MOLECULAR GENETICS OF MENTAL DISORDERS

Release Date:  March 6, 1998

RFA:  MH-98-010

P.T.

National Institute of Mental Health

Letter of Intent Receipt Date:  April 14, 1998
Application Receipt Date:  May 19, 1998

PURPOSE

The purpose of this Request for Applications (RFA) is to solicit
applications for multidisciplinary, collaborative research projects
that employ state-of-the-art diagnostic procedures and analytic
methods to (1) collect and clinically characterize a large pedigree
sample of adequate statistical power for identifying genomic
regions which may harbor loci conferring susceptibility to
schizophrenia, bipolar disorder, or early-onset recurrent unipolar
depression, and (2) conduct a whole-genome scan to establish the
chromosomal localization of such loci. Data and biological
materials collected and produced in projects funded under this RFA
will augment existing resources distributed by the National
Institute of Mental Health (NIMH) for genetic analyses by the wider
scientific community.

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 RFA, Molecular Genetics of Mental Disorders, is related
to many 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 organizations such
as universities, colleges, hospitals, laboratories, units of State
and local governments, and eligible agencies of the Federal
government.  Racial/ethnic minority individuals, women, and persons
with disabilities are encouraged to apply as principal
investigators. The collection of clinically well-characterized
samples of sufficient size for linkage analyses and for linkage
disequilibrium mapping studies in genetically isolated populations
may be facilitated by the establishment of international consortia. 
Full collaborations between American scientists and scientists at
international institutions are encouraged, when scientifically
appropriate. In these cases, awards may be made to international
institutions or to domestic applications that include international
components.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research
project grant (R01) or the collaborative R01 research project grant
for clinical studies of mental disorders. The multi-institutional
cooperative research project grant (R10) mechanism will no longer
be accepted by NIMH, as indicated in a notice in the NIH Guide for
Grants and Contracts, Vol 26, No. 40, December 19, 1997 and
available on the World Wide Web at
http://grants.nih.gov/grants/guide/notice-files/not97-242.html.  Further
information on the collaborative R01 research project grant may be
found in a program announcement entitled, þCollaborative R01s for
Clinical Studies of Mental Disordersþ in the December 19, 1997
issue of the NIH Guide on the Web at
http://grants.nih.gov/grants/guide/pa-files/PAR-98-017.html.

FUNDS AVAILABLE

This RFA is a one-time solicitation. It is anticipated that $4.8
million (including direct and indirect costs) will be available for
this initiative in Fiscal Year 1998, during which it is anticipated
that 10 to 12 awards will be made.  Additional funding for new
awards will be made available in Fiscal Year 1999.  Awards pursuant
to this RFA are contingent upon the availability of funds for this
purpose.  The amount of funding for this initiative may be
increased if a large number of highly meritorious applications are
received and if funds are available.  Only applications that are
found to be of the highest scientific merit will be considered for
funding and not all of the funding will be spent if there are not
enough highly meritorious applications. Funding in future years
will be subject to the availability of funds.

The total project period for an application submitted in response
to this RFA may not exceed four years. Investigators who submit an
individual R01 application requesting direct costs of $500,000 or
more for any one year, and investigators as a group who submit a
collaborative R01 application requesting an overall total direct
cost budget of $500,000 or more for any one year, are strongly
encouraged to consult with the program staff listed under
INQUIRIES. The earliest anticipated award date is September 30,
1998.

Because the nature and scope of the research proposed in response
to this RFA may vary, it is anticipated that the size of an award
also will vary. Responsibility for the planning, direction, and
execution of the proposed project will be solely that of the
applicant. Awards will be administered under PHS grants policy as
stated in the PHS Grants Policy Statement. Future unsolicited
competing continuation applications will compete will all
investigator-initiated applications, and will be reviewed according
to the customary peer review procedures. All awards will be issued
and managed by NIMH.

RESEARCH OBJECTIVES

Background

Much of current biomedical research is based upon the expectation
that understanding the genetic basis of disease will revolutionize
diagnosis, treatment, and prevention. Defining and understanding
the role of genetic factors will also ultimately allow the non-
genetic, environmental contributions to illness to be more clearly
identified and understood.  While tremendous advances have occurred
in mapping and cloning genes for rare diseases that follow
predictable Mendelian patterns in families, the discovery of genes
that influence susceptibility to more common human conditions like
mental disorders has proceeded much more slowly.

