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World’s Largest Genetic Study in Iceland Produced New Insights into Gene Function and Disease Predisposition that Could Lead to New Clinical Laboratory Tests

Researchers sequenced the entire genomes of 2,636 Icelanders and gained useful insights into how human genes evolve and mutate

Over the past 15 years, Iceland has managed to be at the forefront of genetic research tied to personalized medicine and new biomarkers for diagnostics and therapeutics. This is true because, as most pathologists know, Iceland has a small population that has seen little immigration over the past 1,000 years, along with a progressive government and business community.

The relatively closed society of Iceland makes it much easier to identify genetic sequences that contribute to different diseases. The latest example of such research findings comes after the genomes of 2,636 Icelanders were sequenced. In addition to this being the world’s largest-ever study of the genetic makeup of a single population, the findings suggest a strategy for analyzing the full-spectrum of genetic variation in a single population.

Of equal importance: this study, which was funded by Amgen’s  deCODE Genetics, offers scientists a better understanding of what goes wrong when disease develops. It does this by researching how illness emerges from specific gene variations.

Researchers Identified 20 Million Genetic Variants in Population of 500,000

The findings from this study are also raising questions about how society should use this knowledge. The new data could speed efforts to develop targeted treatments for disease and further the goals of the Obama Administration’s Precision Medicine Initiative, noted Lisa D. Brooks, Ph.D., Director of the Genetic Variation Program at the National Human Genome Research Institute in Bethesda, Maryland. Brooks was interviewed in a Los Angeles Times report.

Lisa D. Brooks, Ph.D., Director of the Genetic Variation Program at the National Human Genome Research Institute believes that the Icelandic project is particularly useful in detecting uncommon variants that contribute to diseases, or help protect against them. (Picture copyright LinkedIn.)

Lisa D. Brooks, Ph.D., Director of the Genetic Variation Program at the National Human Genome Research Institute believes that the Icelandic project is particularly useful in detecting uncommon variants that contribute to diseases, or help protect against them. (Picture copyright LinkedIn.)

The deCODE Genetics study began in 1996. The number of study participants represented 1 in 100 of Iceland’s total population of 268,916 at that time. All of the participants in this study are descendants of Nordic ancestors with family records dating back 1,000 years.

The genomes of participants were compared to less extensive genotype data from more than 104,000 other Icelanders. This enabled researchers to identify more than 20 million genetic variants in the Iceland population, noted Myles Axton, Ph.D., Chief Editor of Nature Genetics, which reported the results of the Icelandic genome project in the March 25, 2015 of Nature Genetics. The journal’s four papers on the Icelandic project provide insights into human mutation, evolution, gene function, and disease predisposition.

The Iceland population was ideal for studying the genetic origins of disease because this small, homogenous society with Nordic origins can trace its ancestor to Vikings who settled here 1,000 years ago. Additionally, Iceland is among a few nations that provide excellent national healthcare and maintain comprehensive records on matters pertaining to citizens' health, including kinship relations. This allowed deCODE Genetics researchers to cross-reference their findings with medical records. (Photo copyright Anton Brink.)

The Iceland population was ideal for studying the genetic origins of disease because this small, homogenous society with Nordic origins can trace its ancestor to Vikings who settled here 1,000 years ago. Additionally, Iceland is among a few nations that provide excellent national healthcare and maintain comprehensive records on matters pertaining to citizens’ health, including kinship relations. This allowed deCODE Genetics researchers to cross-reference their findings with medical records. (Photo copyright Anton Brink.)

This information was crosschecked against Iceland’s extensive genealogical and healthcare information records, which documented diagnoses, described treatment response, and allowed researchers to see how a single disease might run through generations of a given family.

Axton wrote that the selection of a 1-in-100 population ratio for gene sequencing, combined with shared sets of common genetic variance to predict the full spectrum of genetic variance carried by the whole population, should be an effective research model for the future study of human genetics.

Scientists Discover Genetic Variants and Their Role in Manifesting as Disease

One part of the Icelandic study yielded new information about a common human ancestor for the male Y chromosome. Further the emergence of this male Y chromosome was narrowed to between 174,000 and 321,000 years ago, based on the latest calculation of human mutation rates.

