Scientists at deCODE Genetics and academic collaborators from Iceland, the USA, The Netherlands and Spain today report the discovery of variants in the human genome that associate with levels of thyroid stimulating hormone and risk of thyroid cancer. The paper ‘Discovery of common variants associated with low TSH levels and thyroid cancer risk‘ is published today in the online edition of Nature Genetics.

Using data obtained by applying both Illumina whole-genome sequencing technology and Illumina SNP chip technology, deCODE’s scientists performed a genome wide association study on levels of thyroid stimulating hormone (TSH) in 27,758 Icelanders. 22 SNPs with genomewide significance were discovered, of which one, rs965513 had previously been shown to associate with thyroid cancer. The remaining 21 SNPs were genotyped in 561 Icelandic thyroid cancer cases and 40,013 controls. Variants suggestively associated with thyroid cancer were then genotyped in an additional 595 non-Icelandic cases and 2,603 controls.

After combining the results, three separate variants on chromosomes 2q35, 8p12 and 14q13.3 were shown to associate with risk of thyroid cancer, conferring an added risk of 30 – 100%, compared to the general population. These variants were also found to associate with low levels of TSH, a key regulator in the biology and endocrinology of the thyroid gland.

“This study underscores the important role that the genetics of diversity in normal physiologic function can play in understanding the risk of disease. To date, the at-risk alleles of all the variants that confer risk of thyroid cancer associate with decreased serum levels of TSH, suggesting that the primary disorder in non-medullary thyroid cancer is an endocrine one, characterized by decreased concentration of TSH,” said Kari Stefansson, deCODE’s CEO and senior author of the study.

Thyroid Cancer is a malignant thyroid neoplasm, which can be treated with radioactive iodine or surgical resection of the thyroid gland. The contribution of genetics to the risk of thyroid cancer is greater than to any other cancer. Thyroid cancer is classified into four main histology groups: papillary (PTC), follicular (FTC), medullary (MTC), and undifferentiated or anaplastic thyroid carcinomas. The great majority of malignant thyroid tumours are nonmedullary, either PTC (80–85%) or FTC (10–15%).

deCODE’s discovery capabilities combine its extensive population and genetic resources, including DNA samples and medical data, complete genealogical information, next generation sequencing technology, and deCODE’s proprietary bioinformatics and statistical capabilities. Over the next 18 months, deCODE and Pfizer will work together to analyse the genomes of patients to search for sequence variants that would be useful for understanding drug targets and discovering novel drug targets, that may ultimately lead to tools for patient stratification and companion diagnostics.

“This agreement is a part of deCODE’s ongoing strategy to unleash the value of human genetics,” said Dr. Kari Stefansson, founder and CEO of deCODE, “our research platform allows us to understand the genetic basis of disease and modifiers of clinical phenotypes in actual patient populations; by doing so, we can rapidly move from targets to patient stratification and from there to companion diagnostics.”

The research collaboration will utilize the expertise and capabilities of both deCODE and Pfizer: deCODE’s comprehensive population genetics resources and analytical expertise and Pfizer’s dedication to the application of genomic analysis to the discovery and development of drugs.

Scientists at deCODE Genetics and academic collaborators from Iceland, Norway, Denmark, the Netherlands and the USA today report the discovery of low frequency variants in the human genome that associate with risk of gout, a common inflammatory arthritis, and serum uric acid levels. The study was done in collaboration with Illumina Inc., and is published today in the online edition of Nature Genetics.

Using Illumina sequencing technology, deCODE scientists determined the sequences of the entire genomes of 457 Icelanders, and identified 16 million single nucleotide polymorphisms (SNPs). Through a combination of SNP genotyping and computational techniques utilizing the extensive Icelandic genealogy, they were able to propagate those 16 million variants into over 40,000 Icelanders, including over 1,200 patients with gout and over 22,000 individuals for whom serum uric acid measurements were available.

The researchers observed a sequence variant in a previously unidentified gout susceptibility gene located on chromosome 19 that has a large effect on serum uric acid levels and gout. The sequence variant is a mis-sense mutation that causes an increase in the level of uric acid by 0.04 mmol/L and a three-fold increase in the risk of gout. Close to 4% of individuals in the overall Icelandic population carry this variant, and ~0.2% of the individuals assessed by academic collaborators in Norway, Denmark, The Netherlands and the United States.

The variant encodes an amino acid change in ALDH16A1, a member of the aldehyde dehydrogenase (ALDH) superfamily, and could motivate further biological studies of this pathway. Other members of the ALDH superfamily have been associated with other clinical phenotypes including alcohol-induced flushing.

Also, at a previously reported locus on chromosome 1, the researchers discovered another novel low frequency variant associating with serum uric acid level and gout. The variant decreases the risk of gout by 50%, and the level of uric acid by 0.05 mmol/L. Approximately 3% of the Icelandic population carry this variant and 1.5% of the European subjects.