Considerable research has been conducted to investigate the
familial bases of schizophrenia and mood disorders. Data from
family, twin and adoption studies spanning six decades have
consistently supported the involvement of genetic factors in the
familial transmission of these disorders, but conclusive
identification and replication of a chromosomal region that harbors
a susceptibility locus has not been forthcoming.

Several molecular genetic studies produced sizeable lod scores
linking bipolar disorder to the X chromosome. However, methodologic
criticisms have been raised about many of the earlier studies, and
multiple failures to replicate have occurred. In one case
additional analyses of the same pedigrees with DNA markers in Xq28
led to a diminution of linkage evidence in this region. Linkage to
chromosomal region 11p was found in the Amish, but the lod score
was diminished to non-significance by additional analyses in the
same pedigrees. Recent studies have collectively implicated a
chromosomal region of over 80 Megabases (Mb) that spans most of
both arms of chromosome 18. Convincingly replication of linkages to
these or other genomic regions has not occurred. An association
between trinucleotide repeat expansions and bipolar disorder was
reported, but has not been followed by identification of a specific
expanded gene.

The history of linkage studies in schizophrenia is marked by
comparable difficulties. Significant evidence for 5q linkage in
several pedigrees was not replicated in other samples, and a
combined re-analysis of several data sets excluded a susceptibility
locus from this region. Chromosomal regions 6p and 8p have each
been implicated twice. However, post-hoc analyses of over 700
families contributed by 14 research groups worldwide failed to find
more than suggestive evidence of linkage to either 6p or 8p.
Additional studies have failed to convincingly replicate linkages
to these or other genomic regions. Weak associations between
schizophrenia and different candidate genes have not been
convincingly replicated in large samples. An association between
trinucleotide repeat expansions and schizophrenia was reported, but
has not been followed by identification of a specific expanded
gene.

In several family studies probands were subdivided according to
age-of-onset and/or history of recurrent depression; greatest risk
was to relatives of early-onset, recurrent depressive probands.
Consequently, depression appears more familial when probands are
chosen on the basis of an early-onset recurrent illness. A recent
segregation analysis of early-onset recurrent depression yielded
some evidence of a major gene effect. Reported associations between
unipolar depression and two candidate genes have not been
replicated in other samples. No molecular genetic studies have
focused exclusively on the early-onset recurrent variant.

In summary, the modes of inheritance of schizophrenia and mood
disorders are complex and likely involve environmental factors and
multiple genes in interaction. It is clear that single major genes
do not account for their familial aggregation in most pedigrees.
The number of susceptibility loci involved and the recurrence risk
ratios conferred by each, the extent of locus heterogeneity, the
role of gene-environment interaction, and the degree of epistatic
interaction remain unknown. A similar lack of knowledge exists for
early onset recurrent depression, which is likely to be the most
heritable variant of depressive illness. Molecular genetic studies
of schizophrenia and bipolar disorder have implicated several
chromosomal regions that may harbor susceptibility loci, but the
magnitude of the statistical evidence and the failure to
convincingly replicate demonstrate that these are clearly not
confirmed, convincing findings. Inconsistent results may reflect
the influence of small relative gene effects, locus heterogeneity,
false-positive results, or a lack of power in small samples.
Insufficient data exist to strongly implicate a genomic region as
containing a susceptibility locus for early onset recurrent
depression.

New technologies have been developed for rapid high-throughput
genotyping, and dense maps of polymorphisms are widely available.
Automated methods for the discovery and scoring of simple, bi-
allelic polymorphisms (termed single nucleotide polymorphisms, or
SNPs) currently being developed will lead to the generation of a
dense map of thousands of new markers across the genome and will
permit the rapid and efficient cataloging of human DNA sequence
variation. These developments will complement the three major
analytic methods that have proved successful for the discovery of
Mendelian disease genes: localization to a chromosomal region of
several Mb by linkage analysis of family data, followed by fine
genetic mapping; analysis of haplotypes for linkage disequilibrium
mapping; and direct detection of an increased prevalence of a
functional variant in affected individuals, through association
analysis.

