107] the most important common known genetic risk factor known, and variants in the CDKAL1 and other genes linked to insulin response and both increased and decreasednT2D risk.[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.
In 2014, Stefansson met David Altshuler, then deputy director of the Broad Institute, who stopped at deCODE on his way back from Finland and Sweden. Altshuler had been leading a T2D research effort and had found a rare variant that seemed to protect even those with common lifestyle risk factors from developing the disease. Stefansson looked for an association in deCODE data which confirmed that Icelanders did not have the exact variant found by Altshuler's team but did have another in the same gene that was clearly protective for T2D.[118] The deCODE team then added their variant to the paper that was published in Nature Genetics.[119]
Public-private collaboration and the development of precision medicine
While deCODE comprises the first and most comprehensive national genome project in the world, it has never been government funded. It has always been a business that relies on the voluntary participation of citizens and national health system doctors as partners in scientific discovery. This relationship between citizens and private enterprise, which seemed logical to Stefansson, counterintuitive to others and is disliked by some, is becoming ever more common.[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. Another is that discoveries are applied to trying to create and sell actual products to improve medicine and health. In a 2017 interview Iceland's former president Vigdis Finnbogadottir captured a common view: "If Icelanders can contribute to the health of the world, I'm more than proud. I'm grateful."[121]
Personal genomics and disease risk diagnostics
Stefansson has worked to turn his company's discoveries into medically useful and commercially successful products. Some were highly innovative and paved the way for new industries and markets. In the years after Íslendingabok put Icelanders' genealogies online, the Genographic Project and companies like MyHeritage, FamilyTreeDNA and Ancestry launched websites to enable people everywhere to try to use genetics to build out their genealogies.[122] In November 2007, deCODE launched deCODEme, the first personal genomics service, followed the next day by Google-backed 23andMe.[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. deCODE's published risk markers provided the most rigorously validated foundation for all such services.[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. These tests are using more markers and new algorithms to build upon the risk variants and approach pioneered in Iceland for these same diseases.[126]
Drug discovery
Yet Stefansson's principal goal has always been to use the genome to inform the development of better drugs. Years before precision medicine became a common term, he wanted to provide its foundation : to find and validate drug targets rooted in disease pathways rather than rely on trial and error in medicinal chemistry,[127] and to be able to test and prescribe drugs for patients likely to respond well.[128] This addresses longstanding productivity challenges in drug development and Stefansson has funded the company principally by partnering with pharmaceutical companies. A $200 million gene and target discovery deal with Roche in 1998 was an early sign of the industry's interest in genomics to make better drugs.[129] Other partnerships were formed with Merck, Pfizer, Astra Zeneca and others. In the mid-2000s the company brought several of its own compounds into clinical development but did not have the financial resources to continue their development after its insolvency and restructuring in 2009.[130]
By far the longest, deepest and most productive partnership has been that with Amgen. In 2012, Amgen bought deCODE for $415 million. 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.[131] With Amgen's full support it has continued to publish both commercially relevant gene and drug target discoveries and on human diversity and evolution, providing a high-profile example of how commercial goals, basic science and public dissemination of results can be mutually beneficial.[132]
The integration with Amgen coincided with the beginning of large-scale whole-genome sequencing at deCODE and the imputation of that data throughout the company's Iceland dataset. With that data, Stefansson and his colleagues at Amgen believed that genomics could be transformative to drug development in a way that was not possible with only SNP-chip and GWAS data.[133] Importantly, they could identify rare, high-impact mutations affecting common phenotypes — in brief, the most extreme versions of common diseases — yielding drug targets with potentially better validated and more tractable therapeutic potential. This "rare-for-common" approach is now being followed by many drug companies.[134] The identification of ASGR1 was an example of this and was taken into drug discovery to develop novel cholesterol-fighting drugs.[135]
More broadly, Amgen's longtime chief scientific officer Sean Harper said in 2018 that "with the acquisition of deCODE we gained an industrial capability to do population genetics" that could provide human genetic validation for any target or compound. deCODE assessed Amgen's entire clinical pipeline within a month of the acquisition, delivering information that has helped to avoid clinical failures and prioritize and guide trials. Harper claims that this "target-first drug development" model enabled the company to address its own version of the industry's endemic productivity problem. He estimated that "just [by] having strong genetic support for half your pipeline you can improve your rate of return on R&D investments by approximately 50%."[136]
Public health: BRCA2 screening
In 2018, deCODE launched a website that enables Icelanders to request the analysis of their sequence data to determine whether they carry a SNP in the BRCA2 gene linked to significantly increased risk of breast and prostate cancer in Icelanders.[137] This was the first time that deCODE, which is primarily a research organization, returned information from its research data to participants. Stefansson had tried for many years to convince the Icelandic Ministry of Health that this was a serious public health issue that deCODE's data could address at virtually no cost, and it was but one of the clearest-cut of many such possible precision medicine applications to healthcare in Iceland.[138]
With no response from the health system, Stefansson went ahead and put the matter in the hands of citizens. As of late 2018, some 40,000 people, more than ten percent of the population, had utilized the site to learn their BRCA2 status. Hundreds of people have been able to learn that they are carriers and the National Hospital has built up its counseling and other services to help those decide how they wish to use this information to protect their health.[139] Given the disease and mortality rates from breast and prostate cancer associated with BRCA2, the availability of this information should enable the prevention and early detection of hundreds of cancers and save dozens of lives.[140]
"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. What is often overlooked is that Kári and his colleagues at deCODE provided the template for this discovery engine. Moreover, it is easy to forget that when Kári founded deCODE Genetics 21 years ago, these concepts were considered quite radical and unlikely to succeed. He was both literally and figuratively on a small island of his own. As Peter Donnelly put it, "the number of countries now investing millions in similar resources is an astonishing testament to the perspicacity of his vision."[141]
Following on Iceland's success, countries now pursuing or planning national genome projects of varying scale, scope and rationale include the UK (via the UK Biobank as well as Genomics England and the Scottish Genomes Partnership separately); the US (All of Us as well as the Million Veteran Program[142]), Australia,[143] Canada,[144] Dubai,[145]Estonia, Finland,[146] France,[147] Hong Kong,[148] Japan,[149] Netherlands,[150] Qatar,[151] Saudi Arabia,[152] Singapore,[153] South Korea,[154] Sweden,[155] and Turkey.[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.[158]
In April 2019, Stefansson was named first president of the Nordic Society of Human Genetics and Precision Medicine, formed to create a pan-Nordic framework for human genetics research and the application of genomics to healthcare across the region, with the aim of generating and integrating genomic and healthcare data from Iceland, Norway, Sweden, Denmark, Finland and Estonia.