For both loci the effect on risk of gout is significantly higher among men than women, but the effect on serum uric acid levels is the same in both sexes.

“This study underscores the importance of whole genome sequencing of well-phenotyped populations. We are pleased that the clinical and genetic resource that deCODE has built enables us to make such discoveries,” said Kari Stefansson, deCODE’s CEO and senior author of the study.

“We are committed to turning discoveries such as this, as well as our recent findings in ovarian cancer and sick sinus syndrome, and our future discoveries, into real benefit for patients,” Dr. Stefansson continued.

Gout is a common inflammatory arthritis caused by urate crystal formation resulting from a high concentration of uric acid in the blood, which is in turn caused by an imbalance in the dietary intake of purines and in the synthesis an excretion of urate. The incidence of gout increases with age and is three times higher in men than in women.

Scientists at deCODE Genetics and academic collaborators from Iceland, The Netherlands, Spain and Finland today report the discovery of variants in the human genome that associate with  increased risk of invasive ovarian cancer, one of the deadliest forms of cancer in women.  The study was done in collaboration with Illumina Inc., and is published today in the online edition of Nature Genetics.

Using Illumina sequencing technology, deCODE scientists determined the sequences of the entire genomes of 457 Icelanders, and identified 16 million single nucleotide polymorphisms (SNPs). Through a combination of SNP genotyping and computational techniques utilizing the extensive Icelandic genealogy, they were able to propagate those 16 million variants into over 40,000 Icelanders, including over 600 patients with ovarian cancer.

The researchers observed a rare sequence variant in a gene named BRIP1 that confers more than eightfold increase in the risk of ovarian cancer in the Icelandic population.  BRIP1 plays an important role in maintaining the stability of the genome and interacting directly with the DNA repair protein encoded by the known breast cancer gene BRCA1.  Interestingly, the mutation also associates with increased risk of being diagnosed with cancer in general, and individuals carrying the variant live 3.6 years fewer on average.

The researchers also searched for mutations in the BRIP1 gene in ovarian cancer patients in other populations.  A rare variant in BRIP1 was found in a Spanish cohort of 144 patients and 896 controls; this mutation confers a significantly increased risk of not only ovarian cancer, but also breast cancer.  Finally, examination of  tumors from ovarian cancer patients that carry the mutation showed a loss of the healthy copy of the gene, further supporting the role of BRIP1 as a classical tumor suppressor.

“This study underscores the important contribution that the Icelandic population can make to the discovery of low frequency sequence variants with large effect.  The potential to do this has been clear since the critical role played by Iceland in the discovery of the BRCA2 gene.  Until now, however, the combination of sequencing technology and analytical techniques were insufficient to unleash the flood of discoveries that we and our collaborators are now making,” said Kari Stefansson, deCODE’s CEO and senior author of the study.

“Our objective is to translate our discoveries most rapidly into benefit for patients.  So, we are committed to working with our collaborators, as we did in this case, to identify the spectrum of mutations occuring in other populations.  This allows us to use the Icelandic resource as a unique discovery cohort, and then quickly elucidate the broader utility,” Dr. Stefansson added.

Ovarian cancer causes more deaths than any other gynecologic malignancy in developed countries.  Five-year relative survival rate is less than 45%, with the stage at diagnosis being the major prognostic factor.  Importantly, only 19% of ovarian cancer cases are diagnosed while the cancer is still localized and chances of cure are over 90%.  Hence, the discovery of genetic variants that increase the risk of ovarian cancer may enable the development of diagnostic tests to identify women at high risk for the disease.  Women at high risk can then be be offered frequent screening for early detection and treatment or preventive intervention.

Scientists at deCODE Genetics and academic collaborators from Iceland, The Netherlands, Spain, Denmark, Germany, Sweden, the USA, the UK and Romania today report the discovery of a variant in the sequence of the human genome associated with risk of developing basal cell carcinoma of the skin (BCC), as well as prostate cancer and glioma, the most serious form of brain cancer.  The study was done in collaboration with Illumina, Inc., and is published today in the online edition of Nature Genetics.

Using Illumina sequencing technology, deCODE scientists determined the sequences of the entire genomes of 457 Icelanders, and identified 16 million single nucleotide polymorphisms (SNPs). Through a combination of SNP genotyping and computational techniques utilizing the extensive Icelandic genealogy, they were able to propagate those 16 million variants into over 40,000 Icelanders for use in this study.

The researchers discovered a single letter variant located in TP53, a gene known to play a central role in tumor biology and for accumulating so called somatic mutations, during the development of cancer in patients.  Until now, however, individuals who are born with defective copies of the gene (germline variants) have been found extremely rarely, only in families with cancer predisposition syndromes, Li Fraumeni syndrome (LFS) and Li-Fraumeni-like syndrome (LFL). The variant found in the present study is an unusual type of mutation that appears to affect the way the gene’s messenger RNA is processed; the messenger RNA in patients with the mutant TP53 gene appears to lack proper termination and polyadenylation.

