NHLBI Working Group
Future of Genotyping
Executive Summary
The National Heart, Lung, and Blood Institute convened a Working Group
of investigators on October 22, 2004, in Bethesda, Maryland via conference
call, to evaluate current genotyping needs, opportunities, and barriers
for human and animal model gene discovery. The Working Group considered
the current genotyping activities of the NHLBI and addressed a number
of questions concerning future efforts in genotyping needs that could
be facilitated by NHLBI.
Discussion:
The NHLBI is committed to discovering and understanding the genetic contributions
to complex diseases of the heart, lung, and blood. In 1994, the NHLBI
established the NHLBI Mammalian Genotyping Service (MGS) with the Marshfield
Clinical Medical Research Foundation to help investigators identify genes
likely to be involved in the etiology of complex diseases. The MGS has
provided whole genome linkage scans, using microsatellite markers, for
the scientific community for the past ten years, and has greatly enhanced
the speed with which candidate regions and genes are able to be linked
to disease. To address the need to pursue these candidate regions, the
Institute established the NHLBI Re-Sequencing and Genotyping Program in
2004. Since an increasing number of researchers and private companies
are developing high-throughput technologies and services to perform millions
of genotypes a month, the need for services such as the NHLBI MGS, whose
contract is near completion, should be carefully considered. The Working
Group members were asked to assess the genotyping needs of the scientific
community in a number of areas: (1) needs for a service to perform genome-wide
scans, including genome-wide linkage, genome-wide association, and regional
genome scans; (2) sharing of genotyping data; (3) public/private partnerships
to create a service for the scientific community; and (4) interaction
with other public efforts in genotyping.
An overview of the MGS and its current capacity, applicant interest,
and types of studies that it supports, facilitated significant discussion
about the need for future genotyping services. Overall, the Working Group
recommended that the NHLBI should remain involved in providing genotyping
services for NHLBI-funded investigators. They discussed: (1) the current
and future need for the MGS, and how to transition from the current MGS
to a new model of genotyping services; (2) genotyping service(s) that
would support association studies for both following up linkage results
and biological candidate genes, as well as SNP-based linkage studies in
humans; (3) genome-wide association studies; (4) genotyping in model organisms;
(5) use of the International HapMap; and (6) the appropriate release of
genotyping data to the public.
Recommendations:
Based on the present and future genotyping needs of the scientific community,
the working group members recommended ways that the NHLBI could best meet
those needs. The Working Group recommended that NHLBI (in priority order):
- Provide Genotyping Facilities to the NHLBI Scientific Community.
The Working Group noted that the need for high quality, cost effective
genotyping for gene discovery is still significant. Over the time of
the NHLBI MGS, technologies and genomic variation discovery efforts
have greatly accelerated. Although the NHLBI MGS has been proactive
in incorporating these changes in genotyping marker sets, the Working
Group recommended that the current NHLBI MGS contract be completed as
funded and that the NHLBI move to new Genotyping Facilities to facilitate
gene discovery using single nucleotide polymorphisms (SNPs), as outlined
below.
- Complete the NHLBI MGS contract.
The Working Group recommended completing the NHLBI MGS with current
obligated funds, with only one more receipt date for service (instead
of two receipt dates). The deadline for the last receipt date should
be extended from March 30, 2005, to May 30, 2005, in order to give
appropriate notice to the scientific community. The Working Group
noted there will be a hiatus in genotyping between the current NHLBI
MGS and a new genotyping service (see below).
- Establish SNP Mapping Centers.
Given the significant changes in gene mapping that have occurred over
the time of the NHLBI MGS, the Working Group recommended that the
NHLBI establish genotyping facilities that use SNP markers, rather
than microsatelite markers. The Working Group recommended these SNP
Mapping Centers initially focus on human mapping projects. These facilities
could be located at multiple sites, rather than at a single site,
and could be developed in cooperation with other NIH institutes. They
would provide services for:
- SNP-based genome-wide linkage studies
- SNP-based association studies for following up on linkage results
- SNP-based association studies for biologically relevant candidate
genes
- Initiate A Pilot Program For Genome-Wide Association Studies.