Dramatic progress in genetic analytic methods and technologies will
facilitate gene discovery in the study of mental disorders.
However, it seems clear that ultimate success will require new
large-scale data collection efforts to obtain samples of sufficient
size that have high power for the detection of susceptibility loci
of small relative effect. Such large-scale data collection efforts
by a single principal investigator, or by self-selected teams of
principal investigators working in collaboration, will permit the
application of uniform methods for data acquisition, diagnosis, and
comprehensive, state-of-the-art clinical characterization on a
scale unprecedented in the molecular genetic studies of these
disorders. Whole-genome analyses conducted in such data sets will
have tremendous potential for identifying chromosomal regions that
harbor susceptibility loci. Such achievements will set the stage
for a new era in the genetic analysis of mental disorders, in which
research efforts will dramatically shift from initial localization
to gene identification.

Objective and Scope

The molecular and statistical tools that will greatly facilitate
gene discovery for complex human diseases like mental disorders are
just beginning to emerge. Such tools undoubtedly will require
clinically well-characterized samples of adequate statistical power
for the detection of genes that exert a small relative effect.
Therefore, NIMH seeks the new collection of large samples, in which
probands and their relatives are clinically characterized through
the application of state-of-the-art diagnostic methods and
comprehensive assessments of psychopathology. Data collection may
occur within the context of a linkage study in an outbred
population, or a linkage disequilibrium mapping study in a
genetically isolated population.  Application of rapid and highly
cost-effective genotyping will permit initial scans to identify
chromosomal regions that harbor disease susceptibility genes. It is
expected that data and biological materials collected and produced
in projects funded under this RFA will augment existing resources
distributed by NIMH for genetic analyses by the wider scientific
community. Positional cloning, in which a gene is identified and
cloned by virtue of its subchromosomal location in the genome
rather than by using knowledge of its biochemistry, has become
increasingly straightforward but remains a formidable, multi-step
task. Genetic mapping of affected families with polymorphic markers
spanning the genome permits localization of the putative disease
genes to a candidate region, often in the range of 2 to 5 Mb. Such
intervals are physically mapped with overlapping DNA clones, which
usually serve as substrates to identify genes (transcripts).
Subsequently, the genes are examined for large-scale sequence
mutations in affected individuals.

Cloning susceptibility genes for common, complex diseases like
mental disorders, in which there is not a perfect correspondence
between phenotype and genotype, presents additional difficulties
not encountered when mapping simple Mendelian traits. Given such
complexities, the focus of molecular and statistical analyses
supported under this RFA will be limited to the goal of initial
chromosomal localization. This will represent a significant
achievement, and set the stage for future positional cloning
efforts.

Principal investigators, or self-selected teams of principal
investigators, are generally expected to focus their application on
schizophrenia, bipolar disorder, or early-onset recurrent unipolar
depression. Recruitment efforts may be consolidated, and a
commensurate time and cost savings expected, if a principal
investigator proposes to collect and analyze data for more than one
disorder. In such cases, review and award criteria will consider
the feasibility of large-scale data collection and analysis of each
disorder. Regardless of the scope of the project, it is expected
that applications will include a multidisciplinary team comprised
of clinicians, diagnosticians, molecular geneticists, and
statistical geneticists. It is expected that the first three years
of the project will be focused predominantly on pedigree
ascertainment and phenotypic assessment, with genetic analyses
being conducted in the final year. Each of the following areas are
expected to be comprehensively addressed in the application.

1) Pedigree Structure

Applications are solicited for the collection of family data that
can be analyzed using the methods that have proved successful for
the mapping of Mendelian disease genes. These methods require
ascertainment of: (1) extended pedigrees in genetically isolated
populations, for linkage disequilibrium mapping studies; or (2)
small nuclear or extended pedigrees consisting of affected sibling
pairs (ASPs) or of multiple affected individuals, for linkage
analyses. Data collection from affected individuals and two parents
for family-based association analyses is strongly encouraged, but
only when such a configuration occurs within a pedigree containing
an ASP or multiple affected individuals. Collection of pedigrees
for family-based association analyses in which diagnostic data and
biological materials can be collected only from an affected
individual and his two parents will not be supported by this RFA.
Applicants must adequately justify the proposed sample size targets
for a three-year data collection period as being both feasible and
sufficient for the chromosomal localization of susceptibility genes
for the disorder under investigation, given the proposed analytic
method.

