PA NUMBER:  PA-02-110

Release Date:  May 29, 2002

Expiration Date:   June 5, 2005

National Institute of General Medical Sciences (NIGMS)
National Human Genome Research Institute
National Institute on Aging
National Institute on Alcohol Abuse and Alcoholism
National Institute of Mental Health 
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute on Drug Abuse
National Institute of Environmental Health Sciences
National Institute of Neurological Disorders and Stroke


o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations


This announcement updates the 1998 Program Announcement PA-98-078, Genetic 
Architecture of Complex Phenotypes.  The program announcement is to solicit 
applications for new studies on genetic variation and the architecture of 
complex phenotypes.  It restates the interest of several components of the 
National Institutes of Health in studies of the underlying causes and 
architecture of complex phenotypes, including human diseases.  It is 
motivated by the amount and complexity of biological data that are being 
generated and by the understanding that complex phenotypes involve many 
genetic components that evolve in a variety of environments.  


Complex phenotypes are those that exhibit familial clustering, which may mean 
that there is some genetic component, but that do not occur in Mendelian 
proportions in pedigrees.  Complex phenotypes may be continuous in 
distribution, like height or blood pressure, or they may be dichotomous, like 
affected and not affected.  The complexity arises from the fact one cannot 
accurately predict the expression of the phenotype from knowledge of the 
individual effects of individual factors considered alone, no matter how well 
understood each separate component may be. 

The past few decades of biological research using largely a reductionist 
approach have yielded vast amounts of data.  In addition, genome sequencing 
projects, as well as structural and functional genomics initiatives, are 
producing data far more rapidly than scientists can analyze them and 
understand their implications to biology and to health.  As overwhelming as 
the current data are, they are only the beginning.  Protein structures, DNA 
sequences, and gene expression patterns vary among individuals, among 
species, among populations within a species, and across environments.  It 
will soon be possible to utilize information on thousands of variable genetic 
sites to investigate the relationships among genotypes, phenotypes, and 

The term genetic architecture refers to the full range of genetic effects on 
a trait; however, when studying variation on such a large scale, it is 
especially important to consider the context or environments in which genetic 
variation arises, is selected, and is maintained.  Genetic architecture is 
less a fixed property of the phenotype than a characteristic of a phenotype 
in a particular population. Genetic architecture is a moving target that 
changes according to gene and genotype frequencies, distributions of 
environmental factors, and such biological properties as age and sex.  

Studies of variation or genetic architecture may employ a variety of 
conceptual approaches.  A researcher may consider the combinatorial effects 
of many variable sites, whether the scale is within a gene or across a 
genome.  Comparative genomics, where the goal is to identify patterns of 
variation among genomes, is also a productive way of identifying attributes 
of variation, such as which genomic regions are rapidly evolving.  Another 
approach is to study variation related to biological levels of organization, 
such as DNA sequence, protein structure, metabolic pathways, cell dynamics, 
individual phenotype, and population characteristics.  

The following are typical of research areas targeted by this initiative:

Biological Variation
Studies of genetic architecture have historically focused on associations of 
genotype and phenotype (e.g., between DNA markers and a disease).  However, 
an organism is a unique consequence of both genes and environment and is 
created by complex interactions of multiple events and forces.  How genes are 
expressed depends on their cellular, developmental, physiological, and 
environmental context.  This initiative encourages research on biological 
variation and interactions, such as:

o Variation in basic biological systems, including sequences, structures, and 
pathways that direct metabolism and development 
o Variation in these systems within individuals, among individuals, among 
populations, and among species with the goal of learning how these complex 
systems interact and evolve  
o Determination of the extent to which genetic architecture is shared across 
populations and among species
o Effects of admixture, population history, recombination, mutation, 
population structure, selection, and drift on the organization of variation
o Collection and analysis of both new and existing data 
o Tools and models for identifying and measuring important contextual 
o Measuring the impact of context on biological data. 

Evolution of Genome Properties
An emerging area of research focuses on how properties of genomes arise in 
evolutionary history.  Such research has important consequences for 
understanding genome organization and for interpreting data on genetic and 
phenotypic variation.  Such research could include the evolution of 
haplotypes, selection for genetic interactions, and the evolution of 
recombination and methylation patterns.  

Extensions to Other Organisms
Many organisms have been studied for their value in agriculture or ecology.  
Thus, there is considerable information about the population structure, 
natural history, and genetics of these systems.  It will be valuable to take 
advantage of this wealth of information to study variation in the natural 
settings in which it evolved.