As the International Haplotype Map (HapMap) project nears completion,
investigator interest in applying genome-wide association studies to
disease gene discovery is increasing. As the Working Group noted that
the technology to perform genome-wide association studies is far beyond
the analytic strategies needed to gain meaningful insights from the
data generated, they recommended the NHLBI initiate a pilot program
for genome-wide association studies. The purpose of the pilot program
would be to develop methods and test various approaches. Potential pilot
projects are:
- Test a large (multimegabases) genomic region for SNP-disease associations.
- Test a sparse collection of SNPs (e.g., 50,000 SNPs) that span
the entire genome for association with a variety of diseases.
- Select one disease for investigation that is highly heritable. Support
a project with the best sample, genotyping, and analysis plan to test
the ability to understand the data handling, design, and analysis
for genome-wide association. Although difficult to pick an appropriate
project and the costs will be extensive, it will provide valuable
information.
- Develop a Rodent SNP Mapping Center. The focus of SNP discovery
has been in the human.
Some additional SNP discovery efforts are being conducted in mouse,
with discussions on initiating a similar program in rat. Thus, it is
somewhat premature to initiate either Linkage or Association SNP Mapping
Centers for all animal models. However, the Working Group noted that
animal model research is key in bench to bedside efforts, systems biology
approaches, and understanding function and mechanism. The Working Group
recommended that NHLBI partner with other NIH Institutes to develop
a Rodent SNP Mapping Center, initially in the mouse. It was also recommended
that the NHLBI lead a Trans-NIH effort to determine the best way for
variation discovery to proceed in other model organisms.
- Convene A Standing Working Group to Identify and Annotate Genes,
Validate SNPs, and Identify Haplotypes.
Curating and annotating the information derived from genomic and genetic
studies is critical to understand the genetic influences on health and
disease. Without standard nomenclatures and descriptions of discoveries,
knowledge can be lost, duplicated, or misinterpreted. The Working Group
recommended that the NHLBI convene a standing Working Group to identify
and annotate genes, validate SNPs, and identify haplotypes related to
heart, lung, blood, and sleep processes and diseases in order to stimulate
translation of genetic and genomic findings to public health.
The working group also recommended that any new genotyping service should
make the data that it produces publicly available, such that data sharing
becomes and integral part of the work scope.
NHLBI Contact:
Dina N. Paltoo, Ph.D., M.P.H., NHLBI, NIH
paltood@mail.nih.gov
Susan E. Old, Ph.D., NHLBI, NIH
Oldse@mail.nih.gov
Working Group Members
Chair: Eric Boerwinkle, Ph.D.,Human Genetics Center, University
of Texas-Houston Health Science Center
Members:
- David Ginsberg, M.D, University of Michigan
- Joel Hirschhorn, M.D., Ph.D., Children's Hospital
- Sharon Kardia, Ph.D., University of Michigan, Ann Arbor
- Anne Kwitek, Ph.D., Medical College of Wisconsin
- Susan Redline, M.D., Ph.D., Case Western Reserve University
- Charles Rotimi, Ph.D., National Human Genome Center at Howard University
- Gaulberto Ruano, M.D., Ph.D., Genomas, LLC.
- Ed Silverman, M.D., Ph.D., Brigham and Women's Hospital
NIH Staff:
- Dr. Deborah Applebaum-Bowden, DHVD, NHLBI, NIH
- Dr. Susan Banks-Schlegel, DLD, NHLBI, NIH
- Ms. Joanne Deshler, DEA, NHLBI, NIH
- Dr. Gregory Evans, DBDR, NHLBI, NIH
- Dr. Sandra Hatch, DLD, NHLBI, NIH
- Dr. Teri Manolio, DECA, NHLBI, NIH
- Dr. Pankaj Qasba, DBDR, NHLBI, NIH
- Dr. Phyliss Sholinsky, DECA, NHLBI, NIH
Last updated: December 13, 2004
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