Scientists in Iceland have performed an unprecedentated genetic analysis of an entire nation, associating previously undiscovered mutations with disorders such as liver disease and gallstones.
In 4 articles published last week in Nature Genetics, researchers at DeCODE, an Icelandic genetics firm owned by Amgen, described sequencing the genomes of 2636 Icelanders—the largest collection ever analyzed in a single human population.
The New York Times wrote that with this trove of genetic information, the scientists were able to accurately infer the genomes of more than 100,000 other Icelanders—almost a third of the entire country.
Daniel F Gudbjartsson et al identified 20 million single-nucleotide polymorphisms and 1.5 million insertions-deletions, and described the density and frequency spectra of sequence variants in relation to their functional annotation, gene position, pathway, and conservation score.
The authors reported an excess of homozygosity and rare protein-coding variants in Iceland. They found a recessive frameshift mutation in MYL4 that causes early-onset atrial fibrillation and several mutations in ABCB4 that increase risk of liver disease.
A genetic analysis of 8258 individuals with gallstone disease led to a missense single nucleotide polymorphism (encoding p.Gly622Glu) and a frameshift insertion (encoding p.Leu445Glyfs*22) in ABCB4. Gudbjartsson et al state that the variants are rare (0.22% and 0.21%) but have large effects (allelic odds ratios of 2.74 and 3.10, respectively).
Rare coding variants in ABCB4 have been previously associated with progressive familial intrahepatic cholestasis, intrahepatic cholestasis of pregnancy, and low phospholipid–associated cholelithiasis.
Gudbjartsson et al also found that more than 2000 men and women carry a loss-of-function mutation in BRCA2 encoding p.Asn257Lysfs*17, which confers a 4.6-fold increase in the lifetime risk of developing any cancer.
Interestingly, an intron variant in GNAS was associated with increased levels of thyroid-stimulating hormone, but only when inherited maternally. “When Icelanders get the mutation from their mother, they make more of the hormone, the researcher found. But when they get it from their father, they make less,” explained The New York Times.
Luke Jostins (Oxford University) called the discovery “super-weird” and wants to see the result replicated elsewhere. “If it is real, it is quite the find, the sort of thing that could really inform some new biology,” he said.
Geneticists are particularly interested in individuals who lack an entire gene, which they call “human knockouts”. The Decode team found that nearly 8% of Icelanders lack a working version of a gene—a total of 1171 genes are missing from these individuals.
Kari Stefansson, chief executive officer of DeCode and the senior author of 4 articles, told the New York Times that he and his colleagues are getting in touch with the “Icelandic knockouts” to see if they will consent to more studies designed to figure out the physiological consequences of the missing genes.
An editorial that accompanied the article added that the Y-chromosome sequences of 753 Icelandic men offer insight into evolution, through accurate measurements of the different rates of mutation and gene conversion in unique and repeat regions of this chromosome.
Bloomberg explained that they researchers were able to reach their conclusions because Iceland’s population has relatively little genetic variation, compared with more diverse countries like the US.
TIME added that most residents can trace their lineage back to a few founding fathers, which made it possible to infer the distribution of the genetic variants found in the study’s 2636 participants to the remaining 325,000 Icelanders.