Icelandic Population Genomic Study Results by deCODE Genetics come to Fruition: Curation of Current genomic studies
Reporter/Curator: Stephen J. Williams, Ph.D.
UPDATED on 9/6/2017
On 9/6/2017, Aviva Lev-Ari, PhD, RN had attend a talk by Paul Nioi, PhD, Amgen, at HMS, Harvard BioTechnology Club (GSAS).
Nioi discussed his 2016 paper in NEJM, 2016, 374:2131-2141
Variant ASGR1 Associated with a Reduced Risk of Coronary Artery Disease
N Engl J Med 2016; 374:2131-2141June 2, 2016DOI: 10.1056/NEJMoa1508419
- Abstract
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BACKGROUND
Several sequence variants are known to have effects on serum levels of non–high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease.
METHODS
We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability.
RESULTS
We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10−16), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10−6). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10−3).
CONCLUSIONS
ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.)
Amgen’s deCODE Genetics Publishes Largest Human Genome Population Study to Date
Mark Terry, BioSpace.com Breaking News Staff reported on results of one of the largest genome sequencing efforts to date, sequencing of the genomes of 2,636 people from Iceland by deCODE genetics, Inc., a division of Thousand Oaks, Calif.-based Amgen (AMGN).
Amgen had bought deCODE genetics Inc. in 2012, saving the company from bankruptcy.
There were a total of four studies, published on March 25, 2015 on the online version of Nature Genetics; titled “Large-scale whole-genome sequencing of the Icelandic population[1],” “Identification of a large set of rare complete human knockouts[2],” “The Y-chromosome point mutation rate in humans[3]” and “Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease[4].”
The project identified some new genetic variants which increase risk of Alzheimer’s disease and confirmed some variants known to increase risk of diabetes and atrial fibrillation. A more in-depth post will curate these findings but there was an interesting discrete geographic distribution of certain rare variants located around Iceland. The dataset offers a treasure trove of meaningful genetic information not only about the Icelandic population but offers numerous new targets for breast, ovarian cancer as well as Alzheimer’s disease.
View Mark Terry’s article here on Biospace.com.
“This work is a demonstration of the unique power sequencing gives us for learning more about the history of our species,” said Kari Stefansson, founder and chief executive officer of deCode and one of the lead authors in a statement, “and for contributing to new means of diagnosing, treating and preventing disease.”
The scale and ambition of the study is impressive, but perhaps more important, the research identified a new genetic variant that increases the risk of Alzheimer’s disease and already had identified an APP variant that is associated with decreased risk of Alzheimer’s Disease. It also confirmed variants that increase the risk of diabetes and a variant that results in atrial fibrillation.
The database of human genetic variation (dbSNP) contained over 50 million unique sequence variants yet this database only represents a small proportion of single nucleotide variants which is thought to exist. These “private” or rare variants undoubtedly contribute to important phenotypes, such as disease susceptibility. Non-SNV variants, like indels and structural variants, are also under-represented in public databases. The only way to fully elucidate the genetic basis of a trait is to consider all of these types of variants, and the only way to find them is by large-scale sequencing.
Curation of Population Genomic Sequencing Programs/Corporate Partnerships
Click on “Curation of genomic studies” below for full Table
Curation of genomic studies
| Study | Partners | Population | Enrolled | Disease areas | Analysis |
| Icelandic Genome
Project |
deCODE/Amgen | Icelandic | 2,636 | Variants related to: Alzheimer’s, cardiovascular, diabetes | WES + EMR; blood samples |
| Genome Sequencing Study | Geisinger Health System/Regeneron | Northeast PA, USA | 100,000 | Variants related to hypercholestemia, autism, obesity, other diseases | WES +EMR +MyCode;
– Blood samples |
| The 100,000 Genomes Project | National Health Service/NHS Genome Centers/ 10 companies forming Gene Consortium including Abbvie, Alexion, AstraZeneca, Biogen, Dimension, GSK, Helomics, Roche, Takeda, UCB | Rare disorders population UK | Starting to recruit 100,000 | Initially rare diseases, cancer, infectious diseases | WES of blood, saliva and tissue samples |
| Saudi Human Genome Program | 7 centers across Saudi Arabia in conjunction with King Abdulaziz City Science & Tech., King Faisal Hospital & Research Centre/Life Technologies | General population Saudi Arabia | 20,000 genomes over three years | First focus on rare severe early onset diseases: diabetes, deafness, cardiovascular, skeletal deformation | Whole genome sequence blood samples + EMR |
| Genome of the Netherlands (GoNL) Consortium | consortium of the UMCG,LUMC, Erasmus MC, VU university and UMCU. Samples where contributed by LifeLines, The Leiden Longevity Study, The Netherlands Twin Registry (NTR), The Rotterdam studies, and The Genetic Research in Isolated Populations program. All the sequencing work is done by BGI Hong Kong. | Families in Netherlands | 769 | Variants, SNV, indels, deletions from apparently healthy individuals, family trios | Whole genome NGS of whole blood no EMR
Ref paper in Nat. Genetics Ref paper describing project |
| Faroese FarGen project | Privately funded | Faroe Islands | Faroese population 50,000 | Small population allows for family analysis | Combine NGS with EMR and genealogy reports |
| Personal Genome Project Canada | $4000.00 fee from participants; collaboration with University of Toronto and SickKids Organization; technical assistance with Harvard | Canadian Health System | Goal: 100,000 | ? just started no defined analysis goals yet | Whole exome and medical records |
| Singapore Sequencing Malay Project (SSMP) | Singapore Genome Variation Project | Malaysian | 100 healthy Malays from Singapore Pop. Health Study | Variant analysis | Deep whole genome sequencing |
| GenomeDenmark | four Danish universities (KU, AU, DTU and AAU), two hospitals (Herlev and Vendsyssel) and two private firms (Bavarian Nordic and BGI-Europe). | 150 complete genomes; first 30 published in Nature Comm. | ? | See link | |
| Neuromics Consortium | University of Tübingen and 18 academic and industrial partners (see link for description) | European and Australian | 1,100 patients with neuro-
degenerative and neuro- muscular disease |
Moved from SNP to whole exome analysis | Whole Exome, RNASeq |
References
- Gudbjartsson DF, Helgason H, Gudjonsson SA, Zink F, Oddson A, Gylfason A, Besenbacher S, Magnusson G, Halldorsson BV, Hjartarson E et al: Large-scale whole-genome sequencing of the Icelandic population. Nature genetics 2015, advance online publication.
- Sulem P, Helgason H, Oddson A, Stefansson H, Gudjonsson SA, Zink F, Hjartarson E, Sigurdsson GT, Jonasdottir A, Jonasdottir A et al: Identification of a large set of rare complete human knockouts. Nature genetics 2015, advance online publication.
- Helgason A, Einarsson AW, Gumundsdottir VB, Sigursson A, Gunnarsdottir ED, Jagadeesan A, Ebenesersdottir SS, Kong A, Stefansson K: The Y-chromosome point mutation rate in humans. Nature genetics 2015, advance online publication.
- Steinberg S, Stefansson H, Jonsson T, Johannsdottir H, Ingason A, Helgason H, Sulem P, Magnusson OT, Gudjonsson SA, Unnsteinsdottir U et al: Loss-of-function variants in ABCA7 confer risk of Alzheimer’s disease. Nature genetics 2015, advance online publication.
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