deCODE and Iceland: A Critique

deCODE Genetics Inc. was a for-profit American corporation built around the idea of cloning and characterising the genes of Icelanders and marketing the information so obtained through a central database containing health information, genetic information and genealogy. deCODE's database plan in Iceland brought into focus business practices of the genomics industry and a number of ethical issues. The company promoted and sold its shares to the public in Iceland through a ‘grey market’ before its initial public offering, leading to large investment losses for common Icelanders with little investment experience. The law permitting the health sector database was found unconstitutional and the company never built the controversial database. Instead it pursued traditional genome-wide association studies attempting to identify genetic changes contributing to common diseases. Through this work, the company created a large database and contributed a large number of scientific papers, but was a commercial failure going bankrupt in 2009. After a stalking-horse sale it rose from the ashes and continued operation as a private company under almost the same name, focusing on whole genome sequencing data to understand common diseases and human variation. At the end of 2012, Amgen announced that it would pay $415 million to acquire deCODE. The sale price was based on a product derived from an Icelandic resource but no compensation was given to the Icelandic people. Key Concepts: deCODE was founded on the belief that unifactorial methods of searching for identity by descent in extensive pedigrees, so important in searching for Mendelian traits, would yield the genetics of common disease. The genetic variants in most current GWA studies only explain a portion of the heritability. Multiple variants, each with a small effect, seem to contribute to common diseases. Rare genetic variant conferring a larger effect may also contribute to common diseases. As a foundation for a commercial company, the identification of genetic variants in common disease was a failure for deCODE Genetics. deCODE lays claim to a number of scientific papers but turning the science into a profitable busienss failed. deCODE Genetics Inc. employed questionable business practices when raising funds from the public in Iceland. The health sector database law in Iceland was found to be unconstitutional and deCODE Genetics never built the database on which its initial public offering was based. deCODE Genetics Inc. declared bankruptcy but rose from the ashes after a stalking-horse sale to a company partly owned by some of initial investors and by sequencing giant Illumina. It now operates under the name deCODE Genetics ehf. In December 2012 deCODE was purchased by Amgen and is now operated as a wholly owned Amgen subsidiary. Keywords: medical records; health sector database; genealogy; ethics; informed consent; fair compensation; privacy; biotechnology; human genetics; questionable busines practices

[1]  J. Gulcher,et al.  Genomewide scan for hand osteoarthritis: a novel mutation in matrilin-3. , 2003, American journal of human genetics.

[2]  H. Greely.  The uneasy ethical and legal underpinnings of large-scale genomic biobanks. , 2007, Annual review of genomics and human genetics.

[3]  C. Gieger,et al.  A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke , 2009, Nature Genetics.

[4]  L. Kruglyak.  Prospects for whole-genome linkage disequilibrium mapping of common disease genes , 1999, Nature Genetics.

[5]  A. Sigurdsson,et al.  Common variants on chromosome 5p12 confer susceptibility to estrogen receptor–positive breast cancer , 2008, Nature Genetics.

[6]  Bjarni V. Halldórsson,et al.  New sequence variants associated with bone mineral density , 2009, Nature Genetics.

[7]  Kevin M. Bradley,et al.  Common sequence variants on 2p15 and Xp11.22 confer susceptibility to prostate cancer , 2008, Nature Genetics.

[8]  J. Gulcher,et al.  An Icelandic saga on a centralized healthcare database and democratic decision making , 1999, Nature Biotechnology.

[9]  J. Gulcher,et al.  The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke , 2004, Nature Genetics.

[10]  Clement Adebamowo,et al.  Ancestry-Shift Refinement Mapping of the C6orf97-ESR1 Breast Cancer Susceptibility Locus , 2010, PLoS genetics.

[11]  David B. Goldstein,et al.  The Importance of Synthetic Associations Will Only Be Resolved Empirically , 2011, PLoS biology.

[12]  A. Gylfason,et al.  Mutations in BRIP1 confer high risk of ovarian cancer , 2011, Nature Genetics.