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.[165]
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.[167][168]
Popular culture
Stefansson is the model for professor Lárus Jóhannsson in Dauðans óvissi tími by Þráinn Bertelsson and the principal villain of Óttar M. Norðfjörð's satirical 2007 book Jón Ásgeir & afmælisveislan, in which he creates a female version of Davíð Oddsson from a sample of Davíð's hair. He is the model for Hrólfur Zóphanías Magnússon, director of the company CoDex, in CoDex 1962 by Sjón.[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.[171] He was also in the documentary Bobby Fischer Against the World where he engaged in controversial debate with late Bobby Fischer.[172][173]
Contrary to popular belief, Kári Stefánsson was not the model for Odinn in Vargold,[174] a series of graphic novels inspired by Norse mythology. Graphic artist Jón Páll Halldórsson explains that the similarities between his portrayal of the Norse God Odinn and Kári Stefánsson are purely accidental.
Notes
^This is an Icelandic name. The last name is patronymic, not a family name; in Iceland he is referred to by the given name Kári, but internationally he may be referred to as Stefansson.
References
^Gunnlaugur Haraldsson, ed. (2000). Læknar á Íslandi [Short biographies of Icelandic physicians]. Þjóðsaga. p. 963.
^His particular focus was myelin degeneration in multiple sclerosis. A selection of his publications from this period can be searched on Google Scholar.
^Adam Piore, "Bring us your genes: A Viking scientist's quest to conquer disease," Nautilus, 2 July 2015
^Gulcher, JR, Vartanian, T, and Stefansson K, "Is Multiple Sclerosis an automimmune disease?" Clinical Neuroscience 2(3-4):246-52 (1994)
^For contemporary views of this potential, MS Guyer and FS Collins, "The Human Genome Project and the future of medicine," American Journal of Diseases of Children, 147(11):1145-52 (November 1993)
^An authoritative mid-1990s view of the promise of genetics in diagnostics, Min J Khoury and Diane K Wagener, "Epidemiological evaluation of the use of genetics to improve the predictive value of disease risk factors," American Journal of Human Genetics, 56:835-844, 5 January 1995
^FS Collins et al., " New Goals for the U.S. Human Genome Project: 1998 –2003," Science, Vol. 282, pp. 682-689, 23 October 1998
^An influential early – and at that time still largely theoretical – discussion of different possible approaches to common rather than rare diseases is ES Lander and NJ Schork, "Genetic dissection of complex traits," Science, Vol. 265, Issue 5181, pp. 2037–2048, 30 September 1994
^This was not an obvious thing to look for. Even prominent experts who predicted the future power of population genetics and association studies seem not to have considered that linkage analysis could be extended to common diseases, and aid in association studies, through population-wide genealogies. Neil Risch and Kathleen Merikangas, "The future of genetic studies of complex human diseases," Science, Vol. 273, No. 5281, pp 1516–1517, 13 September 1996; Aravinda Chakravarti, "Population genetics: making sense out of sequence," Nature Genetics 21, pages 56–60, 1 January 1999
^Nicholas Wade, "SCIENTIST AT WORK/Kari Stefansson; Hunting for Disease Genes In Iceland's Genealogies," New York Times, 18 June 2002
^Announcement of deCODE starting operations on the front page of Morgunblaðið, 31 May 1996
^An early description of the discovery model and process by Stefansson and Gulcher when they still planned to build the IHD, in "Population genomics: laying the groundwork for genetic disease modeling and targeting," Clinical Chemistry and Laboratory Medicine(subscription required) 36(8):523-7, 1 August 1998
^A good early outline of Stefansson's vision and the business model in Stephen D. Moore, "Biotech firm turns Iceland into a giant genetics lab," Wall Street Journal(subscription required), 3 July 1997
^Gulcher, J, Helgason A, Stefansson, K, "Genetic homogeneity of Icelanders," Nature Genetics(subscription required) volume 26, page 395, December 2000. One example of the relative genetic homogeneity but global utility of studying the Icelandic population is breast cancer. Around the world there are many variants in the BRCA2 gene known to confer substantial increased risk of breast cancer, but in Iceland there is essentially one disease-linked variant, which was published on the eve of deCODE's operational launch in Iceland: Steinnun Thorlacius et al., "A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes," Nature Genetics(subscription required), Volume 13, pages117–119, 1 May 1996. deCODE now has a website that enables Icelanders to find out if they carry the mutation.