This is the first evidence of a germline variant in TP53 associated with cancer predisposition beyond LFS and LFL. While the mutations causing LFS and LFL syndromes are very rare (occuring 1:5,000 to 1:20,000 births), the variant described in this paper occurs in ~ 1 in 25 individuals in Iceland, and at comparable frequencies in US and UK populations.

“This mutation is one of a growing number of deCODE discoveries of relatively low frequency sequence variants with large effect,” said Kari Stefansson, deCODE’s CEO and senior author of the study.  “The discovery of such variants is made possible through the breadth and quality of the data that the Icelandic population provides.”

Dr. Stefansson emphasized, “We will, together with our collaborators, including Illumina, extend ourselves to turn this discovery into benefit for patients and those at risk of cancer.”

BCC is the most common cancer in people of European ancestry. Sun exposure is the primary risk factor for BCC, but genetic predisposition also plays a substantial role.   Until now, no mechanistic causal connection between cancers as diverse as BCC, prostate cancer, glioma, and colorectal adenoma was known.

The paper, “A Germline Variant in the TP53 Polyadenylation Signal Confers Cancer Susceptibility” is published online in Nature Genetics at www.nature.com/ng and will appear in an upcoming print edition of the journal.

Scientists at deCODE genetics and academic colleagues from Iceland, The Netherlands, Denmark, USA and Illumina, Inc., today report the discovery of single-letter variants (SNPs) in the sequence of the human genome associated with high risk of sick sinus syndrome. The study is published today in the online edition of Nature Genetics.

The study reports a genetic variant in the gene MYH6 that is associated with high risk of sick sinus syndrome in Icelanders. The lifetime risk of being diagnosed with Sick sinus syndrome is about 6% for individuals without this genetic variant but is increased by 12.5 times, to approximately 50%, for those that carry the variant. Sick sinus syndrome is a heart rhythm disorder that is characterized by an inappropriately slow heart rate. It is commonly seen in the elderly and many with Sick sinus syndrome eventually need a permanent pacemaker.

With the aim of searching for sequence variants that predispose to Sick sinus syndrome, a genome-wide association study was performed including 792 Icelanders with Sick sinus syndrome and 37,592 Icelandic controls. The study utilized SNP data from several sources including Illumina SNP chip genotyping as well as whole-genome sequencing of 7 Icelanders with Sick sinus syndrome and 80 Icelanders not diagnosed with Sick sinus syndrome. The whole-genome sequencing data yielded a strong association between Sick sinus syndrome and a rare missense mutation in MYH6 that could not be accounted for by any other sequence variation. MYH6 encodes one form of myosin, a major component of the contractile system of the heart, and was recently associated with the function of the conduction system of the heart by studies from deCODE and others. This is the first time that MYH6 is implicated in the development of heart rhythm disorders.

“This work constitutes our first entry into the study of rare variants in common diseases that confer large risk of disease. It is clear that the risk of common diseases in our society is accounted for by both common and rare variants in the sequence of the genome. We here at deCODE and scientists all over the world have over the past few years discovered large numbers of common variants that confer risk of common diseases. Now we are entering into the era of rare variants that are providing us with clear insights into the pathogenesis of diseases and possibilities of putting together very effective diagnostics” said Kari Stefansson, deCODE’s CEO and senior author of the study.

The paper, “A rare variant in MYH6 is associated with high risk of sick sinus syndrome” is published online in Nature Genetics at www.nature.com/ng and will appear in an upcoming print edition of the journal.

Sick sinus syndrome, or sinus node dysfunction, is a common clinical disorder that is characterized by pathological slow heart rate, sinus arrest and/or attenuated heart rate response to exercise. The syndrome comprises a wide range of electrophysiological abnormalities, including failure of the sinus node and atrial impulse formation or propagation, as well as susceptibility to atrial tachyarrhythmias, particularly atrial fibrillation. Although encountered at any age, Sick sinus syndrome is primarily a disease of the elderly and is often secondary to other cardiac disorders when diagnosed in younger individuals. Symptoms are often intermittent and/or nonspecific and include dizziness, syncope and heart failure. The only effective treatment for symptomatic and irreversible sinus node dysfunction is permanent cardiac pacing, and Sick sinus syndrome remains the most common indication for permanent pacemaker implantation.

