GENETIC ARCHITECTURE OF COMPLEX PHENOTYPES

Release Date: June 9, 1998

PA NUMBER:  PA-98-078

National Institute of General Medical Sciences
National Institute of Environmental Health Sciences
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute on Aging
National Institute of Mental Health
National Institute of Drug Abuse
National Institute on Alcohol Abuse and Alcoholism
National Institute of Child Health and Human Development
National Human Genome Research Institute
National Heart, Lung, and Blood Institute

PURPOSE

The purpose of this initiative is to support new studies on the architecture of
complex phenotypes, including research using human and model systems as well as
research using theoretical approaches.  The studies targeted by this program
announcement are expected to expand our understanding of the roles of genetic and
environmental variation and their interactions in causing phenotypic variation
in populations; increase the quantity and quality of population-based data; lead
to development of mathematical and statistical tools for analyzing measured
genotype data; lead to improvements in study design; and create biologically
relevant models for understanding the origins, roles and implications of genetic
variation in causing variation in phenotypes.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This PA, Genetic Architecture of Complex
Phenotypes, is related to several priority areas.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report:  Stock No. 017- 001-00474-0
or Summary Report:  Stock No. 017-001-00473-1) through the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325 (telephone
202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-profit
organizations, public and private, such as universities, colleges, hospitals,
laboratories, units of State and local governments, and eligible agencies of the
Federal government.  Foreign institutions are not eligible for program projects
(P01) grants.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.

MECHANISM OF SUPPORT

This Program Announcement will use the National Institutes of Health (NIH)
research project grant (R01) and program project grant (P01) mechanisms. 
Supplements to existing NIH grants will also be considered.  Responsibility for
the planning, direction, and execution of the proposed project will be solely
that of the applicant.

Applications requesting direct costs of $500,000 in any one year must obtain
written agreement from the assigned institute that the application will be
accepted for consideration of award, in accordance with NIH policy, which is
available at http://www.nih.gov/grants/guide/notice-files/not98-030.html.

RESEARCH OBJECTIVES

Complex phenotypes are those that exhibit familial clustering, which suggests at
least some genetic component, but they do not occur in Mendelian proportions in
pedigrees.  Such phenotypes may have relatively simple underlying genetics, but
their transmission appears complex because of its context, including interactions
with other loci and with the environment.  Alternatively, complex phenotypes may
have multiple genetic and environmental causes.  Most chronic, common diseases
are complex by this definition. 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 that many genetic
and environmental factors may interact with each other in unpredictable ways,
such that the association between the phenotype and any single factor taken by
itself may be imperceptible.  Nonlinear interactions, including epistasis and
genotype by environment interactions, mean that the expression of the phenotype
may not accurately predicted from knowledge of the individual effects of each of
the component factors considered alone, no matter how well understood the
separate components may be.

The term genetic architecture is used to encompass the full range of genetic
effects on a trait, with emphasis on the context dependence of the expression of
those genes in manifesting a phenotype.  A full cataloging of the genetic
architecture of complex phenotypes consists of a description of all of the
genetic and environmental factors that affect the phenotype, along with the
magnitude of their individual effects and the magnitudes of interactions among
the factors.  It is, in principle, possible to describe the genetic components
in terms of Mendelian segregation and location along a genetic map. 
Environmental factors are, in general, much less easily partitioned into separate
factors whose individual effects and interactions can be sorted out.

Consideration of the evolutionary and developmental context of complex phenotypes
is critical, since these approaches may yield important information about how the
architecture of a phenotype arises.  Other scientific disciplines, including
mathematics, biochemistry, ecology, molecular biology, and physics, may also make
important contributions to understanding genetic architecture.

Genetic architecture is less a fundamental biological property of the phenotype
than a characteristic of a phenotype in a particular population. The genetic
architecture is a moving target that changes according to gene and genotype
frequencies, the distributions of environmental factors, and such biological
properties as age and sex.  The implication of the population dependence is that
the predominant genetic factors contributing to a complex phenotype may seem to
differ from population to population. This is one explanation for the apparent
heterogeneity sometimes found in the results of genetic linkage studies in
different populations.  Alternative explanations include insufficient statistical
power in the linkage tests and the possibility that superficially identical
complex phenotypes in different populations may actually have different
biological causes.  It is not now possible, in most cases, to differentiate among
these various explanations.