^Quoted in Michael Specter, "Decoding Iceland," The New Yorker(subscription required), 18 January 1999
^See for example Francesco Cuca et al., "The distribution of DR4 haplotypes in Sardinia suggests a primary association of type I diabetes with DRB1 and DQB1 loci," Human Immunology, Volume 43, Issue 4, pp 301-308, August 1995; EM Petty et al., "Mapping the gene for hereditary hyperparathyroidism and prolactinoma (MEN1Burin) to chromosome 11q: evidence for a founder effect in patients from Newfoundland," American Journal of Human Genetics, 54(6): 1060–1066, June 1994; Melanie M Mahtani et al., "Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families," Nature Genetics(subscription required), Volume 14, pp 90–94, 1 September 1996; Steinnun Thorlacius et al., "A single BRCA2 mutation," op. cit.
^Stephen D. Moore, "Biotech firm turns Iceland into," op. cit.
^Gulcher and Stefansson, "Population genomics: laying the groundwork," op. cit.
^Stefansson and Gulcher cite polls showing public support for the IHD of 75%, in "An Icelandic saga on a centralized healthcare database and democratic decision making," Nature Biotechnology(subscription required)(subscription required), volume 17, page 620, July 1999. Icelandic opponents to the IHD created an organization called Mannvernd to fight it and to encourage people to exercise their right to opt-out. The number of opt-outs provides one concrete measure of opposition to the idea as well as, conversely, a measure of how many people either favored the idea or held no strong opinion. According to an archived snapshot of Mannvernd's website from September 2003, in the five years following the passage of the law authorizing the IHD, just over 20,000 people had opted out, or 7% of a 2003 population of 288,000.
^Books and major research articles by bioethicists on these themes include: Mike Fortun, Promising genomics: Iceland and deCODE genetics in a World of speculation (Berkeley: University of California Press, 2008); David Winickoff, "Genome and nation: Iceland's Health Sector Database and its legacy," Innovations: Technology Governance Globalization 1(2):80-105, February 2006"; Henry T. Greely, "Iceland's plan for genomics research: Facts and implications," Jurimetrics(subscription required) 40, no. 2, pp153-91, Winter 2000; and Jon Merz, "Iceland, Inc?: On the ethics of commercial population genomics", Social Science & Medicine 58(6):1201-9, April 2004. Apart from Mannvernd's, another website in Berkeley, California was devoted to the anthropological implications of deCODE and genetics research in Iceland: http://www.lib.berkeley.edu/iceland/
^Stefansson and Gulcher estimated that by 1999 more than 700 articles and interviews had been published. For this and their view on the benefits of what deCODE was doing: "An Icelandic saga on a centralized healthcare database," op. cit. A partial snapshot of the number, flavor and sources of articles can be seen from an archived view from May 1999 of the website of Mannvernd, the Icelandic organization formed to oppose the IHD, and in a highly detailed bibliographyArchived 7 May 2019 at the Wayback Machine created by Dr Skúli Sigurðsson, a leading member of Mannvernd.
^J Gulcher, K Kristjansson, H Gudbjartsson, K Stefansson, "Protection of privacy by third-party encryption in genetic research in Iceland," European Journal of Human Genetics(subscription required), volume 8, pp. 739–742, 3 October 2000
^Henry T Greely, "Iceland's plan for genomics research," op. cit.
^How Stefansson's population strategy transformed thinking in the field and gene discovery by the mid-2000s in Lee Silver, "Biology reborn: A genetic science breakthrough," Newsweek, 9 October 2007.
^A list of deCODE's key publications, on virtually all of which Stefansson is senior author, are listed by year on the company's website at https://www.decode.com/publications/
^JL Weber, "The Iceland Map," and A Kong et al., "A high resolution recombination map of the human genome," Nature Genetics(subscription required), Volume 31, pp 225–226 and 241–247, respectively, 10 June 2002. On how the map improved the accuracy of the reference sequence see Nicholas Wade, "Human genome sequence has errors, scientists say," New York Times, 11 June 2002.
^In 1999, Icelandic anthropologist Gisli Palsson already noted the success of the deCODE model: Gisli Palsson and Paul Rabinow, "Iceland: The case of a national genome project," Anthropology Today Vol. 15, No. 5, pp. 14-18, 5 October 1999. A 2009 report by genetics ethics watchdog GeneWatch, a vehement opponent of the IHD and the use of medical records data in research without explicit consent, notes deCODE as a major inspiration for the UK Biobank. In 2000, bioethicist George Annas already noted emulation of the deCODE approach, New England Journal of Medicine(subscription required), 342:1830-1833, 15 June 2000; David Winickoff, "Genome and nation," op. cit. On deCODE's early successes and their importance as an example to other biobank projects and the field in general see also Nicholas Wade, "Scientist at Work/Kari Stefansson: Hunting for disease genes in Iceland's genealogies," New York Times, 18 June 2002.
^Jocelyn Kaiser, "Population databases boom from Iceland to U.S.," Science(subscription required) Vol. 298, Issue 5596, pp. 1158–1161, 8 November 2002. No one else had comparable genealogies, but Eric Lander was inspired by the scale and data-driven approach in Iceland and founded the Broad Institute on the idea of using rapidly developing technologies for generating more data – SNP chips and then sequencing – to power discovery. Lee Silver, "Biology reborn: a genetic science breakthrough," Newsweek, 9 October 2007
^This database is overwhelmingly complete going back to the Icelandic census of 1703, the world's first complete national census and now part of UNESCO's registered world heritage, and extending back to before the arrival of the first inhabitants in the 9th century.