Analysis of four SNPs, in tandem with genetic risk factors detected by the deCODE ProstateCancer™ test, yields substantial improvement in efficacy of PSA screening

Scientists from deCODE genetics and academic colleagues from Iceland, the UK, US, Netherlands, Spain and Romania today report the discovery of a set of single-letter variations in the sequence of the human genome (SNPs) that impact individual baseline levels of prostate specific antigen, or PSA. Testing for PSA levels is the most commonly used screening tool for the detection of prostate cancer. A prostate biopsy is routinely recommended for men with PSA above a certain threshold. However, PSA levels can rise for reasons unrelated to prostate cancer and baseline healthy levels vary substantially between individuals, resulting in many men without cancer being biopsied while cancer in others is not detected. The paper published today demonstrates that analysis of four SNPs can be used to derive a personalized PSA threshold that more accurately identifies those men who are more likely to have a positive biopsy and for whom one should therefore be recommended.

“This is straighforward genetics with direct clinical utility. Detected early, prostate cancer can be treated with near total success. The challenge is to more effectively risk stratify the population, identifying and biopsying those at high risk and with aggressive disease while minimizing the number of negative biopsies we perform. And using the genetics we are improving the sensitivity and specificity of PSA testing. Like virtually every protein in the body, PSA levels vary between individuals according to SNPs that regulate gene expression. The SNPs reported today enable us to personalize PSA thresholds, thereby changing the recommendation on whether to biopsy for a substantial proportion of men. Moreover, the discriminatory power of testing for these SNPs is highest when done in tandem with the SNPs associated directly with risk of the disease measured by our deCODE ProstateCancer™ test. We are working to swiftly incorporate these PSA markers into our testing portfolio,” said Kari Stefansson, CEO of deCODE and senior author on the study.

The paper, entitled “Genetic correction of PSA values using sequence variants associated with PSA levels,” is published today online in Science Translational Medicine and will appear in an upcoming print edition of the journal. The study was conducted in several stages and involved tens of thousands of men with and without prostate cancer. First, more than 300,000 SNPs were analyzed in 16,000 Icelandic men with PSA measurements but who had never been diagnosed with prostate cancer. SNPs that correlated with PSA levels were identified and then validated in a cohort from the UK. These SNPs were then studied in large case-control cohorts from Iceland, the Netherlands, Spain, Romania and the US to establish the association with PSA levels independent of risk of prostate cancer itself. The authors then demonstrated how measuring four SNPs correlated with PSA levels can be used to obtain a personalized threshold for when to biopsy, and that using such thresholds improves the ratio of positive to negative biopsies. The greatest improvement in prediction accuracy was seen when men were tested both for the PSA correction SNPs as well as a panel of prostate cancer risk SNPs detected by the deCODE ProstateCancer™ test.

deCODE and the authors wish to thank the thousands of participants who took part in this study. It was funded in part by grant 202059 (PROMARK) and grant 218071 (CancerGene), both from the 7^th Framework Program of the European Union.

The most detailed template yet of the different ways in which women and men, individuals and populations, are driving one of the main motors of evolution

Scientists from deCODE genetics today publish in Nature the highest resolution recombination map of the human genome yet developed. Recombination is the reshuffling of the genome that occurs in the formation of eggs and sperm: we inherit one version of each chromosome from each of our parents, and create novel blends of the two that we pass on to our offspring. This process is fundamental to generating human diversity, providing novel configurations of the genome that enable the species to adapt to ever-changing environments. The map is published and made freely available to the scientific community at www.nature.com, and at www.decode.com/addendum, where updates will be provided.

In 2002, deCODE created a 6000-marker framework recombination map that enabled the correct assembly of the first sequence of the human genome. The map published today, which is put into the public domain as deCODE and other institutions begin to sequence and analyze large numbers of whole genomes, was constructed using 300,000 single-letter markers, or SNPs. It incorporates data from more than 15,000 parent-offspring pairs participating in deCODE’s gene discovery work in Iceland to show in high resolution where recombinations tend to take place. Among the findings are that some 15% of male and female recombination hotspots are unique to each sex. Moreover, women tend to contribute more to generating new combinations of genes, while men are doing more to create new versions of the genes themselves. So too, new variations in the PRDM9 gene have been identified that correlate with differences between individuals in how evenly recombinations are spread across the genome, and with different distributions of recombinations between people of African and European origin.

“This map is to me a thing of beauty. We are looking in quite high definition at the ingenious processes driving the generation of human diversity. From our previous work we have seen in basic terms that recombination is different between women and men, and between individuals and families. There are genetic factors that increase recombination in one sex while decreasing it in the other; women recombine at 1.6 times the rate of men; and women who recombine more tend to have more children. So we knew that nature is putting a premium on the generation of diversity. Here we see in detail the variations involved in generating variation, from women and men playing complementary roles in generating new versions and new configurations of genes, to differences in versions of PRDM9 between Africans and Europeans,” said Kari Stefansson, deCODE CEO and senior author on the paper.