[13]  E. Árnason.  Genetic Heterogeneity of Icelanders , 2003, Annals of human genetics.

[14]  Paolo Vineis,et al.  Sequence variants at the TERT-CLPTM1L locus associate with many cancer types , 2009, Nature Genetics.

[15]  H. Stefánsson,et al.  The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm , 2008, Nature Genetics.

[16]  D. Gudbjartsson,et al.  Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes , 2007, Nature Genetics.

[17]  A. Gylfason,et al.  Genetic Correction of PSA Values Using Sequence Variants Associated with PSA Levels , 2010, Science Translational Medicine.

[18]  D. Postma,et al.  Sequence variants affecting eosinophil numbers associate with asthma and myocardial infarction , 2009, Nature Genetics.

[19]  Joshua M. Korn,et al.  Association between microdeletion and microduplication at 16p11.2 and autism. , 2008, The New England journal of medicine.

[20]  J. Gulcher,et al.  Localization of a gene for peripheral arterial occlusive disease to chromosome 1p31. , 2002, American journal of human genetics.

[21]  J. Gulcher,et al.  Linkage of Osteoporosis to Chromosome 20p12 and Association to BMP2 , 2003, PLoS biology.

[22]  D. Gudbjartsson,et al.  Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche , 2009, Nature Genetics.

[23]  Mark Gurney,et al.  The gene encoding phosphodiesterase 4D confers risk of ischemic stroke , 2003, Nature Genetics.

[24]  K. Stefánsson,et al.  The Icelandic Healthcare Database and informed consent. , 2000, The New England journal of medicine.

[25]  A. Abbott.  Sweden sets ethical standards for use of genetic ‘biobanks’ , 1999, Nature.

[26]  Vilmundur Gudnason,et al.  Localization of a susceptibility gene for common forms of stroke to 5q12. , 2002, American journal of human genetics.

[27]  J. Gulcher,et al.  Genetics of psoriasis in Iceland: evidence for linkage of subphenotypes to distinct Loci. , 2005, The Journal of investigative dermatology.

[28]  R. Fossdal,et al.  A whole genome association study in Icelandic multiple sclerosis patients with 4804 markers , 2003, Journal of Neuroimmunology.

[29]  Ellen Kampman,et al.  Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity , 2009, Nature Genetics.

[30]  J. Gulcher,et al.  The BARD1 Cys557Ser Variant and Breast Cancer Risk in Iceland , 2006, PLoS medicine.

[31]  J. Gulcher,et al.  A major susceptibility gene for asthma maps to chromosome 14q24. , 2002, American journal of human genetics.

[32]  Judy H. Cho,et al.  Finding the missing heritability of complex diseases , 2009, Nature.

[33]  Kari Stefansson,et al.  Discovery of common variants associated with low TSH levels and thyroid cancer risk , 2012, Nature Genetics.

[34]  Vilmundur Gudnason,et al.  A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction , 2006, Nature Genetics.

[35]  Variant in the sequence of the LINGO1 gene confers risk of essential tremor. , 2009, Nature genetics.

[36]  David B. Goldstein,et al.  Rare Variants Create Synthetic Genome-Wide Associations , 2010, PLoS biology.

[37]  E. Árnason.  The Icelandic Healthcare Database. , 2000, The New England journal of medicine.

[38]  Daniel F. Gudbjartsson,et al.  A variant associated with nicotine dependence, lung cancer and peripheral arterial disease , 2008, Nature.

[39]  N. Risch.  Searching for genetic determinants in the new millennium , 2000, Nature.

[40]  Nilanjan Chatterjee,et al.  Estimation of effect size distribution from genome-wide association studies and implications for future discoveries , 2010, Nature Genetics.

[41]  Pall I. Olason,et al.  Common variants conferring risk of schizophrenia , 2009, Nature.

[42]  D. Gudbjartsson,et al.  Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24 , 2007, Nature Genetics.

[43]  Gerard Tromp,et al.  Genome-wide association study identifies a sequence variant within the DAB2IP gene conferring susceptibility to abdominal aortic aneurysm , 2010, Nature Genetics.