^Usage numbers cited on the Íslendingabok Wiki page. A more detailed discussion by a longtime observer, anthropologist Gísli Pálsson, in "The Web of Kin: An Online Genealogical Machine," in Sandra C. Bamford, ed., Kinship and Beyond: The Genealogical Model Reconsidered (New York: Berghahn Books, 2009), pp. 84–110.
^Details of how the privacy protection system works in Gulcher et al., "Protection of privacy by third-party encryption," op. cit.
^A good early description of how people are asked to participate and how their data is used in research is on pp. 7-9 of deCODE's 2002 annual report filed with the SEC.
^By 2004, the government and deCODE had effectively stopped all work on the IHD and moved on. On page 10 of deCODE's 2003 annual report filed with the SEC, the company described the mutual lack of activity: "As of March 2004, a government-mandated review of the IHD's data encryption and protection protocols, which began in April 2000, had not been completed. When and if this review and issuance of related security certification is completed, we will evaluate whether and when, if at all, to proceed with the development of the IHD in light of our priorities and resources at that time. In light of our current business plans and priorities, we do not expect the IHD to be a material aspect of our business in the near future."
^James Butcher, "Kari Stefansson, general of genetics," The Lancet, 27 January 2007
^Anna Azvolinsky, "Master Decoder: A Profile of Kári Stefánsson," The Scientist, 1 March 2019
^In 2018, most advanced national genome efforts were still aspiring to generate and assemble 100,000 whole genome sequences in one place. See Alex Phillipidis, "10 Countries in the 100K genome club," Clinical Omics, 30 August 2018
^A pioneering early methodology for phasing and imputation is in A Kong et al., "Detection of sharing by descent, long-range phasing and haplotype imputation," Nature Genetics(subscription required) volume 40, pages 1068–1075, 17 August 2008. The first published sequence imputation dates from 2015: DF Gudbjartsson et al., "Large-scale whole-genome sequencing of the Icelandic population" published as part of the "Genomes of Icelanders" special edition, Nature Genetics(subscription required), 47, pp. 435–444, 25 May 2015
^Axton also pointed out that notwithstanding deCODE scientists' hundreds of publications elsewhere, 111 papers, or five percent of the papers published during his tenure at the journal over the preceding twelve years, had come out of deCODE. Axton's comments are from his remarks at deCODE's 20th anniversary conference, held in Reykjavík on 30 September 2016, available in video on the company website at https://www.decode.com/20-years/
^A Kong et al., "A high resolution recombination map of the human genome," Nature Genetics(subscription required), Volume 31, pp 241–247, 10 June 2002
^A Kong et al., "Reproduction rate and reproductive success," Nature Genetics(subscription required), volume 36, pp 1203–1206, 3 October 2004
^H Stefansson et al., "A common inversion under selection in Europeans," Nature Genetics(subscription required), volume 37, pages 129–137, 16 January 2005
^A Kong et al., "Fine-scale recombination rate differences between sexes, populations and individuals," Nature(subscription required), volume 467, pp 1099–1103, 28 October 2010
^A Kong et al., "Rate of de novo mutations and the importance of father's age to disease risk," Nature, volume 488, pp 471–475, 23 August 2012
^H Jonsson et al., "Parental influence on human germline de novo mutations in 1,548 trios from Iceland," Nature(subscription required), volume 549, pp 519–522, 28 September 2017
^A Jonsson et al., "Multiple transmissions of de novo mutations in families," Nature Genetics(subscription required), Volume 50, pp 1674-1680, 5 November 2018
^BV Halldorsson et al., "The rate of meiotic gene conversion varies by sex and age," Nature Genetics(subscription required), volume 48, pp 1377–1384, 19 September 2016
^BV Halldorsson et al., "Characterizing mutagenic effects of recombination through a sequence-level genetic map," Science, Vol. 363, Issue 6425, eaau1043, 25 January 2019
^A Helgason et al., "The Y chromosome point mutation rate in humans," Nature Genetics,(subscription required), volume 47, pp 453–457, 25 March 2015
^A Helgason et al., "Sequences from first settlers reveal rapid evolution in Icelandic mtDNA pool," PLoS Genetics, 16 January 2009
^A Helgason et al., "Estimating Scandinavian and Gaelic ancestry in the male settlers of Iceland," American Journal of Human Genetics, 67(3): 697–717, 7 August 2000; and A Helgason et al., "mtDNA and the Origin of the Icelanders: Deciphering Signals of Recent Population History," American Journal of Human Genetics, 66(3):999-1016, 23 February 2000
^SS Ebenesersdottir et al., "Ancient genomes from Iceland reveal the making of a human population," Science(subscription required), Vol. 360, Issue 6392, pp. 1028-1032, 1 June 2018
^A Helgason et al., "An association between the kinship and fertility of human couples," Science(subscription required), Vol. 319, Issue 5864, pp. 813-816, 8 February 2008
^A Helgason et al., " An Icelandic example of the impact of population structure on association studies," Nature Genetics(subscription required), Volume 37, pages 90–95, 19 December 2004
^P Sulem et al., " Identification of a large set of rare complete human knockouts," Nature Genetics(subscription required), Volume 47, pages 448–452, 25 March 2015
^A Jagadeesan et al., "Reconstructing an African haploid genome from the 18th century," Nature Genetics(subscription required), volume 50, pp199–205, 15 January 2018. Hans Jonatan is the subject of a book by Icelandic anthropologist Gisli Palsson, The Man Who Stole Himself (Chicago: University of Chicago Press, 2016) and Stefansson addressed the reconstruction of Hans Jonatan's genome in the New York Times, The Atlantic, Newsweek, Der Spiegel and elsewhere.