The construction of this map was made possible by the unique breadth and comprehensiveness of deCODE’s population genetics resources in Iceland, and by new methods developed by deCODE statisticians for determining the parental origins of genetic markers. Because this new map is built by looking directly at real recombination events in large numbers of real families, it provides the first detailed picture of recombination differences between the sexes and individuals. By contrast, other recent recombination maps have been constructed using data on linkage disequilibrium – the frequency with which strings of genetic markers tend to be inherited together – in large numbers of unrelated people. The virtue of the latter maps is that they provide an historical catalogue of recombination as our species has evolved; the new deCODE map provides the complementary view of what this process looks like in a real population at a specific point in time.

Independent of obesity itself, WHR is a key indicator of risk of diabetes, heart disease and mortality, and appears to be regulated differently in women and men.

Reykjavik, ICELAND, 11 October 2010 – In two of the largest metastudies of their kind to date, scientists from the GIANT consortium, including deCODE as well as hundreds of academic institutions on three continents, today report the discovery of eighteen new regions of the human genome contributing to obesity and thirteen new regions influencing waist-hip ratio (WHR). The studies bring together data on body mass index (BMI, a measure of obesity), WHR (a measure of body fat distribution), and detailed genotypic information, from more than a quarter of a million participants from Europe, North America and Australia. The findings demonstrate the effectiveness of collaborations such as GIANT for powering studies large enough to detect lower-impact genetic factors for common traits and diseases.

“To my mind, perhaps the most noteworthy aspect of these findings is that it has indeed been possible to find so many loci for WHR that are independent of BMI. Most of the BMI loci appear to affect central and neuronal processes regulating satiety and appetite. By contrast, the WHR loci appear to be involved in the development and distribution of adipose tissue. Thus, the genetics seems to be pointing us to biological distinctions between two components of the regulation of weight – how much we eat, and how and where calories are stored as fat. Also intriguing, many of the WHR loci show a significantly greater impact in women than in men, a distinction that is stronger here than in any other disease or trait we have looked at. From a health perspective, the distinctions drawn here between BMI and WHR are steps towards better understanding the role of these two traits as risk factors for a range of diseases,” said Kari Stefansson, deCODE CEO and a senior author on the BMI study.

The papers, “Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index,” and “Meta-analysis identifies 13 novel loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution,” are published online in Nature Genetics at www.nature.com/ng and will appear in an upcoming print edition of the journal.

Scientists at deCODE genetics and academic colleagues from Iceland, China, Sweden, the UK and Australia today report the discovery of the most important single-letter variation (SNP) in the sequence of the human genome yet associated with risk of primary open-angle glaucoma. This is the most common form of glaucoma and a major cause of blindness worldwide.

The SNP on chromosome 7q31 is common among Europeans, with approximately 6% of people of European ancestry carrying two copies of the at-risk version, putting them at roughly 60% greater risk of developing the disease than those who carry none. But among Chinese, the impact of the SNP is markedy different. In study groups from Hong Kong and Shantou, the at-risk version of the SNP is shown to be carried by less than 1% the population, but each copy carried confers a more than five-fold increase in risk. The SNP is near the genes encoding caveolin 1 and 2, membrane proteins that are expressed in the meshwork that drains fluid from the eye, a process that if disturbed can increase pressure on the optic nerve and lead to glaucoma.

“The key to reducing the personal and public health impact of glaucoma is early diagnosis and treatment to slow the loss of sight. Discoveries such as today’s, which follows on our previous landmark findings in exfoliation glaucoma, are important because we can fold them directly into tests to target screening and to detect and treat more disease earlier. Moreover, among Chinese this latest SNP alone can define a small fraction of the population that should be very carefully screened. This underscores the value of being able to systematically analyze the impact of genetic risk factors across continental ancestries. Not only are these markers medically useful, they also tell us a bit about evolution and the spread of humanity across the globe,” said Kari Stefansson, deCODE’s Executive Chairman and President of Research and senior author of the study.

The authors would like to thank the more than 40,000 people who participated in this study, both glaucoma patients and control subjects. The paper, “Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma,” is published online in Nature Genetics at www.nature.com/ng and will appear in an upcoming print edition of the journal.

Primary open-angle glaucoma is a disease in which the optic nerve becomes damaged, leading to a progressive loss of sight. It affects tens of millions of people worldwide, mostly those over the age of 50. Incidence increases with age and varies between populations. Other known risk factors include high blood pressure and diabetes. Current treatments include eye drops that reduce pressure on the optic nerve, as well as surgery.

deCODE genetics and ARUP Laboratories today announced a partnership  through which ARUP will offer deCODE’s DNA-based prostate cancer risk assessment test  to its clients nationwide.

