GENOTYPING RESOURCE FOR MAPPING COMPLEX PHENOTYPES 

NIH GUIDE, Volume 26, Number 26, August 8, 1997

 

P.T.





Keywords:

 

National Human Genome Research Institute

 

PURPOSE

 

The National Human Genome Research Institute announces the

availability of resources and facilities for high throughput

genotyping at the Center for Inherited Disease Research (CIDR).  CIDR

has been established as a resource to provide, on a fee-for-service

basis, high throughput genotyping services to research efforts that

are attempting to identify genetic loci and allelic variants involved

in multifactorial human disease.  The mapping activities at CIDR will

concentrate on the use of human populations and families but may

involve analysis of pertinent animal models as well.  The purpose of

this document is to describe procedures through which investigators

can request access to CIDR.

 

ELIGIBILITY REQUIREMENTS

 

Access to CIDR will be determined on a competitive basis and is

intended to be a resource for investigators who receive their primary

research funding from NIH.  CIDR will also be available on a

competitive basis to NIH intramural scientists.  Extramural

investigators who have or are seeking NIH funding and who would like

to use the services offered by CIDR, including those investigators

submitting competing continuation (renewal) applications, and

investigators submitting applications for competing supplements to

add a genotyping component, are encouraged to request CIDR access

prior to submitting their research grant applications to the NIH (for

details see below).  Those already funded for genotyping can also

request access to the facilities of CIDR; for further information

please contact Dr. Jerry Roberts (see information below).

 

BACKGROUND

 

A major thrust of human genetics research in this decade,  the

identification and analysis of genes which underlie disease, is now

being directed to the common diseases, those that cause major

morbidity and mortality in the population and which are usually

complex in their etiology.  The recent genome-wide searches for genes

for insulin dependent diabetes mellitus and multiple sclerosis are

representative examples of this approach in medical genetics

research.  Identification of genes contributing to common diseases

brings with it an expansion in our knowledge of the pathophysiology

of such disorders as well as  the hope of early diagnostic

techniques, pharmacological intervention, and effective preventative

strategies.

 

Diseases such as diabetes, heart disease, cancer, and psychiatric

illness are challenging to analyze since they often result from a

number of environmental and genetic factors acting in concert. An

important consequence of the identification of the genetic components

of such diseases would be the development of the ability to

distinguish between genetic effects and environmental effects.  To

facilitate identification of the genetic factors underlying these

diseases, genotyping must be carried out on a scale much larger than

has previously been possible. Yet the labor intensive nature of such

analyses will discourage many investigators from initiating such

studies.  This need has led the NIH to develop a new center, the

Center for Inherited Disease Research (CIDR), to provide the research

community with the resources necessary to conduct such studies.  CIDR

will specialize in high throughput genotyping in support of NIH-

supported investigators.

 

CIDR is a joint effort by eight participating institutes at NIH: the

National Human Genome Research Institute (NHGRI),  the National

Cancer Institute (NCI), the National Institute of Child Health and

Human Development (NICHD), the National Institute on Deafness and

Other Communication Disorders (NIDCD), the National Institute on Drug

Abuse (NIDA), the National Institute of Environmental Health Sciences

(NIEHS), the National Institute of Mental Health (NIMH), and the

National Institute of Neurological Disorders and Stroke (NINDS).  The

NHGRI serves as the lead agency and manager of the CIDR facility

which will be housed at the Bayview Campus of Johns Hopkins

University.  While the NIH Institute or Center to which an

application may be assigned is not relevant for CIDR access

consideration, the charge for this resource will be higher for

scientists supported by non-participating institutes.

 

SCOPE OF CIDR SERVICES

 

Using samples provided by the principal investigators, CIDR will

carry out genome-wide genotyping scans.  A variety of different

mapping approaches will be supported, including affected pedigree

member methods, transmission disequilibrium testing, and linkage

analysis in pedigrees.  Consultation on study design and on

statistical analysis are available, as additional services, to

investigators.  The data and analyses will remain the property of the

principal investigators and once the studies at CIDR have been

completed, will be returned to the principal investigators.  At the

outset CIDR will use automated fluorescent microsatellite analysis

using standard marker sets (^10 cM average spacing) with an initial

goal of 1-2 million genotypes (marker x DNA sample) per year.  With

this capacity, it is estimated that CIDR will initially be able to

work on 6 to 9 projects per year, although that number will obviously

depend on the size of the projects.