2) Structured Diagnostic Criteria

The application of standardized and structured diagnostic criteria
is essential to the accurate phenotyping of subjects for genetic
analyses of mental disorders. While the use of operational
diagnostic criteria has undeniably improved the reliability of
psychiatric diagnoses, the validity of any such category is
indeterminate. Most importantly, it is still unclear which, if any,
diagnostic system offers the phenotypic definitions that correlate
most highly with underlying genotypes. In this sense, there is no
clear indication as to which diagnostic system (e.g., the revised
third (DSM-III-R) or fourth (DSM-IV) editions of the American
Psychiatric Associationþs Diagnostic and Statistical Manual for
Mental Disorders, Research Diagnostic Criteria (RDC), International
Classification of Diseases (ICD)) should be employed. On the other
hand, efforts to replicate results and combine data across
different samples may be hampered if diagnostic criteria for
pedigree recruitment are widely variable.

Consequently, the definition of þaffectedþ status when defining
ASPs or when specifying a minimum number of affected individuals in
projects supported under this RFA, for the purpose of pedigree
ascertainment, is expected to follow DSM-IV criteria. This will
permit pooling of these data with existing NIMH resources and will
provide some uniformity, but does not in any way preclude the use
of other diagnostic systems and criteria in establishing diagnoses
in probands and relatives. In fact, where scientifically
appropriate, investigators are encouraged to use the full range of
diagnostic definitions under multiple systems when making
phenotypic assessments.

Given that it is unclear which diagnostic system offers the
phenotypic definitions that correlate most highly with underlying
genotypes, it is essential that it be possible to establish
diagnoses in multiple diagnostic systems. Such a polydiagnostic
approach requires recording clinical information accurately and in
sufficient detail to allow different definitions of an illness to
be applied. The comprehensive phenotypic information collected in
projects funded under this RFA (see below) is expected to permit
the establishment of diagnoses within a multitude of systems,
according to different criteria sets. In addition, such information
may form the basis for future approaches to phenotyping after
susceptibility genes are discovered.

Most importantly, the definition of þaffectedþ for the purpose of
ascertainment should be limited exclusively to core phenotypes
(schizophrenia, bipolar disorder, or early-onset recurrent unipolar
depression), which are diagnosed with greater reliability than
broadened illness definitions (so-called þspectrumþ phenotypes).
Such a focus is expected to decrease misclassification and
diagnostic error while maximizing genetic homogeneity. For example,
an applicant proposing to collect 500 ASPs to identify genes that
confer susceptibility to schizophrenia will assure that both
siblings in each ASP are diagnosed with DSM-IV schizophrenia.

Other diagnostic systems, criteria sets, and phenotypes may be used
to classify subjects as affected in the analyses conducted;
however, each ascertained pedigree will have either multiple
affected individuals and/or an ASP in which affected status
reflects a DSM-IV diagnosis of a core phenotype. While there is no
DSM-IV criterion for þearly onsetþ recurrent depression, the
applicant will clearly specify the age-cutoff for onset that was
uniformly applied.

3) Comprehensive Phenotypic Assessment

Minimization of phenotypic error and imprecision, especially that
which contributes to false-positive diagnoses of affected status,
requires the careful application of state-of-the-art diagnostic
techniques. This is expected to include the comprehensive synthesis
of information systematically collected from structured or semi-
structured diagnostic interviews of high reliability, medical
records, and multiple family informants. Applicants should fully
document their procedures for establishing such a final "best
estimate" lifetime psychiatric diagnosis.