Strictly speaking, it may not be possible to fully quantify the complete genetic
architecture of a complex trait.  One is limited by statistical power to identify
only factors and interactions having relatively large effects.  In an ideal case,
when the factors are not numerous, when their main effects are quite large and
their interaction effects quite small, and when interpopulation heterogeneity is
minimal, very rapid progress in characterizing the underlying architecture of a
phenotype can be made. An important goal is to be able to rapidly identify
phenotypes whose underlying genetics is more tractable from those having much
more complex etiology.

Technological advances are, in part, responsible for the current excitement over
the prospects for advances in understanding complex phenotypes.  Large amounts
of data on DNA sequences and variation are now available, and new technologies
will soon make it easy and inexpensive to produce many times more.  DNA chips and
other technologies for scoring enormous numbers of single nucleotide
polymorphisms (SNPs) throughout the genome will greatly accelerate application
of genomic scans.  Our capacity for synthesizing, analyzing, and interpreting
this amount of genomic data is currently inadequate.  The challenges are
conceptual (for example, how to identify nonlinear interactions or how to
optimize computational algorithms), clinical (how to define phenotypes), and
epidemiological (how to sample in such a way as to minimize spurious associations
due to population structure and population history while maximizing the power to
detect biologically significant associations).

This program announcement restates the interest of several components of the
National Institutes of Health in studies of the underlying causes and
architecture of complex phenotypes.  It is motivated by the amount and complexity
of data that are being generated and by the understanding that complex phenotypes
involve many genes that evolve in a variety of environments.  The areas listed
below exemplify some research efforts appropriate to this program announcement.

Data Collection:
Although in many fields, there is a preference for hypothesis-driven research,
studies on genetic architecture suffer from a paucity of high-quality,
population-based data.  This program announcement encourages efforts to collect
useful information that will support the ultimate goals of the program
announcement.  These efforts include the following:

Organization of DNA sequence variation in populations and subpopulations with the
goal of understanding the causal forces that shape that organization
o  Structure of variation across the genome, populations, and phylogenies
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

Studies of the relationship of genotypic and phenotypic variation
o  Causes and implications of genotype by environment interactions and genotype
by sex interactions
o  Genetic, population, environmental, and evolutionary dynamics that are
responsible for observed levels of genotypic and phenotypic variation
o  Determination of the extent to which genetic architecture is shared across
populations and between species

Data Analysis:
Tools for analyzing and interpreting data on the architecture of complex
phenotypes should be developed in the context of real biological information. 
The focus is on approaches that may be applied to a variety of biological data. 
Areas of particular interest include the following:

Research on study design, including comparisons of different strategies for
studying complex phenotypes
o  Implications and appropriate uses of different sampling strategies
o  Implications of various methods of ascertainment
o  Implications of subdividing or pooling samples

Development of statistical and analytical tools
o  Tools that will allow scientists to make inferences about architecture of
complex phenotypes from genomic data
o  Tools to allow the integration of various kinds of relevant data such as
linkage, linkage disequilibrium, and sequence data
o  Statistical tools for analyzing data to discover genotypic and phenotypic
relationships
o  Analytical tools to discover patterns of genotypic variation and their roles
in conferring phenotype

Taking into account the future scale of genotype data, construction of meaningful
tests of relationships between genotypic and phenotypic data
o  Determining the patterns of haplotype variation that will direct the search
for sequence variation that is causal to phenotype
o  Incorporation of phase-known and phase-unknown haplotype data
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  Incorporation of epistasis tests for multiple locus interaction and linkage
disequilibrium
o  Robust methods to detect errors in phenotyping, classification of phenotypes,
or redefinitions of phenotypes
o  Methods to interpret observed relationships

Models:
Models should be based on empirical information which includes such biological
realities as epistasis, crossing over, mutation, gene conversion, interference,
population history and subdivision, selective sweeps, background selection, and
so on.  We need to learn more about how these forces shape the relationship
between genotype and phenotype, and how knowledge of these effects can be used
to investigate genetic architecture empirically.  Both simulation studies and
analytic formulations are appropriate.  Areas of interest include the following:

Models to help optimize research study design in a variety of human and model
populations
o  Sampling schemes and theory for determining genotype/phenotype relationships
o  Use of special populations, such as admixed, founder, and isolates, to study
genotype/phenotype relationships
o  Models of non-human organisms with the goal of helping investigators select
the best model for specific research questions
o  Evolutionary history of the genetic architecture of complex traits as applied
to research designs
o  Patterns of linkage disequilibrium and variation in admixed populations, given
variability in population history, including relationships of gene conversion and
crossing over with admixture
o  Gene genealogies of underlying causal genes and how selection on a complex
phenotype may leave a signature on patterns of extant genetic variation

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and their
subpopulations must be included in all NIH supported biomedical and behavioral
research projects involving human subjects, unless a clear and compelling
rationale and justification is provided 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
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994.

Investigators also may obtain copies of the policy from the program staff listed
under INQUIRIES.  Program staff may also provide additional relevant information
concerning the policy.

NIH POLICY AND GUIDELINES ON THE INCLUSION OF CHILDREN AS PARTICIPANTS IN
RESEARCH INVOLVING HUMAN SUBJECTS

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 was published in the NIH Guide for Grants
and Contracts, March 6, 1998, and is available at the following URL address: 
http://www.nih.gov/grants/guide/notice-files/not98-024.html

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
5/95) and will be accepted at the standard application deadlines as indicated in
the application kit.  Applications kits are available at most institutional
offices of sponsored research and may be obtained from the Division of Extramural
Outreach and Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email:
grantsinfo@nih.gov.

The title and number of this program announcement must be typed in Section 2 on
the face page of the application.

The completed original application and five legible copies must be sent or
delivered 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)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral
guidelines.  Applications will be reviewed for scientific and technical merit by
an appropriate initial review group.  As part of the initial merit review, a
process will be used by the initial review group in which applications will be
determined to be competitive or non-competitive based on their scientific merit
relative to other applications received in response to the PA.  Applications
judged to be competitive will be discussed and be assigned a priority score. 
Applications determined to be non-competitive will be withdrawn from further
consideration and the Principal Investigator and the official signing for the
applicant organization will be notified.  Following the initial scientific-
technical review, the applications will receive a second level review by an
appropriate National Advisory Council.

Review Criteria

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 review, comments on the following aspects of the application will be made
in order to judge the likelihood that the proposed research will have a
substantial impact on the pursuit of these goals.  Each of these criteria will
be addressed and considered in the assignment of the overall score.

o  Significance.  Does the proposal address an important problem? If the aims of
the application are achieved, how will scientific knowledge be advanced?  What
will be the effect of these studies on the concepts or methods that drive this
field

o  Approach.  Are the conceptual framework, design, methods, and analyses
adequately developed, well integrated, and appropriate?  Are there appropriate
interdisciplinary components? Does the applicant acknowledge potential problem
areas and consider alternative tactics?

o  Innovation.  Does the project employ novel concepts, approaches or method? 
Are the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?

o  Investigator.  Is the investigator appropriately trained and well suited for
the project?  Is the work proposed appropriate to the experience level of the
principal investigator and other researchers (if any) on the project?

o  Environment.  Does the scientific environment in which the work will be done
contribute to the probability of success?  Do the proposed experiments take
advantage of unique features of the scientific environment? Is there evidence of
institutional support?

The initial review group will also examine the provisions for the protection of
human and animal subjects and the safety of the research environment as well as
the adequacy of plans to include both genders, minorities and their subgroups,
and children as appropriate for the scientific goals of the research.  Plans for
the recruitment and retention of subjects will also be evaluated.

AWARD CRITERIA

Applications will compete with all other approved applications for available
funds.  The following will be considered in making funding decisions:

o  the quality of the proposed project as determined by peer review
o  program priority
o  availability of funds.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or questions
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. Irene Anne Eckstrand
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
Email:  Irene_Eckstrand@nih.gov

Jose M. Velazquez, Ph.D.
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-4998
FAX:  (919) 541-4937
Email:  velazqu1@niehs.nih.gov

Dr. William J. Sharrock
Musculoskeletal Diseases Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-37A
Bethesda, MD  20892-6500
Telephone:  (301) 594-5055
FAX:  (301) 480-4543
Email:  ws19h@nih.gov

