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Posts Tagged ‘Genome project’


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

Paul Nioi, Ph.D., Asgeir Sigurdsson, B.Sc., Gudmar Thorleifsson, Ph.D., Hannes Helgason, Ph.D., Arna B. Agustsdottir, B.Sc., Gudmundur L. Norddahl, Ph.D., Anna Helgadottir, M.D., Audur Magnusdottir, Ph.D., Aslaug Jonasdottir, M.Sc., Solveig Gretarsdottir, Ph.D., Ingileif Jonsdottir, Ph.D., Valgerdur Steinthorsdottir, Ph.D., Thorunn Rafnar, Ph.D., Dorine W. Swinkels, M.D., Ph.D., Tessel E. Galesloot, Ph.D., Niels Grarup, Ph.D., Torben Jørgensen, D.M.Sc., Henrik Vestergaard, D.M.Sc., Torben Hansen, Ph.D., Torsten Lauritzen, D.M.Sc., Allan Linneberg, Ph.D., Nele Friedrich, Ph.D., Nikolaj T. Krarup, Ph.D., Mogens Fenger, Ph.D., Ulrik Abildgaard, D.M.Sc., Peter R. Hansen, D.M.Sc., Anders M. Galløe, Ph.D., Peter S. Braund, Ph.D., Christopher P. Nelson, Ph.D., Alistair S. Hall, F.R.C.P., Michael J.A. Williams, M.D., Andre M. van Rij, M.D., Gregory T. Jones, Ph.D., Riyaz S. Patel, M.D., Allan I. Levey, M.D., Ph.D., Salim Hayek, M.D., Svati H. Shah, M.D., Muredach Reilly, M.B., B.Ch., Gudmundur I. Eyjolfsson, M.D., Olof Sigurdardottir, M.D., Ph.D., Isleifur Olafsson, M.D., Ph.D., Lambertus A. Kiemeney, Ph.D., Arshed A. Quyyumi, F.R.C.P., Daniel J. Rader, M.D., William E. Kraus, M.D., Nilesh J. Samani, F.R.C.P., Oluf Pedersen, D.M.Sc., Gudmundur Thorgeirsson, M.D., Ph.D., Gisli Masson, Ph.D., Hilma Holm, M.D., Daniel Gudbjartsson, Ph.D., Patrick Sulem, M.D., Unnur Thorsteinsdottir, Ph.D., and Kari Stefansson, M.D., Ph.D.

N Engl J Med 2016; 374:2131-2141June 2, 2016DOI: 10.1056/NEJMoa1508419

Abstract
Article
References
Citing Articles (22)
Metrics

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

Ref paper

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,LUMCErasmus MCVU university and UMCU. Samples where contributed by LifeLinesThe Leiden Longevity StudyThe 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

Singapore Pharmacogenomics 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

  1. 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.
  2. 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.
  3. 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.
  4. 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.

Other post related to DECODE, population genomics, and NGS on this site include:

Illumina Says 228,000 Human Genomes Will Be Sequenced in 2014

CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics & Computational Genomics

CRACKING THE CODE OF HUMAN LIFE: The Birth of BioInformatics and Computational Genomics – Part IIB

Human genome: UK to become world number 1 in DNA testing

Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

Genomic Promise for Neurodegenerative Diseases, Dementias, Autism Spectrum, Schizophrenia, and Serious Depression

Sequencing the exomes of 1,100 patients with neurodegenerative and neuromuscular diseases: A consortium of 18 European and Australian institutions

University of California Santa Cruz’s Genomics Institute will create a Map of Human Genetic Variations

Three Ancestral Populations Contributed to Modern-day Europeans: Ancient Genome Analysis

Impact of evolutionary selection on functional regions: The imprint of evolutionary selection on ENCODE regulatory elements is manifested between species and within human populations

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Reporter: Aviva Lev-Ari, PhD, RN

Genome.gov National Human Genome Research Institute National Institutes of Health

Online Research Resources

Contents

From NHGRI
Online Research Resources Developed at NHGRI
NHGRI Reports and Publications
The NHGRI Genome Sequencing Program (GSP)
Beyond NHGRI
The Completed Human Sequence
Other Federal Agencies Involved in Genomics
Human Genome Sequence Assemblies and Other Genomic Data Resources
Underlying Map Information
Sequencing Centers of the International Human Genome Sequencing Consortium
Model Organism Genome Projects
Archaea and Bacteria
Eukaryotes
Databases
National Center for Biotechnology Information (NCBI) Databases and Tools
Nucleotide Sequence Databases
Trace Archives (Raw Sequence Data Repositories)
Single Nucleotide Polymorphisms (SNPs)
cDNAs and Expressed Sequence Tags (ESTs)
Model Organism Databases
Additional Sequence, Gene and Protein Databases
Ethical, Legal and Social Implications (ELSI) Information
Funding Agencies
Additional Genome Resources
Biology Resources
Selected Journals

From NHGRI

Online Research Resources Developed at NHGRI
Software, databases and research project Web sites from NHGRI’s Division of Intramural Research (DIR).

NHGRI Reports and Publications

The NHGRI Genome Sequencing Program (GSP) 
Genome sequencing projects currently in production and funded by NHGRI.