^Stefansson presented an early explanation of the 'broad but rigorous' approach to the definition of phenotypes powered by datamining at the European Molecular Biology Laboratory (EMBL) conference in Barcelona in 2000; it is also discussed in many publications. See for example S Gretarsdottir et al., "Localization of a susceptibility gene for common forms of stroke to 5q12," American Journal of Human Genetics, Volume 70, Issue 3, pp 593-603, March 2002
^T Jonsson et al., "A mutation in APP protects against Alzheimer's disease and age-related cognitive decline," Nature, 488, pp 96–99, 11 June 2012; Michael Specter, "The good news about Alzheimer's Disease," The New Yorker, 11 July 2012; Ewen Callaway, "Gene mutation defends against Alzheimer's Disease," Nature, 11 July 2012
^T Jonsson et al., "Variant of TREM2 associated with the risk of Alzheimer's disease," New England Journal of Medicine, 368(2):107-16, 10 January 2013; S Steinberg et al., "Loss-of-function variants in ABCA7 confer risk of Alzheimer's disease," Nature Genetics, 47(5):445-7, 25 March 2015
^H Stefansson et al., "Neuregulin 1 and susceptibility to schizophrenia," American Journal of Human Genetics, Volume 71, Issue 4, pp 877-892, October 2002. Like many early linkage-based findings, this association itself has not proved fruitful, but substantial later work has been done on the pathway. See for example A Buonanno, "The neuregulin signaling pathway and schizophrenia: From genes to synapses and neural circuits," Brain Research Bulletin, Volume 83, Issues 3–4, pp 122-131, 30 September 2010
^H Stefansson et al., "Large recurrent microdeletions associated with schizophrenia," Nature(subscription required), volume 455, pp 232-6, 11 September 2008; H Stefansson et al., Nature(subscription required), "Common variants conferring risk of schizophrenia," Nature, volume 460, pp 744-7, 6 August 2009; Niamh Mullins et al., "Reproductive fitness and genetic risk of psychiatric disorders in the general population," Nature Communications, Volume 8, Article number 15833, 13 June 2017
^H Stefansson et al., "CNVs conferring risk of autism or schizophrenia affect cognition in controls," Nature, volume 505, pp 361-6, 18 December 2013
^RA Power et al., "Polygenic risk scores for schizophrenia and bipolar disorder predict creativity," Nature Neuroscience(subscription required), Volume 18, pp 953–955, 8 June 2015; GW Reginsson et al., "Polygenic risk scores for schizophrenia and bipolar disorder associate with addiction," Addiction Biology, volume 23, issue 1, pp 485-492, 25 February 2017
^B Gunnarsson et al., "A sequence variant associating with educational attainment also affects childhood cognition," Nature Scientific Reports, volume 6, article number 36189
^LT Amundadottir et al., "Cancer as a Complex Phenotype: Pattern of Cancer Distribution within and beyond the Nuclear Family," PLoS Medicine, 1(3):e65, 28 December 2004; T Gudmundsson et al., "A population-based familial aggregation analysis indicates genetic contribution in a majority of renal cell carcinomas," International Journal of Cancer, 100(4):476-9, 13 June 2002; S Jonsson et al., "Familial risk of lung carcinoma in the Icelandic population," Journal of the American Medical Association (JAMA), 292(24):2977-83, 22 December 2004
^J Gudmundsson et al., "Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24," Nature Genetics(subscription required), Volume 39, pp 631–637, 1 April 2007; LA Kiemeney et al., "Sequence variant on 8q24 confers susceptibility to urinary bladder cancer," Nature Genetics, 40(11):1307-12, 14 September 2008; J Gudmundsson et al., "A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer," Nature Genetics(subscription required), Volume 44, pages 1326–1329, 28 October 2012; J Gudmundsson et al., "A common variant at 8q24.21 is associated with renal cell cancer," Nature Communications, Vol 4, Article number: 2776, 13 November 2013
^T Rafnar et al., "Sequence variants at the TERT-CLPTM1L locus associate with many cancer types," Nature Genetics,(subscription required), 41(2):221-7, 18 January 2009; SN Stacey et al., "A germline variant in the TP53 polyadenylation signal confers cancer susceptibility," Nature Genetics, 43(11):1098-103, 25 September 2011; U Styrkarsdottir et al., "Nonsense mutation in the LGR4 gene is associated with several human diseases and other traits," Nature(subscription required), Vol 497, pp 517–520, 5 May 2013
^LT Amundadottir et al., "A common variant associated with prostate cancer in European and African populations," Nature Genetics(subscription required), 38(6):652-8, 27 May 2006; J Gudmundsson et al., "Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer," Nature Genetics(subscription required), 40(3):281-3, 10 February 2008; J Gudmundsson et al., "Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility," Nature Genetics, 41(10):1122-6, 20 September 2009; J Gudmundsson et al., "A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer," Nature Genetics(subscription required), Volume 44, pages 1326–1329, 28 October 2012; SN Stacey et al., "Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer," Human Molecular Genetics, 25(5):1008-18, 1 March 2016; J Gudmundsson et al., "Genome-wide associations for benign prostatic hyperplasia reveal a genetic correlation with serum levels of PSA," Nature Communications, Vol 9, Article number: 4568, 8 November 2018
^SN Stacey et al., "The BARD1 Cys557Ser Variant and Breast Cancer Risk in Iceland," PLoS Medicine, 20 June 2006; SN Stacey et al., "Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor–positive breast cancer," Nature Genetics(subscription required), volume 39, pp 865–869, 27 May 2007; SN Stacey et al., "Common variants on chromosome 5p12 confer susceptibility to estrogen receptor–positive breast cancer," Nature Genetics(subscription required), Volume 40, pp 703–706, 27 April 2008.