[44]  Eric E. Smith,et al.  Variants conferring risk of atrial fibrillation on chromosome 4q25 , 2007, Nature.

[45]  D. Gudbjartsson,et al.  A high-resolution recombination map of the human genome , 2002, Nature Genetics.

[46]  H. Stefánsson,et al.  Neuregulin 1 and susceptibility to schizophrenia. , 2002, American journal of human genetics.

[47]  A. Kong,et al.  The role of linkage studies for common diseases. , 2001, Current opinion in genetics & development.

[48]  Jian Ge,et al.  CFH Y402H Confers Similar Risk of Soft Drusen and Both Forms of Advanced AMD , 2005, PLoS medicine.

[49]  D. Gudbjartsson,et al.  Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor–positive breast cancer , 2007, Nature Genetics.

[50]  J. Gulcher,et al.  Linkage of Essential Hypertension to Chromosome 18q , 2002, Hypertension.

[51]  D. Gudbjartsson,et al.  Common variants on 1p36 and 1q42 are associated with cutaneous basal cell carcinoma but not with melanoma or pigmentation traits , 2008, Nature Genetics.

[52]  T. Thorgeirsson,et al.  Anxiety with panic disorder linked to chromosome 9q in Iceland. , 2003, American journal of human genetics.

[53]  A. Gylfason,et al.  A Common Variant on Chromosome 9p21 Affects the Risk of Myocardial Infarction , 2007, Science.

[54]  D. Gudbjartsson,et al.  A susceptibility gene for psoriatic arthritis maps to chromosome 16q: evidence for imprinting. , 2003, American journal of human genetics.

[55]  A. Gylfason,et al.  Fine-scale recombination rate differences between sexes, populations and individuals , 2010, Nature.

[56]  Thomas W. Mühleisen,et al.  Large recurrent microdeletions associated with schizophrenia , 2008, Nature.

[57]  Kari Stefansson,et al.  A genetic risk factor for periodic limb movements in sleep. , 2007, The New England journal of medicine.

[58]  H. Stefánsson,et al.  Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma , 2010, Nature Genetics.

[59]  J. Ott,et al.  Sometimes it's hot, sometimes it's not , 1998, Nature Genetics.

[60]  P. Visscher,et al.  Common SNPs explain a large proportion of heritability for human height , 2011 .

[61]  J. Gulcher,et al.  Population Genomics: Laying the Groundwork for Genetic Disease Modeling and Targeting , 1998, Clinical chemistry and laboratory medicine.

[62]  H. Stefánsson,et al.  A novel TEAD1 mutation is the causative allele in Sveinsson's chorioretinal atrophy (helicoid peripapillary chorioretinal degeneration). , 2004, Human molecular genetics.

[63]  E. Benedikz,et al.  Genetic homogeneity of Icelanders: fact or fiction? , 2000, Nature Genetics.

[64]  A. Gylfason,et al.  A common variant associated with prostate cancer in European and African populations , 2006, Nature Genetics.

[65]  G. Gibson.  Hints of hidden heritability in GWAS , 2010, Nature Genetics.

[66]  E. Zeggini,et al.  Synthetic Associations Are Unlikely to Account for Many Common Disease Genome-Wide Association Signals , 2011, PLoS biology.

[67]  J. Gulcher,et al.  A variant in CDKAL1 influences insulin response and risk of type 2 diabetes , 2007, Nature Genetics.

[68]  Bjarni V. Halldórsson,et al.  Many sequence variants affecting diversity of adult human height , 2008, Nature Genetics.

[69]  H. Stefánsson,et al.  Support for involvement of the AHI1 locus in schizophrenia , 2007, European Journal of Human Genetics.

[70]  O. Varenne,et al.  A call for accurate phenotype definition in the study of complex disorders , 2004, Nature Genetics.

[71]  Snæbjörn Pálsson,et al.  Genetic determinants of hair, eye and skin pigmentation in Europeans , 2007, Nature Genetics.

