BEHAVIOR GENETICS IN ADULTHOOD AND OLD AGE

Release Date:  May 21, 1998 (see replacement, PAS-03-128)

PA NUMBER:  PA-98-076

P.T.

National Institute on Aging
National Institute of Mental Health

PURPOSE

The National Institute on Aging (NIA) and the National Institute of Mental
Health (NIMH) invite qualified researchers to submit research grant
applications on behavior genetics in adulthood and old age.  The goal of this
program announcement (PA) is to further scientific knowledge about the
relative contributions of hereditary and environmental factors in the health,
well-being, and quality of life of adults (age 21 and over) and older persons. 
This program announcement encourages research that will address one or more of
the following: a) behavior genetics and cognitive functioning/intellectual
ability, and b) behavior genetics and personality.

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 is related to age-related
objectives, genetics and medicine, and mental health and mental disorders. 
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 foreign and domestic 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 organizations are not eligible to
submit program project (P01) applications.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to apply as
principal investigators.

MECHANISM OF SUPPORT

The mechanisms of support will be the investigator-initiated research project
grant (R01) and program project grant (P01).

FISCAL YEAR

In fiscal years 1999 and 2000, a total of $1,000,000 will be available to fund
research grants, contingent on high scientific merit and program priority.

RESEARCH OBJECTIVES

Behavioral genetics involves the identification and characterization of both
genetic and environmental sources of individual variation in behavior.  The
nature vs. nurture debate has slowly given rise to the current perspective of
joint influence of genes and environment on behavioral phenotypes.  The two
standard approaches for examining the genetic basis of complex traits have
been the monogenic and quantitative genetic approaches.  Single gene
approaches have been particularly helpful in classifying behavioral phenotypes
with a dichotomous outcome.  On the other hand, the study of continuously
distributed behavioral phenotypes are not effectively addressed by these
methods.  Similarly, quantitative approaches cannot provide a complete answer. 
In studies of this type, the combinatory effects of multiple genes are
elucidated, but the specific genes involved are not isolated and identified. 
The advent of quantitative trait loci (QTL) methods has allowed us to advance
the notion that genetic influence on complex behaviors and disorders is
largely due to multiple genes, and that these genes can have effects of
varying sizes which contribute cumulatively and interchangeably to behavior. 
Localization of chromosomal regions that have influence on complex behaviors,
identifying the genes and gene products, and studying these genes and gene
constellations in humans and animal models will add further to our knowledge
of the relative contributions of genes and environment to complex behaviors.

The elderly, an age group defined by its variability in behavioral traits
rather than its homogeneity, represent a frontier to be explored in behavioral
genetic studies.  Despite the fact that the relative contribution of genetics
and environment to functioning, health, and longevity is one of the key
questions in gerontology, we know little about the role of genetic and
environmental factors in cognition and personality traits in middle-aged and
older adults.  For example, a long-held assumption from the field of
gerontology was that genetic influence on behavior decreased as people
accumulated experience and expertise.  However, recent research conducted on
adults indicates that the relative magnitude of genetic influence on cognitive
function remains substantial throughout the life span.  Besides providing
elemental contributions to the field of gerontological science, studies such
as the ones encouraged in this Program Announcement will help lay the
foundation for rational recommendations to extend health and vitality in the
elderly.

Studies are encouraged that include: 1) multiple types of subject groups,
including sibling pairs, adoptees, and subjects sampled from the general
population; 2) unlike-sex dizygotic (USDZ) twins, which are the best matched
samples of humans for gender comparisons (USDZ samples allow a greater
understanding of gender-based individual differences in aging); 3) USDZ
samples with siblings to conduct QTL analyses; 4) samples from special
populations, such as centenarians and subpopulations; and 5) same-sex twins
reared together and apart.  Also encouraged are studies that include the use
of transgenic animal models, gene mapping, gene knock-outs/knock-ins, or
conditional gene expression to identify and characterize genes affecting
behavior and to determine whether their effects are modulated with age.  These
approaches promise new insights into individual differences in behavioral
stability and change with age.

Topical areas include, but are not limited to:

A. GENETICS AND COGNITIVE ABILITY

Cognitive functioning and integrity are particularly crucial aspects of
quality of life for older persons.  Projects on the heritability of cognitive
abilities and how genetic effects of cognition  are mediated, as well as on
the environmental sources of variation in cognitive abilities are encouraged. 
Projects incorporating gene mapping, identification, characterization, and the
expression of relevant genes in late life would be particularly useful. 
Cognitive domains that require further study include, but are not limited to:
general intellectual ability, memory, learning, information processing speed,
attention, and temporal organization.  Where practical, adjunct neuroimaging
studies are encouraged as one means of exploring biological markers of genetic
influence.

B. GENETICS AND PERSONALITY

Although issues of genetic and environmental components of variance in
personality traditionally have been important in behavioral genetics research,
little attention has been given to this dimension of behavior in the elderly. 
For example, it is not known whether the relative contributions of genetics
and environment to personality change as people age.  As with cognition, are
some types of traits more likely to change than others?  Research is needed in
several domains in behavior genetics and personality including, but not
limited to: emotionality, sense of control, neuroticism, extroversion,
openness, agreeableness, and conscientiousness. Gene mapping, identification,
and characterization, as well as the examination of the effects of aging on
the expression of relevant genes in late life would be particularly helpful in
studies of personality.  Additionally, research is needed to understand the
correlation between personality and health outcomes in later life.  Does one
cause the other, or are there common factors contributing to both personality
and health?  If so, are any of these common factors genetic?