^DF Gudbjartsson et al., "ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma," Nature Genetics(subscription required), Volume 40, pp 886–891, 18 May 2008; SN Stacey et al., "Common variants on 1p36 and 1q42 are associated with cutaneous basal cell carcinoma but not with melanoma or pigmentation traits," Nature Genetics, Volume 40, pp 1313–1318, 12 October 2008; SN Stacey et al., "New common variants affecting susceptibility to basal cell carcinoma," Nature Genetics, Volume 41, pp 909–914, 5 July 2009; SN Stacey et al., "Germline sequence variants in TGM3 and RGS22 confer risk of basal cell carcinoma," Human Molecular Genetics, Volume 23, Issue 11, pp 3045–3053, 1 June 2014; SN Stacey et al., "New basal cell carcinoma susceptibility loci," Nature Communications volume 6, Article number 6825, 9 April 2015.
^J Gudmundsson et al., "Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations," Nature Genetics(subscription required)volume 41, pp 460–464, 6 February 2009; J Gudmundsson et al., "Discovery of common variants associated with low TSH levels and thyroid cancer risk," Nature Genetics(subscription required)volume 44, pp 319–322, 22 January 2012; J Gudmundsson et al., "A genome-wide association study yields five novel thyroid cancer risk loci," Nature Communications volume 8, article number 14517, 14 February 2017
^L Kiemney et al., "Sequence variant on 8q24 confers susceptibility to urinary bladder cancer," Nature Genetics(subscription required) volume 40, pp 1307–1312, 14 September 2008; L Kiemeney et al., "A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer," Nature Genetics(subscription required), volume 42, pp 415–419, 28 March 2010; T Rafnar et al., "European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene," Human Molecular Genetics, Volume 20, Issue 21, ppages 4268–428, 11 November 2011; T Rafnar et al., "Genome-wide association study yields variants at 20p12.2 that associate with urinary bladder cancer," Human Molecular Genetics, Volume 23, Issue 20, ppages 5545–5557, 15 October 2014.
^T Rafnar et al., "Mutations in BRIP1 confer high risk of ovarian cancer," Nature Genetics(subscription required), volume 43, pp 1104–1107, 2 October 2011
^T Gudbjartsson et al., "A population‐based familial aggregation analysis indicates genetic contribution in a majority of renal cell carcinomas," International Journal of Cancer, 13 June 2002; J Gudmundsson et al., "A common variant at 8q24.21 is associated with renal cell cancer," Nature Communications, volume 4, Article number: 2776, 13 November 2013.
^H Helgason et al., "Loss-of-function variants in ATM confer risk of gastric cancer," Nature Genetics(subscription required), volume 47, pages 906–910, 22 June 2015
^JT Bergthorsson et al., "A genome-wide study of allelic imbalance in human testicular germ cell tumors using microsatellite markers," Cancer Genetics and Cytogenetics, Volume 164, Issue 1, pp 1-91, 1 January 2006
^S Jonsson et al., "Familial Risk of Lung Carcinoma in the Icelandic Population," Journal of the American Medical Association (JAMA), Volume 292(24), pp 2977-2983, 22 December 2004; TE Thorgeirsson et al., "A variant associated with nicotine dependence, lung cancer and peripheral arterial disease," Nature, volume 452, pp 638–642, 3 April 2008
^F Zink et al., "Clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly," Blood, Volume 130, pp 742-752, February 2002
^TE Thorgeirsson et al., "A variant associated with nicotine dependence, lung cancer and peripheral arterial disease," Nature(subscription required), vol 452, pp 638–6423, 3 April 2008; TE Thorgeirsson et al., "Sequence variants at CHRNB3–CHRNA6 and CYP2A6 affect smoking behavior," Nature Genetics(subscription required), volume 42, pp 448–453, 25 April 2010; TE Thorgeirsson et al., "A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences," Molecular Psychiatry, volume 21, pp 594–600, 8 March 2016. Megan Brooks, "Genes affect smoking behaviour, lung cancer risk," Reuters, 26 April 2010
^DF Gudbjartsson et al., "Variants conferring risk of atrial fibrillation on chromosome 4q25," Nature(subscription required), Volume 448, pp 353–357, 19 July 2007; DF Gudbjartsson et al., "A frameshift deletion in the sarcomere gene MYL4 causes early-onset familial atrial fibrillation," European Heart Journal, Volume 38, Issue 1, Pages 27–34, 1 January 2017; RB Thorolfsdottir et al., "A Missense Variant in PLEC Increases Risk of Atrial Fibrillation," Journal of the American College of Cardiology, Volume 70, Issue 17, pp 2157-2168, 24 October 2017; RB Thorolfsdottir et al., "Coding variants in RPL3L and MYZAP increase risk of atrial fibrillation," Communications Biology, Volume 1, Article number 68, 12 June 2018
^See notes 101 and 102 infra and: A Helgadottir et al., "Rare SCARB1 mutations associate with high-density lipoprotein cholesterol but not with coronary artery disease," European Heart Journal, Volume 39, Issue 23, pp 2172–2178, 14 June 2018; E Bjornsson et al., "A rare splice donor mutation in the haptoglobin gene associates with blood lipid levels and coronary artery disease," Human Molecular Genetics, Volume 26, Issue 12, pp 2364–2376, 15 June 2017; S Gretarsdottir et al., "A Splice Region Variant in LDLR Lowers Non-high Density Lipoprotein Cholesterol and Protects against Coronary Artery Disease," PLoS Genetics, 1 September 2015; E Bjornsson et al., "Common Sequence Variants Associated With Coronary Artery Disease Correlate With the Extent of Coronary Atherosclerosis," Arteriosclerosis, Thrombosis, and Vascular Biology, Volume 35, pp 1526–1531, 1 June 2015; A Helgadottir et al., "A Common Variant on Chromosome 9p21 Affects the Risk of Myocardial Infarction," Science(subscription required), Vol. 316, Issue 5830, pp 1491-1493, 8 June 2007; A Helgadottir et al., "The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke," Nature Genetics, Volume 36, pp 233–239, 8 February 2004
