deCODE scientists have discovered a single SNP that confers increased risk if inherited from the father, but is protective if inherited from the mother

Scientists at deCODE genetics, Inc. publish in the journal Nature the discovery of a version of a common single-letter variant in the sequence of the human genome (SNP) with a major impact on susceptibility to type 2 diabetes (T2D). The impact of the T2D variant is not only large, but unusual: if an individual inherits it from their father, the variant increases risk of T2D by more than 30% compared to those who inherit the non T2D-linked version; if inherited maternally, the variant  lowers risk by more than 10% compared to the non T2D-linked version. Nearly one quarter of those studied have the highest risk combination of the versions of this SNP, putting them at a roughly 50% greater lifetime risk of T2D than the quarter with the protective combination. This is the second largest effect of any genetic variant for T2D apart from SNPs in TCF7L2, discovered by deCODE in 2006.

“We could make this discovery beacause we are in the unique position of being able to distinguish what is inherited from the mother from what is inherited from the father. This we can do because of the large amount of data we have assembled on the Icelandic population. These data empower us in many ways. For example, using our ability to impute sequence data, we can multiply by 100 times the amount of information generated by sequencing one individual. We can use these tools to discover and integrate rarer variants into our tests and scans, identify drug targets for licensing, and put our know-how at the disposal of our service customers. We believe that this is an important advantage for conducting large-scale whole sequence studies over the next couple of years,” said Kari Stefansson, CEO of deCODE.

Because the risk is inherited and varies in this way, the SNP, located on chromsome 11, had never been linked to T2D even though it had been genotyped in large, traditional genome-wide association studies (GWAS). These do not distinguish between paternally and maternally inherited SNPs. But deCODE can track the parental origin of virtually any SNP in the genome of the tens of thousands of Icelandic participants in the company’s gene discovery work. In this study, deCODE used its population-wide genealogy database and proprietary statistical tools to determine the parent of origin of a number of SNPs in some 40,000 Icelandic participants in the company’s gene discovery programs. Some of these SNPs had previously been associated with different diseases and are located near “imprinted” genes – genes in which only the maternally or paternally inherited copy is “switched-on” to encode a protein. Five of these, one each in breast and skin cancer and three in T2D, showed that the parental origin of the variants affects the risk they confer.

The paper, “Parental origin of sequence variants associated with complex diseases,” is published online at www.nature.com, and will appear in the December 17 print edition.

It’s Not Just the Sun: deCODE Discovers Sequence Variants Affecting Susceptibility to Skin Cancer.

Scientists at deCODE genetics and academic colleagues from Europe and the United States today present in the journal Nature Genetics the discovery of common genetic risk factors for basal cell carcinoma (BCC) that affect people with fair and dark complexions alike. deCODE had previously discovered five common single-letter variants in the sequence of the human genome (SNPs) linked to risk of BCC, the most common cancer in people of European descent. However, most of these earlier findings were also correlated with fair skin, well known to accompany vulnerability to the damaging effects of ultraviolet radiation in sunlight. By contrast, three of the SNPs presented today do not correlate with light pigmentation…

and may thus provide new insight into the underlying biological perturbations that lead to BCC independent of environmental exposure. One of these, in the keratin 5 (KRT5) gene on chromosome 12, leads to a subtle but potentially damaging alteration to the KRT5 protein, which supports the structural integrity of the skin. Those with one copy of the variant are at more than 30% greater likelihood of developing BCC than those who do not carry the variant, while those who carry two copies are at more than 50% greater risk. Another of the SNPs is located on chromosome 9p21, the same region of the genome that deCODE has linked to increased risk of heart attack and others have linked to type 2 diabetes. deCODE used its population genetics resources in Iceland to demonstrate that a third risk variant, on chromosome 7q32, confers greater risk if inherited from the father than from the mother.