Establishment of a highly reliable psychiatric diagnosis is
facilitated by the use of a structured or semi-structured
diagnostic interview. Applicants shall use one of the self-report
interviews currently available and ready for use at the time the
project is to begin. It is expected that the project does not
include percentage effort or costs for the development or
modification of existing instruments. One such set of instruments
is the Diagnostic Interview for Genetic Studies (DIGS) and the
Family Interview for Genetic Studies (FIGS) that were developed for
the NIMH Human Genetics Initiative. Blank forms and training and
code manuals are available via the Web at
http://zork.wustl.edu/nimh/digs/newpage11.htm.
While their use is not required, applicants who choose not to use
them must clearly document the reliability and adequacy of their
instruments for assessing a comprehensive range of clinical psychopathology.

The structured interview utilized by the investigator must be
sufficiently broad to incorporate the criterion sets for diagnosing
major mental disorders in multiple systems. This is important to
permit creation of the broadest possible dataset for genetic
research on mental disorders, ensure maximum comparability with
other data sets, and to permit comparisons to older studies using
different criterion sets. While it is not required that
investigators establish diagnoses in systems (e.g., ICD, RDC, DSM-
III-R) other than DSM-IV, sufficient clinical data must be
collected to allow diagnostic determinations in multiple systems.

Currently, there is an imperfect correlation between a phenotype
established according to any psychiatric diagnostic criteria set
and an underlying genotype. The future discovery of susceptibility
genes for mental disorders may significantly change current
diagnostic criteria. Consequently, phenotypic assessments are
expected to include not only a psychiatric diagnosis but also
determination of a comprehensive range of clinical psychopathology.
The diagnostic interview utilized by the applicant is expected to
a broad range of psychopathology that may form the basis for future
studies that correlate phenotypic characteristics, and not
exclusively existing diagnostic categories, to underlying
genotypes.

It is expected that the principal investigator will demonstrate
high diagnostic reliability among raters and/or collaborating sites
when employing the diagnostic interview of choice. It is strongly
encouraged that this be demonstrated prior to award. If this is not
feasible, training exercises and limited reliability studies are
expected to occur and be completed during the projectþs first month
or two. Most importantly, such efforts must not delay the
commencement of large-scale data recruitment efforts.

4) Computerized Database

The creation and maintenance of a computerized database that
includes a comprehensive array of clinical, family structure,
diagnostic, and genotypic information is essential for rapid and
efficient genetic analyses. Creation of such an electronic database
is quite time-consuming and labor-intensive. Thus, it is expected
that the applicant will have already developed, or have access to,
such resources prior to the initiation of this project. Inclusion
of a comprehensive range of information about psychopathology may
be facilitated through the use of software that permits
incorporation in an electronic database of all the information
collected from a comprehensive structured interview. All of the
data collected from the DIGS interview (but not the FIGS) may be
input into such a database via a Windows 95 operating system
graphical user interface. Software is available via the Web at
http://zork.wustl.edu/nimh/digs/newpage11.htm. While the use of DIGS
software is not required, applicants who choose not to use it must
clearly document the existence and utility of a transparent
graphical user interface through which data on a comprehensive
array of clinical psychopathology data gathered through use of the
diagnostic instrument they propose to use may be directly entered
into an electronic database. The applicant must maintain a high-
quality electronic database for data entry and analyses throughout
the period of the funded project.

It is expected that investigators shall establish electronic
databases of all clinical, final best estimate diagnostic, and
family structure information for wide dissemination to qualified
investigators in the scientific community for use in genetic
analyses, in accordance with a data sharing plan developed by the
investigator (see below, section 7). The creation and validation of
such datafiles are expected to occur prior to the genetic analyses
conducted in the last year of the award. It is expected that the
minimum data provided for each subject will include a unique
subject and family identification number (ID), parental IDs, sex
status, death status, ethnicity, age, twin status, final best
estimate DSM-IV diagnosis, best estimate of the age at onset, and
the comprehensive range of clinical information obtained from a
structured interview. Data will be maintained without personal
identifiers and thus are unlinked to their sources; such materials
are "anonymous" samples. Creation and initial validation of such
databases will signify that genetic analyses are to begin. Only at
that time is it expected that DNA samples as extracted from cell
lines (see below, section 5) will be required by investigators.

It is also expected that genotyping data produced in projects
funded under this RFA - including DNA marker names, allele sizes in
base pairs and corresponding frequencies, and relative map
distances - will be widely distributed to qualified investigators
in the scientific community, according to the investigatorþs data
sharing plan (see below, section 7).