The study of biological variation depends heavily on rich data sets;  
researchers need the ability to access many kinds of information (e.g., DNA 
sequence, protein structure, development, natural history, and phenotype) in 
organisms from different habitats, from different populations, or from 
different species.  This initiative supports development of tools to help 
researchers use data from many databases to address research questions.  

Improved Dynamic Modeling and Statistical Methods
Mathematical approaches to studying biological variation have changed little 
in several decades.  There is a need to develop new dynamic models to 
illuminate how systems interact and evolve.  Just as important, it is 
critical to study the nature of biological and mathematical assumptions of 
models and statistics.  Tools for analyzing and interpreting data on the 
architecture of complex phenotypes should be developed in the context of real 
biological information.  Areas of particular interest for this initiative 
include the following:

o Implications and appropriate uses of different sampling strategies
o Analytical tools to discover patterns of genotypic variation and their 
roles in conferring phenotype
o Incorporation of data from new technologies
o Development of robust methods that are compatible with real data (missing 
or incomplete data, typing errors, experimental errors)
o Development of mathematical models based on empirical information which 
includes such biological realities as epistasis, recombination, mutation, 
protein structure, cell biology, metabolic pathways, development, population 
history, and evolution.


This Program Announcement will use the National Institutes of Health (NIH) 
research project grant (R01).  As an applicant, you will be solely 
responsible for planning, directing, and executing the proposed project.

This PA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see  Specifically, if 
you are submitting an application with direct costs in each year of $250,000 
or less, use the modular format.  Otherwise follow the instructions for non-
modular research grant applications.


You may submit (an) application(s) if your institution has any of the 
following characteristics:

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, 
and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign institutions


Any individual with the skills, knowledge, and resources necessary to carry 
out the proposed research is invited to work with his or her institution to 
develop an application for support.  Individuals from underrepresented racial 
and ethnic groups as well as individuals with disabilities are always 
encouraged to apply for NIH programs.


We encourage your inquiries concerning this PA and welcome the opportunity to 
answer questions from potential applicants.  Inquiries may fall into two 
areas:  scientific/research, and financial or grants management issues:

o Direct your questions about scientific/research issues to:

Irene Anne Eckstrand, Ph.D.
Division of Genetics and Developmental Biology
National Institute of General Medical Sciences
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-0943
Fax:  (301) 480-2228

Lisa D. Brooks, Ph.D. 
National Human Genome Research Inst
National Institutes of Health
31 Center Drive, 31/B2B07
Bethesda, MD 20892-2033
Telephone:  (301) 435-5544
Fax:  (301) 480-2770

Winifred K. Rossi, M.A.
Genetic Epidemiology and Translational Research
National Institute on Aging
7201 Wisconsin Avenue, Suite 3E327
Bethesda, Maryland 20892-9205
Telephone:  (301) 496-3836
Fax:  (301) 402-1784

Lisa A. Neuhold, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402
Bethesda, MD 20892-7003
[for express mail, use Rockville, MD 20852]
Telephone:  (301) 594-6228
Fax:  (301) 594-0673

Steven O. Moldin, Ph.D.
Genetics Research Branch
Division of Neuroscience & Basic Behavioral Science
National Institute of Mental Health
6001 Executive Blvd., Room 7189, MSC 9643
Bethesda, MD 20892-9643
Telephone:  (301) 443-2037
Fax:  (301) 443-9890

Robert W. Karp, Ph.D.
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, Room 671, MSC 5450
Bethesda, MD 20892-5450
(For FedEx and UPS, use Bethesda, MD 20817)
Telephone:  (301) 451-8875
Fax:  (301) 480-8300

Jonathan D. Pollock, Ph.D.
Genetics and Molecular Neurobiology Research Branch
National Institute on Drug Abuse
6001 Executive Blvd, Rm. 4274
Bethesda, MD 20892
Telephone:  (301) 435-1309
Fax:  (301) 594-6043

Jose M. Velazquez, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
111 Alexander Drive
Research Triangle Park, NC 27709
Telephone:  (919) 541-4998
Fax:  (919) 316-4606

Katrina Gwinn-Hardy, M.D.
National Institute of Neurological Diseases and Stroke
6100 Executive Blvd, Room 2142 MSC 9525
Bethesda, MD 20892
Telephone:  (301) 496-5745
Fax:  (301) 402-1501

o Direct your questions about financial or grants management matters to:

Marcia Cohn
Grants Management Office
National Institute of General Medical Sciences
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-3918
Fax:  (301) 480-1969

Jean Cahill
Grants Administration Branch
National Human Genome Research Institute 
Building 31, Room B2B34
Bethesda, MD  20892-2031
Telephone:  (301) 402-0733
Fax:  (301) 402-1951

Linda Whipp
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Room 2N212
7201 Wisconsin Avenue, MSC 9205
Telephone:  (301) 496-1472
Fax:  (301) 402-3672

Judy Simons
Grants Management Office
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 504
Bethesda, MD 20892-7003
[for express mail, use Rockville, MD 20852]
Telephone:  (301) 443-2434
Fax:  (301) 443-3891

Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
6001 Executive Blvd., Room 6115, MSC 9605
Bethesda, MD 20892-9605
Telephone:  (301) 443-2805
Fax:  (301) 443-6885

Donna Huggins
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Room 711 MSC 5456
Bethesda, MD  20892-5456
(For Express Mail Use Zip Code 20817)
Telephone:  (301) 594-8848
Fax:  (301) 480-3504

Gary Fleming, J.D., M.A.
Grants Management Branch
Office of Planning and Resource Management
National Institute on Drug Abuse/NIH
6001 Executive Boulevard, Room 3131, MSC 9541
Bethesda, MD 20892-9541
Telephone:  (301) 443-6710
Fax:  (301) 594-6847

Carolyn Winters
Grants Management Specialist
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
111 Alexander Drive
Research Triangle Park, NC 27709
Telephone:  (919) 541-7823
Fax:  (919) 541-2860

Kathleen Howe
Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd, Room 3290 MSC 9537
Bethesda, MD 20892
Telephone:  (301) 496-9231
Fax:  (301) 402-0219


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001).  The PHS 398 is available at in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 710-0267, 

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which 
are available at  Application 
deadlines are also indicated in the PHS 398 application kit.
up to $250,000 per year in direct costs must be submitted in a modular grant 
format.  The modular grant format simplifies the preparation of the budget in 
these applications by limiting the level of budgetary detail.  Applicants 
request direct costs in $25,000 modules.  Section C of the research grant 
application instructions for the PHS 398 (rev. 5/2001) at includes step-by-step 
guidance for preparing modular grants.  Additional information on modular 
grants is available at

Applications requesting $500,000 or more in direct costs for any year must 
include a cover letter identifying the NIH staff member within one of NIH 
institutes or centers who has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following steps:

1)  Contact the IC program staff at least 6 weeks before submitting the 
application, i.e., as you are developing plans for the study; 

2)  Obtain agreement from the IC staff that the IC will accept your 
application for consideration for award; and
3)  Identify, in a cover letter sent with the application, the staff member 
and IC who agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing 
continuation (type 2), competing supplement, or any amended or revised 
version of these grant application types. Additional information on this 
policy is available in the NIH Guide for Grants and Contracts, October 19, 
2001 at 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of 
the application, including the checklist, and five signed photocopies in one 
package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD  20892-7710
Bethesda, MD  20817 (for express/courier service)

APPLICATION PROCESSING: Applications must be received by or mailed before the 
receipt dates described at  The CSR will 
not accept any application in response to this PA that is essentially the 
same as one currently pending initial review unless the applicant withdraws 
the pending application.  The CSR will not accept any application that is 
essentially the same as one already reviewed.  This does not preclude the 
submission of a substantial revision of an application already reviewed, but 
such application must include an Introduction addressing the previous 


Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
( will evaluate applications for scientific 
and technical merit.  

As part of the initial merit review, all applications will:

o Receive a written critique
o Undergo a selection process in which only those applications deemed to have 
the highest scientific merit, generally the top half of applications under 
review, will be discussed and assigned a priority score
o Receive a second level review by the appropriate national advisory council 
or board


The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  In 
the written comments, reviewers will be asked to discuss the following 
aspects of your application in order to judge the likelihood that the 
proposed research will have a substantial impact on the pursuit of these 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
The scientific review group will address and consider each of these criteria 
in assigning your application's overall score, weighting them as appropriate 
for each application.  Your application does not need to be strong in all 
categories to be judged likely to have major scientific impact and thus 
deserve a high priority score.  For example, you may propose to carry out 
important work that by its nature is not innovative but is essential to move 
a field forward.

(1) SIGNIFICANCE:  Does your study address an important problem? If the aims 
of your application are achieved, how do they advance scientific knowledge?  
What will be the effect of these studies on the concepts or methods that 
drive this field?