“It is important to find genetic causes of BCC that do not appear to be modulated directly by sensitivity to the sun. This may bring us closer to understanding the underlying biology of a very common form of cancer, and KRT5 in particular may point us to new pathways for developing new drugs or skin care products. We are also pleased to be able to fold these discoveries directly into our deCODEme™ scans. For sun exposure is still the most important risk factor for BCC, and while people with fair skin are already aware of the need to protect themselves when they go outdoors, others with darker complexions may also be at higher risk of BCC than they think. This is also one of the first reports of a sequence variant conferring risk of a disease that is dependent on the parent of origin. With all of our findings over the past year, we believe we have found variants that play a role in most cases of BCC,” said Kari Stefansson, CEO of deCODE.

The study also provided conclusive evidence that a previously identified SNP in the TERT-CLPTM1L region of chromosome 5 confers susceptibility to BCC but protects agains cutaneous melanoma. A previously known SNP in the SLC45A2 gene on chromosome 5 was confirmed to confer risk of squamous cell carcinoma as well as BCC. The study involved three stages. First, the SNPs with the best results from previous genome-wide scans of more than 300,000 SNPs were tested in large numbers of individuals with and without BCC. The first two phases included participants from Iceland, The Netherlands, Sweden, Germany, Italy, Hungary, Romania, and Slovakia. The SNPs on chromosomes 12, 9p21 and 7q32, as well as those on chromosome 5, were then tested and confirmed in participants from the United States and Spain.
In all, the study included genotypic data from some 45,000 people. deCODE and its collaborators would like to thank those who took part for making the work possible. Financial support for various portions of the work was provided by the US National Institutes of Health (grants T32E007155, R01CA082354, and R01CA57494), Radboud University Nijmegen Medical Center, the Netherlands, the National Bank of Austria, the Radiumhemmet Research Funds and the Swedish Cancer Society.

On top of Acropolis on a camping trip in Athens.

By: Anna Peterson
I am a fit, healthy, 27 year old Canadian graduate student looking forward to the future. So why, you might wonder, did I decide to take the deCODEme genetic test? It’s simple really. Information is the key to prevention. By learning about my genetic predisposition for different illnesses, I will be better prepared to take an active role in my future health care decisions.
Many of my friends were surprised that I decided to take this comprehensive genetic test. Some were curious about the story my genes would tell, while others wondered whether or not I really wanted to know. When I put my genetic sample in the mail, I felt a little nervous about the chain of events I had set in motion, but curiosity overcame fear. In my opinion, knowledge is power and I’d rather make lifestyle changes in my 20s than in my 60s.

It wasn’t just curiosity that prompted me to take the deCODEme test. I was particularly interested to better understand my genetic predisposition to both breast cancer and age-related macular degeneration (AMD). According to the Canadian Cancer Society, one in nine women is expected to develop breast cancer in her lifetime. While I have been familiar with this statistic for a long time, it becomes much more real when someone you know is affected. Two and a half years ago, my mother’s sister was diagnosed with breast cancer. At arm’s length, I witnessed the impact of a breast cancer diagnosis. This experience, however, did little to prepare me for the phone call I received in June of this year. Tearfully my mother told me how she had found a lump in her breast and that a recent biopsy had confirmed the lump was indeed cancerous. In a few short moments our lives changed forever. Sharing this difficult journey with a woman I love and admire has been a harrowing privilege. But I couldn’t help wondering if I might find myself in a similar position one day. Still years away from my first mammogram, I thought why wait for time to tell. No matter the results, I wanted to know my relative genetic risk of developing breast cancer.

"Prevention Starts with Knowing the Odds."