^DF Gudbjartsson et al., "A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke," Nature Genetics(subscription required)volume 41, pp 876–878, 13 July 2009; S Gretarsdottir et al., "The gene encoding phosphodiesterase 4D confers risk of ischemic stroke," Nature Genetics(subscription required), Volume 35, pp 131–138, 21 September 2003; S Gretarsdottir et al., "Localization of a Susceptibility Gene for Common Forms of Stroke to 5q12," American Journal of Human Genetics, Volume 70, Issue 3, pp 593-603, March 2002
^TE Thorgeirsson et al., "A variant associated with nicotine dependence, lung cancer and peripheral arterial disease," op. cit.; G Gudmundsson et al., "Localization of a Gene for Peripheral Arterial Occlusive Disease to Chromosome 1p31," American Journal of Human Genetics, Volume 70, Issue 3, pp 586-592, March 2002
^H Holm et al., "A rare variant in MYH6 is associated with high risk of sick sinus syndrome," Nature Genetics(subscription required), Volume 43, pp 316–320, 6 March 2011
^A Helgadottir et al., "The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm," Nature Genetics(subscription required), Volume 40, pp 217–224, 6 January 2008; S Gretarsdottir et al., "Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm," Nature Genetics(subscription required), Volume 42, pp 692–697, 11 July 2010
^P Nioi et al., "Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease," New England Journal of Medicine, Volume 374, pp 2131-2141, 2 June 2016
^This discovery attracted significant scientific and media attention. See, for example, Matt Herper, "Amgen researchers find gene that reduces heart attack risk," Forbes, 18 May 2016; Antonio Regalado, "Amgen finds anti-heart attack gene," MIT Technology Review, 18 May 2016; Ewen Callaway, "Protective gene offers hope for next blockbuster heart drug," Nature, 19 May 2016.
^A Helgadottir et al., "Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease," Nature Genetics(subscription required)volume 48, pages 634–639, 2 May 2016
^SFA Grant et al., "Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes," Nature Genetics(subscription required), Volume 38, pp 320–323, 15 January 2006; A Helgason et al., "Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution," Nature Genetics(subscription required), Volume 39, pp 218–225, 7 January 2007
^V Steinthorsdottir et al., "A variant in CDKAL1 influences insulin response and risk of type 2 diabetes," Nature Genetics(subscription required), Volume 39, pp 770–775, 26 April 2007; V Steinthorsdottir et al., "Identification of low-frequency and rare sequence variants associated with elevated or reduced risk of type 2 diabetes," Nature Genetics(subscription required), Volume 46, pp 294–298, 26 January 2014; EV Ivarsdottir et al., "Effect of sequence variants on variance in glucose levels predicts type 2 diabetes risk and accounts for heritability," Nature Genetics(subscription required), Volume 49, pp 1398–1402, 7 August 2017; J Gudmundsson et al., "Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes," op. cit.
^G Thorleifsson et al., "Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma," Nature Genetics(subscription required), Volume 42, pp 906–909, 12 September 2010; G Thorleifsson et al., "Common Sequence Variants in the LOXL1 Gene Confer Susceptibility to Exfoliation Glaucoma," Science(subscription required), Volume 317, Issue 5843, pp 1397-1400, 7 September 2007
^P Sulem et al., "Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche," Nature Genetics(subscription required), Volume 41, pp 734–738, 17 May 2009
^H Stefansson et al., "Variant in the sequence of the LINGO1 gene confers risk of essential tremor," Nature Genetics(subscription required), Volume 41, pp 277–279, 1 February 2009
^G Sveinbjornsson et al., "HLA class II sequence variants influence tuberculosis risk in populations of European ancestry," Nature Genetics(subscription required), Volume 48, pp 318–322, 1 February 2016
^DF Gudbjartsson et al., "Many sequence variants affecting diversity of adult human height," Nature Genetics, Volume 40, pp 609–615, 6 April 2008; S Benonisdottir et al., "Epigenetic and genetic components of height regulation," Nature Communications, Volume 7, Article number 13490, 16 November 2016
^V Emilsson et al., "Genetics of gene expression and its effect on disease," Nature(subscription required), Volume 452, pp 423–428, 27 March 2008
^P Sulem et al., "Two newly identified genetic determinants of pigmentation in Europeans," Nature Genetics(subscription required), Volume 40, pp 835–837, 18 May 2008; P Sulem et al., "Genetic determinants of hair, eye and skin pigmentation in Europeans," Nature Genetics(subscription required), Volume 39, pp 1443–1452, 12 October 2007
^A Helgadottir et al., "Genome-wide analysis yields new loci associating with aortic valve stenosis," Nature Communications, Volume 9, Article number 987, 7 March 2018
^RP Kristjansson et al., "A loss-of-function variant in ALOX15 protects against nasal polyps and chronic rhinosinusitis," Nature Genetics(subscription required), Volume 51, pp 267–276, 14 January 2019
^The story recounted by Gina Kolata, "Rare mutation kills off gene responsible for diabetes," New York Times, 2 March 2014
^J Flannick et al., " Loss-of-function mutations in SLC30A8 protect against type 2 diabetes," Nature Genetics(subscription required), Volume 46, pp 357–363, 2 March 2014
^In 2006, one Reykjavík resident and a participant in deCODE research said that about 90% of people thought taking part in research funded by pharmaceutical companies made sense, while about 10% were against it, roughly capturing the participation rate of those asked. Michael D Lemomick, "The Iceland experiment: How a tiny island nation captured the lead in the genomic revolution," Time, 12 February 2006. Those who do not agree remain vocal even as emulation of the deCODE model proliferates: See for example Emma Jane Kirby, "Iceland's DNA: the world's most precious genes?," BBC News, 19 June 2014.