Under the terms of the non-exclusive agreement, ARUP will integrate deCODE ProstateCancer™ into the portfolio of tests it offers to leading academic medical centers, public and private healthcare providers, and major hospitals across the United States. ARUP’s clients will order the test, submit samples and receive results through ARUP, with deCODE conducting the genetic analysis in its CAP and CLIA-certified laboratory.

deCODE ProstateCancer measures 25 common single-letter variations, or SNPs, in the sequence of the human genome that are associated with the risk of prostate cancer. These SNPs were validated in tens of thousands of patients and controls in many populations. The risk conferred by these common SNPs is independent of family history, and does not correlate with benign prostatic hyperplasia (a non-cancerous enlargement of the prostate). The test can identify approximately 15% of men in the general population who are at double the average risk of prostate cancer as well as 5% who have triple the average risk. This test is complementary to standard clinical risk screening, including PSA, providing additional information for a more complete and personalized picture of individual risk to help doctors manage effective screening and early-detection strategies.

“The management of patients with elevated or borderline PSA continues to be a challenge, and having the additional knowledge of a patient’s genetic risk for prostate cancer can be very useful. We are pleased to be working with deCODE, who has developed this test through a number of large clinical studies and continues to demonstrate excellent scientific productivity in the area of human genetics,” said Edward Ashwood, MD, President and CEO of ARUP Laboratories.

“We are excited to be partnering with ARUP to increase the availability of our prostate cancer test to physicians and their patients. The quality and breadth of their services, and their range of customers across the healthcare spectrum, make them an excellent partner. Our test helps to meet the need for improved risk stratification and patient outcomes, and we believe that this alliance will make these benefits available to a greater number of patients,” said Kari Stefansson, Executive Chairman and President of Research at deCODE.

ARUP Laboratories plans to begin offering deCODE’s prostate cancer risk test (ARUP test code 2003326) to clients in the fall of 2010.

Cigarette smoking is a major cause of illness and death worldwide. But it is a complex behavior, and how much people smoke, how hard they find it to quit, and the impact of long-term smoking on health varies greatly among individuals. A substantial portion of this variability is genetic. Two years ago, deCODE discovered the first common, single-letter variation (SNP) in the sequence of the human genome, on chromosome 15q25, associated with nicotine addiction and risk of lung cancer.

Today, deCODE scientists and academic colleagues from 23 institutions in a dozen countries build on this work with the discovery of common SNPs on chromosomes 8p11 and 19q13 that among smokers increase the number of cigarettes smoked per day (CPD), a measure of nicotine addiction, and increase risk of lung cancer.

The study, published today in the online edition of Nature Genetics, analyzes detailed genotypic and smoking data from more than 130,000 participants. Both of the new SNPs are common, and in smokers each copy carried associates with a small increase in smoking quantity – about half a cigarrette per day – but an approximately 10% increase in risk of lung cancer compared to non carriers. This is about one third of the increase in lung cancer risk conferred by the SNP on chromosome 15q25. But taken together these variants can identify a sizeable proportion of smokers whose health is at even greater risk than average from their habit, information which may serve as an additional spur to smoking cessation. The study, ‘Sequence variants at CHRNB3-CHRNA6 and CYP2A6 affect smoking behavior,’ can be found at www.nature.com/ng.

“Smoking is bad for anyone’s health. It is even worse for some, and today’s discoveries continue to strengthen our ability to identify who those people are and give them a compelling additional reason to quit. We plan to incorporate these SNPs into our testing products to do that. What we do not yet know is exactly how this additional risk is conferred. To some degree these variants suggest that those for whom nicotine is more addictive are driven to smoke more, increasing their exposure to environmental risk. But given the quite substantial corresponding increases in risk of lung cancer it may also be that they make people more susceptible to the noxious effects of tobacco smoke. What is clear is that these variants — which are all near genes that encode nicotine metabolizing enzymes and receptors — are giving us a solid starting point for finding answers to advance personal and public health,” said Kari Stefansson, executive chairman and president of research at deCODE and senior author on the paper.

deCODE wishes to thank all those who participated in and contributed to this study. It was supported in part by the National Institutes of Health (R01-DA017932), and the European Comission’s GENADDICT project (LSHM-CT-2004-005166) and ENGAGE smoking consortium (HEALTH-F4-2007-201413).

Appearing today in the New England Journal of Medicine is a stealthily encouraging study for the use of genetic testing to improve the assessment of the risk of the common forms of breast cancer. Stealthily, I say, because the authors seem oddly determined to provide a gloomy interpretation of their own data. The study, entitled ‘Performance of Common genetic Variants in Breast-Cancer (sic) Risk Models,’ by Wacholder et al, uses data from several major breast cancer studies to answer an interesting question: does adding the measurement of common SNPs linked to risk of breast cancer add to the risk assessment provided by the traditional ‘Gail score’ criteria – age, family history, age at menarche, age at first live birth and the number of previous breast biopsies?

