deCODE You

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%).

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.

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.

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. Read the rest of this entry »