Dr. Evan Hadley
Geriatrics Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 3E327
Bethesda, MD  20892-9205
Telephone:  (301) 435-3048
FAX:  (301) 402-1784
Email:  HadleyE@exmur.nia.nih.gov

Steven O. Moldin, Ph.D.
Division of Basic and Clinical Neuroscience Research
National Institute of Mental Health
5600 Fishers Lane, Room 10C-26
Rockville, MD  20857
Telephone:  (301) 443-2037
FAX:  (301) 443-9890
Email:  smoldin@nih.gov

Harold Gordon, Ph.D.
National Institute on Drug Abuse
5600 Fishers Lane, 10A46
Rockville, MD  20857
Telephone:  (301) 443-4877
FAX:  (301) 443-6814
Email:  hg23r@nih.gov

Robert W. Karp, Ph.D.
Division of Basic Research
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 402, MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-4223
FAX:  (301) 594-0673
Email:  rkarp@willco.niaaa.nih.gov

Dr. Ralph Nitkin
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 4B09, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-1383
FAX:  (301) 496-3791
Email:  rn21e@nih.gov

Lisa D. Brooks, Ph.D.
Division of Extramural Research
National Human Genome Research Institute
38 Library Drive, Room 614 - MSC 6050
Bethesda, MD  20892-6050
Telephone:  (301) 496-7531
FAX:  (301) 480-2770
Email:  Lisa_Brooks@nih.gov

Cashell E. Jaquish, Ph.D.
Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 8151
Bethesda, MD  20892-7934
Telephone:  (301) 435-0447
FAX:  (301) 480-1667
Email:  jaquishc@gwgate.nhlbi.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. 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
Email:  cohnm@nigms.nih.gov

David L. Mineo
Grants Management Branch
National Institute of Environmental Health Sciences
P. O. Box 12233, EC-22
111 T.W. Alexander Drive, EC-22
Research Triangle Park, NC  27709
Telephone:  (919) 541-1373
FAX:  (919) 541-2860
Email:  Mineo@niehs.nih.gov

Ms. Sally A. Nichols
Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-49F
Bethesda, MD  0892-6500
Telephone:  (301) 594-3535
FAX:  (301) 480-5450
Email:  sn21q@nih.gov

Joseph Ellis
Grants Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N-212
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  EllisJ@exmur.nia.nih.gov

Ms. Diana S. Trunnell
Grants Management Branch
National Institute of Mental Health
5600 Fishers Lane, Room 7C-08
Rockville, MD  20857
Telephone:  (301) 443-2805
FAX:  (301) 443-6885
Email:  diana_trunnell@nih.gov

Gary Fleming, J.D., M.A.
Grants Management Branch
National Institute on Drug Abuse
5600 Fishers Lane
Rockville, MD  20857
Telephone:  (301) 443-6710
FAX:  (301) 594-6847
Email:  gf6s@nih.gov

Linda Hilley
Office of Planning and Resource Management
National Institute on Alcohol Abuse and Alcoholism
6000 Executive Boulevard, Suite 504, MSC 7003
Bethesda, MD  20892-7003
Telephone:  (301) 443-4703
FAX:  (301) 443-3891
Email:  lhilley@willco.niaaa.nih.gov

Mr. Edgar D. Shawver
Office of Grants and Contracts
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A-17, MSC 7510
Bethesda, MD  20892-7510
Telephone:  (301) 496-1303
FAX:  (301) 402-0915
Email:  es65o@nih.gov

Ms. Jean Cahill
Grants Management Office
National Human Genome Research Institute
38 Library Drive, Room 613, MSC 6050
Bethesda, MD  20892-6050
Telephone:  (301) 402-0733
FAX:  (301) 402-1951
Email:  Jean_Cahill@nih.gov

Ms. Marie Willett
Division of Extramural Affairs
National Heart, Lung, And Blood Institute
6701 Rockledge Drive, Room 7156
Bethesda, MD  20892-7934
Telephone:  (301) 435-0144
FAX:  (301) 480-3310
Email:  willettm@gwgate.nhlbi.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance Nos.
93.821, 93.859, 93.862, 93.113, 93.846, 93.866, 93.242, 93.273, 93.279, 93.865, 
93.172, and 93.837.  Awards are made under authorization of the Public Health
Service Act, as amended and administered under PHS grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health Systems
Agency review.

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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