When I logged onto the deCODEme web site to explore my results, I spent several minutes avoiding the link to the breast cancer assessment. A very human hesitation, but I soon realized there was no point staying in the dark. The deCODEme test examines eight genetic variants found to increase the risk of developing breast cancer. The BRCA1 and BRCA2 genes (found in 2-5% of women with breast cancer) are not included in this assessment. My results indicate that the relative genetic risk for someone with my genotype is 1.23. This corresponds to a 14.7% lifetime risk of developing breast cancer, which is 23% greater than for females of European ancestry in general. Not the best news, but certainly not the worst.
To better understand my results, I contacted Dr. Kris Kristjansson, a genetic counselor at deCODE genetics. He stressed that the deCODE test is not a diagnostic tool, so there was no need to be alarmed by what I had learned. He explained the scientific details of my test results in simple terms and brought the Gail Model risk assessment tool to my attention. This tool, originally developed for physicians and now freely available on the web, calculates the impact of non-genetic factors to estimate a woman’s five year and lifetime risk of developing breast cancer. Taken together, the deCODEme test and the Gail Model provide a more complete approximation of a woman’s lifetime risk of developing breast cancer. Entering my age at 35, the Gail Model risk assessment tool estimated my lifetime risk of developing breast cancer at 17.6%, which is above the average 12.6% lifetime risk. To calculate the combined assessment I simply multiplied my deCODEme result of 1.23 with the Gail Model result of 17.6 for a total of 21.6. I now know that I am at higher risk of developing breast cancer from both genetic and non-genetic factors. With a 21.6% lifetime risk of developing breast cancer, I will have to be vigilant. Letting out a breath I didn’t realize I was holding, I still felt good about my choice not to walk blindly into the future. The results of my deCODEme test and the Gail Model have given me the tools to advocate for early screening and a renewed commitment to making positive lifestyle choices.

On a backpacking trip.

How we live our lives today has a tremendous impact on the quality of life we will enjoy in the future. I chose to take the deCODEme complete scan because I also wanted to learn about my genetic predisposition for developing age-related macular degeneration (AMD). My grandmother developed AMD in her mid 70s and, for years, I have wondered if I would one day be among the 40% of Canadians over the age of 75 to develop AMD. I was born with an untreatable visual impairment in one eye and the challenges of growing up with limited sight have made me uniquely aware of the reality of blindness. I have silently worried about the possibility of one-day loosing my sight in both eyes. The deCODE genetic test revealed that the lifetime risk for someone with my genotype is only 2%, which is 75% less than for people of European ancestry in general. I am delighted to know that I have excellent genetic chances of avoiding this debilitating illness.
Before taking the deCODEme test, I never gave skin cancer a second thought (save to lather on sunscreen at the beach). Yet skin cancer is one of the most common cancers in the world. According to the National Cancer Institute of Canada, environmental and genetic factors are thought to play a role in basal cell carcinoma, which accounts for 80% of all skin cancers. Scientists at deCODE genetics have identified two genetic variants that appear to act independently from exposure to UV radiation.
It never occurred to me that I might be genetically predisposed to developing basal cell carcinoma. So you can imagine my surprise, when my results indicated a 45.9% lifetime risk for someone with my genotype. A few days ago, I knew nothing about basal cell carcinoma and now I’m beginning to realize I might come to know this disease all too well in the future.
Eager to learn more, I called home to speak with my parents. My test results provided the perfect opportunity to discuss our family medical history. I soon learned that my grandfather had “skin cancer” (possibly basal cell carcinoma) in his late 60s. For the first time, I understood my mother’s frequent visits to the dermatologist to have moles examined or removed. While she had been aware of a potential risk to herself, none of us had considered that I might also be at risk. No need to panic, however. In fact, I am grateful for the knowledge and the opportunity to take the steps necessary to protect myself now and hopefully avoid this illness in the future.

Camping

Genetic testing is a revolutionary way to protect yourself and the ones you love from unknowns and potential future illness. My genetic makeup isn’t going to change but, through this experience, I have changed. I’ve relaxed my concerns about 13 diseases (AMD, glaucoma, multiple sclerosis, etc.) and have learned of other conditions such as breast and skin cancer that I can now keep an eye on in the future. Empowered by a greater understanding of my genetic predisposition to different illnesses, I have become even more proactive about prevention.

Anna Peterson