(2) APPROACH:  Are the conceptual framework, design, methods, and analyses 
adequately developed, well integrated, and appropriate to the aims of the 
project?  Do you acknowledge potential problem areas and consider alternative 

(3) INNOVATION:  Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project challenge 
existing paradigms or develop new methodologies or technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out 
this work?  Is the work proposed appropriate to your experience level as the 
principal investigator and to that of other researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your work will be 
done contribute to the probability of success?  Do the proposed experiments 
take advantage of unique features of the scientific environment or employ 
useful collaborative arrangements?  Is there evidence of institutional 

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

PROTECTIONS:  The adequacy of the proposed protection for humans, animals, or 
the environment, to the extent they may be adversely affected by the project 
proposed in the application.

INCLUSION:  The adequacy of plans to include subjects from both genders, all 
racial and ethnic groups (and subgroups), and children as appropriate for the 
scientific goals of the research.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria included in the 
section on Federal Citations, below)

DATA SHARING:  The adequacy of the proposed plan to share data.
BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.


Applications submitted in response to a PA will compete for available funds 
with all other recommended applications.  The following will be considered in 
making funding decisions:

o Scientific merit (as determined by peer review) 
o Availability of funds 
o Programmatic priorities.


It is the policy of the NIH that women and members of minority groups and 
their sub-populations must be included in all NIH-supported biomedical and 
behavioral research projects involving human subjects, unless a clear and 
compelling rationale and justification are provided indicating that inclusion 
is inappropriate with respect to the health of the subjects or the purpose of 
the research. This policy results from the NIH Revitalization Act of 1993 
(Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000 (;
a complete copy of the updated Guidelines are available at The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to provide a description of plans 
to conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

It is the policy of NIH that children (i.e., individuals under the age of 21) 
must be included in all human subjects research, conducted or supported by 
the NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for 
receipt dates after October 1, 1998.

All investigators proposing research involving human subjects should read the 
"NIH Policy and Guidelines" on the inclusion of children as participants in 
research involving human subjects that is available at 

policy requires education on the protection of human subject participants for 
all investigators submitting NIH proposals for research involving human 
subjects.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research 
on hESCs can be found at and at  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see   
It is the responsibility of the applicant to provide the official NIH 
identifier(s)for the hESC line(s)to be used in the proposed research.  
Applications that do not provide this information will be returned without 

The Office of Management and Budget (OMB) Circular A-110 has been revised to 
provide public access to research data through the Freedom of Information Act 
(FOIA) under some circumstances. Data that are (1) first produced in a 
project that is supported in whole or in part with Federal funds and (2) 
cited publicly and officially by a Federal agency in support of an action 
that has the force and effect of law (i.e., a regulation) may be accessed 
through FOIA. It is important for applicants to understand the basic scope of 
this amendment. NIH has provided guidance at  
Applicants may wish to place data collected under this RFA (PA) in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time. If so, the application should 
include a description of the archiving plan in the study design and include 
information about this in the budget justification section of the 
application. In addition, applicants should think about how to structure 
informed consent statements and other human subjects procedures given the 
potential for wider use of data collected under this award.

All applications and proposals for NIH funding must be self-contained within 
specified page limitations. Unless otherwise specified in an NIH 
solicitation, internet addresses (URLs) should not be used to provide 
information necessary to the review because reviewers are under no obligation 
to view the Internet sites. Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.

The Public Health Service (PHS) is committed to achieving the health 
promotion and disease prevention objectives of "Healthy People 2010," a PHS 
led national activity for setting priority areas. This Program Announcement 
(PA), Genetic Architecture, Biological Variation, and Complex Phenotypes, is 
related to one or more of the priority areas. Potential applicants may obtain 
a copy of "Healthy People 2010" at

This program is described in the Catalog of Federal Domestic Assistance No. 
93.862, 93.847, 93.848, 93.242, 93.172, 93.279, 93.849 and 93.853 and is not 
subject to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review.  Awards are made under authorization of 
sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 
and 284) and administered under NIH grants policies described at and under Federal Regulations 
42 CFR 52 and 45 CFR Parts 74 and 92. 

The PHS strongly encourages all grant and contract recipients to provide a 
smoke-free workplace and promote the non-use of all tobacco products. In 
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking 
in certain facilities (or in some cases, and portion of a facility) in which 
regular or routine education, library, day care, health care or early 
childhood development services are provided to children. This is consistent 
with the PHS mission to protect and advance the physical and mental health of 
the American people.

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