Beyond NHGRI

The Completed Human Sequence:
Other Federal Agencies Involved in Genomics
Human Genome Sequence Assemblies and Other Genomic Data Resources

 

Underlying Map Information
Sequencing Centers of the International Human Genome Sequencing Consortium

(Listed in order of total sequence contributed to the draft human sequence published February 15, 2001, Nature, 409:860-921)

Model Organism Genome Projects

Archaea and Bacteria

Eukaryotes

Databases

National Center for Biotechnology Information (NCBI) Databases and Tools

Nucleotide Sequence Databases

Trace Archives (Raw Sequence Data Repositories)

Single Nucleotide Polymorphisms (SNPs)

cDNAs and Expressed Sequence Tags (ESTs)

Model Organism Databases

Additional Sequence, Gene and Protein Databases

  • InterPro protein sequence analysis & classification [ebi.ac.uk]
    An integrated database of predictive protein signatures used for the classification and automatic annotation of proteins and genomes.
  • Eukaryotic Promoter Database [epd.isb-sib.ch]
  • PROSITE [expasy.org]
    A database of protein families and domains.
  • SWISS-PROT [web.expasy.org]
    A protein knowledgebase.
  • BioMagResBank [bmrb.wisc.edu]
    NMR spectroscopy data on proteins, peptides, and nucleic acids.
  • Protein Data Bank (PDB) [rcsb.org]
    The repository for 3-D biological macromolecular structure data.
  • DSSP [swift.cmbi.ru.nl]
    A database of secondary structure protein assignments.
  • FSSP [biocenter.helsinki.fi]
    A database of fold classifications based on structure-structure alignment of proteins.
  • HSSP [cmbi.kun.nl]
    A database of homology-derived secondary structure of proteins.
  • Nucleic Acid Database Project (NDB) [ndbserver.rutgers.edu]
    Structural information about nucleic acids.
  • The I.M.A.G.E. Consortium [image.hudsonalpha.org]
    A public collection of genes.
Ethical, Legal and Social Implications (ELSI) Research Program
Funding Agencies
Additional Genome Resources
Biology Resources
Selected Journals

Last Updated: October 16, 2012

SOURCE:

http://www.genome.gov/10000375

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Author and Curator: Dror Nir, PhD

 

As an entrepreneur who is promoting innovations in medical imaging I often find myself confronted with this question. Usually the issue is raised by a project’s potential financier by the way of the following remarks:

  • The Genome Project opens the road to “Star Track” kind of medicine. No one will need imaging.
  • What about development of new disease-specific markers? Would that put imaging out of business?
  • Soon we will have a way to “fix” bad cells’ DNA.  and so we will have no use for screening

In these situations I always find myself struggling to come up with answers rather than simply saying, ‘Well, it will take more time for these applications to be available than for you to reach your exit….’. I always try to find a quantitative citation to show how much time and money still needs to be invested before patients will be able to profit from that kind of futuristic “sci-fi medicine”.

Last week, a very recent source for such information was brought to my attention.  As a contributor to Leaders in Pharmaceutical Business Intelligence I was asked to review and comment on a recent report published in Nature regarding the progress made in the ENCODE project [1]. I was also asked to assess the influence of the progress in understanding the human genome on imaging-based cancer patients’ management, my field of expertise.

This short report is nicely written and is clear to layman’s (which is what I consider myself in this field) reading. My attention was drawn to some important facts:

  • It took 10 years and $288 Million to realise that 80% of 3 Billion DNA bases comprising the human genome serves a purpose.
  • So far a very small percentage (3% to 4%) of this potential was uncovered in the scope of this project.
  • Already now it is clear that much of the “knowledge” regarding the human genome’s functionality will need to be re-written.
  • Researchers anticipate that future studies using advanced technologies will contribute to better estimation of the knowledge gap.
  • Good news: these studies are leading to better understanding of diseases’ pathological characteristics and to more accurate reporting of disease sources. This gives hope to future development of disease specific drug development.

So, back to the subject of this post: it seems to me that we are quite a few decades and many billions of dollars away from “Star-Trek medicine”. In the foreseeable  future, i.e. at least during my life time (and I hope to live a while longer…), the daily routine of cancer patients’ management will have to rely on workflows constituted of screening, diagnosis, a treatment choice that includes a trial and error type of drugs’ choice, and a long-term post treatment follow-up. Smart imaging promises to increase cost efficiency and medical efficacy of these workflows. And I do hope that our children will benefit from the investment our generation is making in understanding the way the human genome is functioning.

  1. Science 7 September 2012: Vol. 337 no. 6099 pp. 1159-1161
    DOI: 10.1126/science.337.6099.1159 http://www.sciencemag.org/content/337/6099/1159.summary?sid=835cf304-a61f-45d5-8d77-ad44b454e448

Written by Dror Nir

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A slight mutation in the matched nucleotides c...

A slight mutation in the matched nucleotides can lead to chromosomal aberrations and unintentional genetic rearrangement. (Photo credit: Wikipedia)

Reporter: Venkat Karra, Ph.D.

A Global Approach to Global Genome Research: to address ELSI at Global Level..

via A Global Approach to Global Genome Research: to address ELSI at Global Level..

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