[72]  Daniel F. Gudbjartsson,et al.  Association of Variants at UMOD with Chronic Kidney Disease and Kidney Stones—Role of Age and Comorbid Diseases , 2010, PLoS genetics.

[73]  N. Holtzman,et al.  Will genetics revolutionize medicine? , 2000, The New England journal of medicine.

[74]  Kari Stefansson,et al.  Association of neuregulin 1 with schizophrenia confirmed in a Scottish population. , 2003, American journal of human genetics.

[75]  Kari Stefansson,et al.  Sequence Variants in the RNF212 Gene Associate with Genome-Wide Recombination Rate , 2008, Science.

[76]  J. Gulcher,et al.  Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution , 2007, Nature Genetics.

[77]  Snæbjörn Pálsson,et al.  Two newly identified genetic determinants of pigmentation in Europeans , 2008, Nature Genetics.

[78]  G. Annas,et al.  Rules for research on human genetic variation--lessons from Iceland. , 2000, The New England journal of medicine.

[79]  J. Gulcher,et al.  Localization of a gene for migraine without aura to chromosome 4q21. , 2003, American journal of human genetics.

[80]  Kari Stefansson,et al.  ASIP and TYR pigmentation variants associate with cutaneous melanoma and basal cell carcinoma , 2008, Nature Genetics.

[81]  Dan M Roden,et al.  A rare variant in MYH6 is associated with high risk of sick sinus syndrome , 2011, Nature Genetics.

[82]  D. Gudbjartsson,et al.  New common variants affecting susceptibility to basal cell carcinoma , 2009, Nature Genetics.

[83]  Kari Stefansson,et al.  A germline variant in the TP53 polyadenylation signal confers cancer susceptibility , 2011, Nature Genetics.

[84]  Ole A. Andreassen,et al.  A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline , 2012, Nature.

[85]  Kari Stefansson,et al.  Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations , 2009, Nature Genetics.

[86]  Kari Stefansson,et al.  Several common variants modulate heart rate, PR interval and QRS duration , 2010, Nature Genetics.

[87]  R. Haraldsdóttir.  Icelandic gene database will uphold patients' rights. , 1999, BMJ.

[88]  H. Stefánsson,et al.  Identification of low-frequency variants associated with gout and serum uric acid levels , 2011, Nature Genetics.

[89]  Tony Fletcher,et al.  Sequence variant on 8q24 confers susceptibility to urinary bladder cancer , 2008, Nature Genetics.

[90]  Kari Stefansson,et al.  Multiple genetic loci for bone mineral density and fractures. , 2008, The New England journal of medicine.

[91]  Peter Kraft,et al.  Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis , 2012, Nature Genetics.

[92]  Bjarni V. Halldórsson,et al.  Sequence variants in the CLDN14 gene associate with kidney stones and bone mineral density , 2009, Nature Genetics.

[93]  Kari Stefansson,et al.  Common Sequence Variants in the LOXL1 Gene Confer Susceptibility to Exfoliation Glaucoma , 2007, Science.

[94]  H. Stefánsson,et al.  Mapping of a familial essential tremor gene, FET1, to chromosome 3q13 , 1997, Nature Genetics.

[95]  L Kruglyak,et al.  Genetic isolates: separate but equal? , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[96]  H. Stefánsson,et al.  Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes , 2006, Nature Genetics.

[97]  Paolo Vineis,et al.  A sequence variant at 4p16.3 confers susceptibility to urinary bladder cancer , 2010, Nature Genetics.

[98]  J. Gulcher,et al.  Association of Vitamin D Binding Protein Variants with Chronic Mucus Hypersecretion in Iceland , 2004, American journal of pharmacogenomics : genomics-related research in drug development and clinical practice.

[99]  J. Gulcher,et al.  Localization of a susceptibility gene for type 2 diabetes to chromosome 5q34-q35.2. , 2003, American journal of human genetics.

[100]  D. Goldstein,et al.  Uncovering the roles of rare variants in common disease through whole-genome sequencing , 2010, Nature Reviews Genetics.