Insights into Mendelian diseases (conditions caused by more than one genetic abnormality) were developed over the course of this genetic study. For example, researchers discovered that about 7% of Iceland’s modern day population have a rare “knockout” gene, which has been disabled by mutations. This revelation indicated that some genetic transcription errors thought to doom its owner to early death may not be as deadly as originally thought, noted the LA Times report.

Additionally, during the course of the study, researchers discovered new, highly reliable genetic marketers for onset of atrial fibrillation before age 60. This is a rare syndrome that results in blindness and balance issues. They also identified a pair of rare genetic variants responsible for gall bladder disease in more than 8,000 Icelanders, noted the LA Times story.

New Insights into Genetic Mutations Associated with Alzheimer’s Disease

Another mutation that was identified for the first time is in the ABCA7 gene that doubles the risk for Alzheimer’s disease in Icelanders and other populations with European ancestry. Combing through the DNA of 3,419 Icelanders with Alzheimer’s, and 150,000 other people without this disease, the researchers identified eight rare variants that appear to increase the risk for Alzheimer’s by influencing the production of proteins essential to waste cleanup and disposal in the brain. Six of these variants were found to be more common in Alzheimer’s patients in Finland, Germany, Norway and the United States.

“These are just a handful of observations that have come out of the ability to look at the sequence of the genome of an entire nation,” stated Kari Stefansson, M.D., Dr. Med, Founder and CEO of deCODE Genetics, a biopharmaceutical company in Reykjavík, Iceland, during a press briefing reported by IEEE Spectrum. “What is more, we are now sitting in Iceland with the possibility of taking advantage of these insights when it comes to the Icelandic healthcare system.”

Kari Stefansson, M.D., Dr. Med, Founder and CEO of deCODE Genetics, told IEEE Spectrum that it would be “criminal” to not take advantage of deCODE Genetics’ research. “It’s just one example, a tiny little example of what you can do when you have a deep insight into the genome of an entire population,” he said. (Picture copyright Investiga Medicina.)

Kari Stefansson, M.D., Dr. Med, Founder and CEO of deCODE Genetics, told IEEE Spectrum that it would be “criminal” to not take advantage of deCODE Genetics’ research. “It’s just one example, a tiny little example of what you can do when you have a deep insight into the genome of an entire population,” he said. (Picture copyright Investiga Medicina.)

Findings Universally True for Global Populations, Despite Lineage Differences

Steven McCarroll, Ph.D., a Geneticist at Harvard Medical School, commented that the Icelandic researchers’ identification of specific genetic variants and how they manifest as disease are likely to be universal in humans, despite differences in genetic lineage. He was commenting on the Iceland project in the LA Times article. “The things that they’re learning about, what genes contribute to disease, are generally biologically true,” added McCarroll.

Brook pointed out that similar studies of human genomes in nations with diverse populations—such as the United States—could generate additional information. U.S. genome studies could also help scientists determine how gene expression is influenced by environmental factors, such as diet, exercise, pollution and other toxic exposures, she said.

Study Results May Lead to New Clinical Laboratory Tests

Findings from this groundbreaking study of the whole human genomes of 1% of a nation’s population show pathologists and medical laboratory professionals how quickly faster sequencing technology combined with research studies are expanding genetic knowledge. Moreover, this new knowledge will be utilized to create new clinical laboratory tests for diagnosis to guide selection of most appropriate therapies and in monitoring patients.

—Patricia Kirk

Related Information:

Loss-of-Function Variants in ABCA7 Confer Risk of Alzheimer’s Disease

Identification of a Large Set of Rare Complete Human Knockouts

Large-Scale Whole-Genome Sequencing of the Icelandic Population

Sequence Variants From Whole Genome Sequencing a Large Group of Icelanders

Icelanders Boost Medical Research by Donating Their DNA to Science

Iceland’s Giant Genome Project Points to Future of Medicine

Obama’s $215 Million Precision Medicine Initiative: Will Congress Fund It and Can It Advance Genetic Testing and the Value of Clinical Laboratory Services?

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