 

Though focusing on genotyping services, CIDR scientists will also be

engaged in research efforts across five main components: 1)

statistical genetics, which applies the power of statistics to the

hereditary patterns of genes to determine modes of inheritance from

parents to their children; 2) genetic epidemiology, which applies

genetic analysis gathered from disease-prone families to the general

population to determine if the genetics patterns of the research

families hold in large diverse populations; 3) medical informatics

and database management, which uses computer programs to store,

manipulate, and analyze the research data; 4) state-of-the-art

technology to rapidly scan whole genomes for multiple gene regions

associated with a particular disorder; and 5) technology development,

which continues to refine existing methods and generate new ways to

perform high-capacity genotyping efficiently and cost effectively.

 

While many investigators will only request use of the genotyping

capabilities of CIDR, others may wish to avail themselves of the

expertise of CIDR personnel in designing the studies and in the

analysis of data.  Investigators requesting such collaborations with

CIDR scientists should detail these collaborations in their requests

and include appropriate letters of commitment from those involved.

Investigators wishing more information on CIDR personnel for

potential collaborations should contact Dr. Jerry Roberts at the CIDR

Office in NHGRI (see below under Inquiries.)

 

PROCEDURE FOR REQUESTING CIDR ACCESS

 

Investigators intending to seek NIH support for gene mapping projects

and who wish to utilize the genotyping resources of CIDR are

encouraged to request CIDR access prior to submitting a research

grant application to the NIH.  A short document (ideally 5-8 pages,

single spaced) describing the project and justifying the need for

such a resource is required.  The CIDR Access Committee (CAC) will

review these requests and determine if a project is suitable for

CIDR.  If suitable, a letter of commitment will be sent to the

investigator.  Investigators denied CIDR access will be notified and

a letter will briefly detail the reason(s) for denial.

 

The CAC will hold three meetings per year as summarized below.

Decisions by the CAC will be transmitted to investigators immediately

after the CAC meeting.  While no firm deadlines for accepting

requests are set, investigators are advised to plan their submission

strategy so that they can learn the outcome of the CAC evaluation

prior to submitting a research grant application to NIH.  For

example, investigators planning to submit NIH grant applications for

the February/March receipt date are advised to submit their requests

to the CAC by mid-November to insure sufficient time for evaluation

by the CAC at its regular, scheduled meeting in December/January and

transmittal of the CAC's decision to investigators.  The following

schedule should be used to guide investigators in preparing and

submitting requests.  Requests for access received too late to

transmit to the CAC members will be held and taken to the next CAC

meeting.

 

Date for Requesting    CAC Meeting/Reporting    Date for Submitting

CIDR Access                                     NIH Grant Application

Mid-November             Dec/Jan                    Feb/Mar

Mid-March                Apr/May                    Jun/Jul

Mid-July                 Aug/Sep                    Oct/Nov

 

Investigators already funded for genotyping are also eligible to

apply for CIDR access.  Interested investigators should prepare a 5-8

page request as described above.

 

ACCESS CRITERIA

 

Factors that will be weighed in determining the suitability of a

project for CIDR access include:

 

- the size and scope of the project and the need for large capacity

genotyping to complete the project.

 

- significance and complexity of the disorder/trait.

 

- the quality and completeness of the phenotyping carried out on the

subjects.

 

- strength of the evidence for a genetic component to the disease

phenotype.

 

- the ability and preparedness of the investigator to manage the

large amount of data that is generated by large genotyping projects.

 

- the appropriateness of the study population for the specific

disease mapping project.

 

- the availability of adequate numbers of patient samples and the

completeness of the patient sample set.

 

- the appropriateness of proposed analytic methods and the ability of

the investigators to carry out the methods.

 

- the quality, availability and completeness of the DNA samples.

 

Investigators who are informed that their request for CIDR access has

been granted should use this information in preparing their NIH

research grant application.  Other investigators have the option of

seeking genotyping services elsewhere.

 

SCHEDULING OF FUNDED PROJECTS FOR CIDR ACCESS

 

It is anticipated that, because of the demands on CIDR resources, a

schedule of priority for project initiation will have to be

established.  Final scheduling of funded projects will be determined

by the CIDR Director in consultation with the Board of Governors,

which oversees CIDR.  The Board is comprised of the Directors of the

eight institutes that are contributing funds to the contract, as well

as two non-voting members: the CIDR Director and a representative of

Johns Hopkins University, the contractor for this facility.

 

INQUIRIES

 

Inquires are encouraged.  The opportunity to clarify any issues or

questions is welcomed.  Potential investigators who wish to discuss

issues related to research grant application submission may contact

Dr. Jerry Roberts for identification of an appropriate institute or

center staff member.  Telephone, electronic and/or written inquiries

are welcomed.

 

Direct inquiries regarding CIDR access and CAC review to:

 

Jerry Roberts, Ph.D.

National Human Genome Research Institute

Building 38A, Room 609

38 Library Drive

Bethesda, MD 20892-6050

Telephone: (301) 402-0838

Fax: (301) 480-2770

Email: [email protected]

 

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