The answer is clearly yes, though the authors of the paper seem not to want you to know that. Most importantly, the authors define as elevated risk those women between the ages of 50 and 79 who are at a greater than 0.575% chance of developing breast cancer in any given year. Using the Gail criteria alone, 18.9% of study participants were considered to be at elevated risk. But with the addition of the genetic risk factors – which are ten of the twelve risk factors tested for by deCODE Breast Cancer test – another 9% of participants could be identified as being in the higher risk category. A 50% improvement.

Similarly, using an Area Under the Curve calculation (customarily used to evaluate the accuracy of methods for diagnosing disease) the Gail model yielded an AUC of 58%, and the Gail-plus-genetics model yeilded an AUC of 61.8%. In an AUC model, the amount over 50% (the baseline of a test that is no better than random) is the measure of relative discriminatory power. So an increase from 8 to 11.8 is, yes, a small number, but also an improvement of something in the neighborhood of 45%. The study also shows that compared to each other, the set of genetic risk factors were more accurate predictors of breast cancer than were the Gail factors that are the current mainstay of risk assessment.

So I can see why the authors wouldn’t want to celebrating these results too loudly – because we need to do better. But what this study shows is that genetics is already taking us in the right direction, and that the addition of genetic risk to current clinical practice can – right now, today – provide a substantial improvement in the crucial task: to better risk stratify the population, focus screening on those who should have it, pick up more cancers earlier and save lives. I can’t see anythig but good news in that. Our task is to keep discovering new risk factors that will continue to increase the power of these tests, and we are committed to doing so.

Dr. Kari Stefansson

We are very happy to announce today that deCODEme has been awarded the presitigious HONcode certification. This is the oldest and best known system for certifying that information on medical websites is ethically and credibly presented.

HONcode stands for the same principles we do. It conducts a rigorous and dynamic evaluation of how information is presented to users – involving individuals, physicians, and the provider of the service. The goal is to ensure that medically relevant information is presented in a way that enables users to understand what the information is useful for as well as the science upon which it is based. deCODEme provides this information to individual subscribers and, through the deCODEHealth interface, it also enables individuals to share their profile with their doctor and to integrate deCODEme as a component of their personal healthcare strategy.

As we have always said, and as our users know, what sets deCODEme and deCODEHealth apart is the scientific leadership of the team behind the service. These are online services, but we are not a dot-com company. Our services are developed and offered by the same people who over more than a decade have discovered most of the important genetic risk factors we test for. This is our commitment to our subscribers, and to the medical professionals and healthcare systems that are leading the way in employing genetics to deliver the best healthcare for their patients.

So this certification is as much about you as it is about us – congratulations!

The deCODEme Team

Pancreatic cancer has been added to the deCODEme Complete Scan. Pancreatic cancer is a particularly difficult form of cancer. It is virtually asymptomatic in its earliest stages. The cancer typically spreads rapidly and aggressively into surrounding tissue and organs, it is resistant to standard chemotherapy and has a strong tendency to recur. These characteristics make pancreatic cancer one of the most challenging cancers to treat unless caught early enough, and provide a grim prognosis for many diagnosed with the disease.

Currently there is no screening test available for this cancer, but genetic variants have been identified that are associated with increased risk of developing non-endocrine pancreatic cancer, the most common type of pancreatic cancer.  The deCODEme Complete Scan recently added non-endocrine pancreatic cancer to its genetic risk assessment profile.

deCODE genetics ehf today emerged as a newly financed, private company focused on advancing the science of human genetics and its application to products and services that improve human health. The new company will be building on the scientific leadership in genetics it developed over more than a decade as a subsidiary of deCODE genetics, Inc. deCODE ehf was this week purchased from its former parent company by Saga Investments LLC, a consortium that includes Polaris Ventures and ARCH Venture Partners, two leading life science investors. deCODE will continue all of its operations and product lines in this field, including its deCODE diagnostics disease risk tests; deCODEme™ personal genome scans; and contract service offerings including genotyping, sequencing and data analysis. Going forward, deCODE  will concentrate on translating its science into medically and commercially important products and services.  The company will be led by a two-man executive committee comprised of Earl “Duke” Collier, previously an executive vice president at Genzyme Corp.,who will serve as CEO, and Kari Stefansson, who will serve as executive chairman and president of research.

deCODE operates the most productive human gene discovery engine in the world. It is driven by genetic and medical data from 500,000 participants from around the globe taking part in its gene discovery work; comprehensive genealogies linking the 140,000 Icelandic participants; a major CLIA- and CAP-certified genotyping and sequencing facility; and statistical and informatics tools for mining large datasets, for maximizing the information derived from genotyping and sequencing data, and for visualizing genetic and disease data in research, in the clinic, and for subscribers to its genome scans.