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, March 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994.

Investigators 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

NOTE:  Applications received in response to this program announcement are
expected to focus on scientific issues related to aging and to aging-related
aspects of disease.  In describing the plan to recruit human subjects,
investigators may cite a focus on aging or on aging-related aspects of disease
as the justification for why children will be excluded.  In this regard,
applicants may use Justification 1, the research topic to be studied is
irrelevant to children, from the policy announcement.

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: [email protected]

The title and number of the program announcement must be typed in line 2 on
the face page of the application.  The completed original application and five
legible copies must delivered to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, SUITE 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 Public Health
Service referral guidelines.  Applications will be reviewed for scientific and
technical merit by appropriate review committees of NIH, in accordance with
the standard NIH peer review procedures. As part of the initial merit review,
all applications will receive a written critique and undergo a process in
which only those applications deemed to have the highest scientific merit,
generally the top half of applications under review, will be discussed,
assigned a priority score, and receive a second level review by the
appropriate national advisory council or board.

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 the following
criteria will be addressed and considered by the reviewers in assigning the
overall score weighting them as appropriate for each application.

o  Significance.  Does this study 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 to the aims of the
project?  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 to
carry out this work?  Is the work proposed appropriate to the experience level
of the principal investigator and other researchers (if any)?

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 or employ
useful collaborative arrangements?  Is there evidence of institutional
support?

The initial review group will also examine: the appropriateness of proposed
project budget and duration; the adequacy of plans to include both genders,
children, and minorities and their subgroups as appropriate for the scientific
goals of the research and plans for the recruitment and retention of subjects;
the provisions for the protection of human and animal subjects; and the safety
of the research environment.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications assigned.  The following will be considered in making funding
decisions: quality of the proposed project as determined by peer review,
availability of funds, and program priority.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Jared B. Jobe, Ph.D.
Behavioral and Social Research
National Institute on Aging
7201 Wisconsin Avenue, Suite 533, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-3137
FAX:  (301) 402-0051
Email:  [email protected]

Molly V. Wagster, Ph.D.
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 3C307, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-9350
FAX:  (301) 496-1494
Email:  [email protected]

Huber R. Warner, Ph.D.
Biology of Aging Program
National Institute on Aging
7201 Wisconsin Avenue, Suite 2C231, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email: [email protected]

Mary E. Farmer, M.D., M.P.H.
Genetic Basis of Behavior Program
National Institute of Mental Health
5600 Fishers Lane, Room 10C-28
Rockville, MD  20857
Telephone:  (301) 443-1411
FAX:  (301) 443-9890
Email:  [email protected]

Direct inquiries regarding fiscal matters to:

Mr. Joseph Ellis
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212, MSC 9205
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  [email protected]

Ms. Diana 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:  [email protected]

Relevant Literature

Cho, Y. H., Giese, K.P., Tanila, H., Silva, A., & Eichenbaum, H.  (1998). 
Abnormal hippocampal spatial representations in alpha-CaMKII and CREB mice. 
Science, 269, 267-269.

Giese, K. P., Federov, N. B., Filipkowski, R. K., & Silva, A. J.  (1998).
Autophosphorylation at threonine 286 of the alpha-calcium-calmodulin-kinase II
in LTP and learning.  Science, 269, 270-273.

Mayford, M., Bach, M. E., Huang, Y.-Y., Wang, L., Hawkins, R. D., & Kandel, E.
R.  (1996).  Control of memory formation through regulated expression of a
CaMKII transgene.  Science, 274, 1678-1683.

McArdle, J. J., & Prescott, C. A. (1996). Contemporary models for the
biometric genetic analysis of intellectual abilities. In D. P. Flanagan, J. L.
Genshaft, & P. L. Harrison, Contemporary intellectual assessment: Theories,
tests, and issues (pp. 403-436). New York: Guilford.

McClearn, G. E., Johansson, B., Berg, S., Pedersen, N. L., Ahern, F., Petrill,
S. A., & Plomin, R. (1997). Substantial genetic influence on cognitive
abilities in twins 80 or more years old. Science, 276, 1560-1563.

Pedersen, N. L. (1993).  Genetic and environmental continuity and change in
personality.  In T. Bouchard & P. Propping (Eds.), Twins as a tool of
behavioral genetics (pp. 147-162). New York: Wiley.

Plomin, R. Pedersen, N. L., Lichtenstein, P., & McClearn, G. E. (1994).
Variability and stability in cognitive abilities are largely genetic later in
life. Behavior Genetics, 24, 207-215.

Tonegawa, S., Tsien, J. Z., McHugh, T. J., Huerta, P., & Blum, K. I.  (1996). 
Hippocampal CA1-region-restricted knockout of NMDAR1 gene disrupts synaptic
plasticity, place fields, and spatial learning.  Cold Spring Harbor Symposia
on Quantitative Biology, 61, 225-38.

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.866, Aging Research, and No. 93.242, Mental Health Research.  Awards are
made under authorization of the Public Health Service Act, Title IV, Part A
(Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) 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, any 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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