^The breadth of impact of the model and Finnbogadottir quote in Catherine Offord, "Learning from Iceland's Model for Genetic Research," The Scientist, 1 June 2017
^David P Hamilton, "Genetic genealogy hits the big time," VentureBeat, 17 October 2007
^Nicholas Wade, "Company offers genome assessments," New York Times, 16 November 2007; David P Hamilton, " 23andMe lets you search and share your genome — today," VentureBeat, 17 November 2007
^deCODEme and other tests apart from 23andMe are no longer offered, but contemporaneous examples of deCODE discoveries being foundational to personal genome scans examining validated risk for type 2 diabetes and coronary artery disease can be seen in G Palomaki et al., "Use of genomic panels to determine risk of developing type 2 diabetes in the general population: a targeted evidence-based review," Genetics in Medicine, Volume 15, pp 600–611, August 2013; Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group, "Recommendations from the EGAPP Working Group: genomic profiling to assess cardiovascular risk to improve cardiovascular health," Genetics in Medicine, Volume 12, pp 839-43, December 2010
^Amit V Khera et al, "Genetic Risk, Adherence to a Healthy Lifestyle, and Coronary Disease," New England Journal of Medicine, Volume 375, pp 2349-2358 (December 2016); Amit V Khera, "Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations," Nature Genetics(subscription required), Volume 50, pp 1219–1224, 13 August 2018. Coverage of these papers in the New York Times, Nature, Forbes, and the MIT Technology Review revived nearly verbatim discussions from a decade earlier about both the value of such tests and the gaps in doctors' and the general public's understanding about what the results mean.
^See Stephen D Moore, "Biotech firm turns island into a giant genetics lab," op. cit. On the advent of "precision medicine" as a term, Luke Timmerman, "What's in a Name? A Lot, When It Comes to 'Precision Medicine'," Xconomy, 4 February 2013
^One instance of Stefansson's view of the role of genetics in drug development and in the context of the growing genomics industry in Ann Thayer, "The Genomics Evolution: Small technology providers and major drug firms become allies to find the causes of disease, to validate targets, and to understand drug response," Chemical and Engineering News, 8 December 2003
^On the thinking behind the Roche deal, with only a modest dose of the fevered hyperbole and innuendo of the time, see Eliot Marshall, "Iceland's blond ambition," Mother Jones, May/June 1998
^Emily Singer, "DeCODE ditches drug development," MIT Technology Review, 22 January 2010
^On acquisition and its rationale in broad context, as well as deCODE being left in independent control over its data, see Matt Herper, " With DeCode deal, Amgen aims to discover drugs like we meant to in 1999," Forbes, 10 December 2012
^The science page of Amgen's website prominently features many deCODE publications and projects.
^A Kamb, S Harper and K Stefansson, "Human genetics as a foundation for innovative drug development," Nature Biotechnology(subscription required), Vol 31, pp 975–978, November 2013
^The best known example of this the inhibitors of PCSK9, identified in families with rare hypercholesterolemia and then developed more broadly for lowering cholesterol and reducing risk of heart disease.
^A discussion of progress in this strategy is in Meg Tirrell, "Iceland's genetic goldmine and the man behind it," CNBC, 6 April 2017
^Quoted in Asher Mullard, "An audience with...Sean Harper," Nature Reviews Drug Discovery(subscription required), Vol 17, pp 10-11, January 2018
^Company press release on the opening of the website Arfgerd.is (Icelandic only), 15 May 2018
^On lack of response from the government see Andy Coghlan, "Warn people of genetic health risks, says deCODE boss," New Scientist, 25 March 2015
^The US National Cancer Institute estimates that about 75% of women with a BRCA2 risk mutation will develop breast cancer before the age of 80. On the poorer prognosis of carriers of BRCA2 variants with prostate cancer, see MR Akhbari et al., "The impact of a BRCA2 mutation on mortality from screen-detected prostate cancer," British Journal of Cancer, Volume 111, pp 1238–1240, 9 September 2014
^M Daly, "2017 William Allan Award Introduction: Kári Stefansson," American Journal of Human Genetics, Volume 102, Issue 3, p 350, 1 March 2018
^A literary critique of these references in Lucy Burke, "Genetics at the Scene of the Crime: DeCODING Tainted Blood," Journal of Literary & Cultural Disability Studies, Volume 6, Number 2, pp. 193-208
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