“deCODE has led the world in discovering variants in the sequence of the human genome that affect the risk of common diseases. Our resources and expertise have also enabled us to develop the leading analytical tools in the field, and we are putting all of this to work to provide unique value for patients, physicians and researchers. As we enter the era of sequencing entire genomes, we believe our ability to make sense of ever larger amounts of data will continue to keep us in the lead in discovery. And with our now solid financial backing and the splendid addition of Duke Collier to our management, we will be taking a lead in the translation of our science into powerful products and services.” said Kari Stefansson.

“I am pleased to be joining Kari and the outstanding scientific team at deCODE,” said Duke Collier. “deCODE combines world class science devoted to human genetics, unmatched access to genetic data, and a powerful set of tools for managing and analyzing this data. SNP genotyping, and now genomic sequencing, is taking human genetics into an ever expanding world of research, discovery and translation. With its scientific skill and industrial scale analytical capacity, deCODE will be an invaluable partner to investigators, labs and companies working at the highest levels of sophistication in this exciting field. I am thrilled by the challenge and the opportunity.”

We have just made some updates to the deCODEme ancestry service. Now you have more power and flexibility when you compare your genome with that of friends or individuals from different populations around the world.

Your genome can be viewed as a mosaic or tapestry made up of fragments of chromosomes from your ancestors. Fragments of chromosomes inherited from very recent ancestors, say grandparents, are expected to be large – typically tens of millions of nucleotides in size. As ancestors become more ancient, then the size of the chromosome fragments inherited from them become smaller – down to a few thousand or hundred nucleotides for ancestors born thousands of years ago.

Our new and improved genome comparison tool enables to you compare your genome with another individual in order to determine which chromosome fragments you share and to see how much of your genome is shared. The fascinating thing about this analysis is that each shared fragment represents a common ancestor. The number of shared fragments and their size reflects the number of common ancestors and how far back in time they are found. In other words, you can see how closely you are related.

When genomes are compared, your chromosomes are broken down into fragments of a particular size and sharing is evaluated for each fragment. Before the fragment size was fixed at 1 million nucleotides. Now you can change the size of fragments that are compared, from a minimum of 250 thousand nucleotides (250Kb) to a maximum of 20 million nucleotides (20Mb). The minimum fragment size will reveal shared chromosome fragments from common ancestors going back thousands of years. The maximum fragment size will reveal only shared chromosome fragments from very recent common ancestors – i.e. going back only a few generations. Setting the fragment size thus lets you select how far back in time you want to hunt for common ancestors.

This image shows results of a comparison between an Icelander and an Orkney Islander using a fragment size of 3Mb. The brown lines are shared fragments, inherited from common ancestors from more than 1000 years ago!

Scientists at deCODE genetics today report the discovery of seven novel and common single-letter variations in the sequence of the human genome (SNPs) that are involved in modulating the electrical impulses that govern the working of the heart. Two of these SNPs, which correlate with electrocardiogram (ECG or EKG) measurements that are used in the clinical evaluation of heart health and activity, were then shown to confer increased risk of atrial fibrillation (AF), one of the most common causes of irregular heartbeat and a leading cause of stroke. The paper, “Several common variants modulate heart rate, PR interval and QRS duration,” is published online in Nature Genetics and will appear in an upcoming print addition of the journal.

The deCODE team began by correlating ECG measurements with genome-wide SNP data from more than 40,000 Icelandic participants in its gene discovery program. This search identified one novel SNP influencing heart rate and four each linked to PR interval and QRS duration, measurements of how quickly the electrical impulses that cause the heart muscles to pump achieve their purpose. Intriguingly, SNPs on chromosome 3 linked to both longer PR interval and QRS duration are in the gene encoding SCN10A, a sodium channel that has never before been linked to heart activity. Individuals with the same variants were also more likely to have been fittted with a pacemaker. A follow-on analysis of all of the novel SNPs in Icelandic and Norwegian heart patients and controls demonstrated the association of two of the SNPs linked to PR interval to risk of AF, and another SNP to increased risk of advanced atrioventricular block. Two other papers published today in the same journal provide further validation of some of the deCODE findings.

“Over the past two years, we have discovered major genetic risk factors for heart disease and stroke and introduced tests for these risk factors into clinical practice. We are building the power of these tests through our ongoing discovery work, and today’s findings demonstrate again the fruitfulness of using intermediate risk factors and clinical measurements as entry points for finding risk factors for disease. Our population resources enable us to do so efficiently and with exciting results. These latest findings will be incorporated into our deCODE AF test and deCODEme scans,  and certain of these discoveries may also provide opportunities for out-licensing for therapeutic development,” said Kari Stefansson, CEO of deCODE.

Season’s Greetings And Best Wishes For The New Year from deCODE.

We at deCODEme just wanted to let you know that we have added a Forum where you can discuss genetics, ancestry and health. Our experts are looking forward to your questions and comments so we hope you take advantage of this new feature.

We are constantly working on making deCODEme more valuable and informative and we appreciate your continued interest.

We hope you have a pleasant and festive holiday.

The deCODEme Team