If requested by the investigator, NIMH will provide no-cost access
to a data management facility; extensively documented electronic
files ready for immediate genetic analysis will be created for use
by the wider scientific community. Applicants may request funds to
defray the costs of establishing databases with extensive
documentation for wide distribution to the scientific community,
with adequate justification. If another resource is utilized, it is
expected that the adequacy, efficiency and cost of creating,
maintaining, and documenting electronic databases as stipulated in
their data sharing plan (see below, section 7) for dissemination to
qualified investigators in the scientific community will be
comparable to what could be achieved by using the resource to which
NIMH provides no-cost access.

5) Lymphoblastoid Cell Lines and DNA Samples

Creation of lymphoblastoid cell lines from blood samples
establishes an infinitely renewable source of DNA for subsequent
genetic analyses. In addition, these biological materials will be
invaluable source for future studies that employ genetic maps of
much higher density  (e.g., those with SNPs as a basis) and that
employ efficient technologies to study gene function and
expression. Therefore, it is expected that permanent cell lines
will be established for subjects studied in projects funded under
this RFA. The creation of cell lines and extraction of DNA for
genetic analyses requires provision of blood samples to a cell
repository.

It is expected that investigators shall obtain blood samples to
establish cell lines and extract DNA samples for wide dissemination
to qualified investigators in the scientific community for use in
genetic analyses, in accordance with a data sharing plan developed
by the investigator (see below, section 7). If requested by the
investigator, NIMH will provide no-cost access to a cell
repository; high-quality cell lines will be created upon receipt of
blood samples, and DNA will be extracted and provided to applicants
at no cost for their exclusive use in the quantities specified in
their application. Applicants may request funds to defray the costs
of establishing cell lines and extracting DNA for distribution to
the wider scientific community, with adequate justification. If
another repository is utilized, it is expected that the adequacy,
efficiency and cost of the procedures for establishing cell lines
and extracting DNA for wide dissemination to qualified
investigators in the scientific community as stipulated in their
data sharing plan will be comparable to what could be achieved by
using the resource to which NIMH provides no-cost access.

6) Molecular and Statistical Genetic Analyses

Identification and cloning of a disease susceptibility locus first
requires chromosomal localization. Genetic analyses to be conducted
in projects funded under this RFA will focus on genome-wide scans
and statistical analyses to identify chromosomal regions that may
harbor disease susceptibility loci. Fine mapping studies (including
the saturation of regions of interest with multiple markers), gene
sequencing, mutation analysis, and other steps in the positional
cloning process will not be supported by this RFA.

One resource currently available to applicants is the Center for
Inherited Disease Research (CIDR), a centralized facility
established to provide high-throughput genotyping and statistical
genetics services for investigators seeking to identify genes that
contribute to human disease.

CIDR utilizes automated fluorescent microsatellite analysis using
a standard marker set (Weber Screening Set 8), consisting of 387
primer pairs spaced approximately 10 CentiMorgans throughout the
genome. Current capacity is approximately 120,000 genotypes per
month. CIDR was established in 1996 as a joint effort of eight NIH
Institutes, and is supported through a contract to Johns Hopkins
University.

CIDR is available to all investigators through competitive peer
review by a chartered CIDR Access Committee (CAC). The CAC is a
standing NIH committee comprised of scientists who have expertise
in gene mapping and the genetic dissection of complex diseases.
Projects are evaluated on the need for high throughput genotyping
and the likelihood that genotyping will lead to successful mapping
of genes contributing to that disease. Given that NIMH is one of
the supporting NIH Institutes, research projects funded under this
RFA are eligible for CIDRþs special introductory rate of no-cost
genotyping. Further information about CIDR may be found on the
World Wide Web at http://www.cidr.jhmi.edu. Submission deadlines
for applications requesting CIDR access are November 1, March 1 and
July 1. Applicants are expected to request access to CIDR.

Applicants will not learn the outcome of the CAC evaluation in time
to include an approval letter from the CAC in their application.
Thus, investigators are expected to include in their application a
scientific plan to accomplish a high throughput genome-wide scan at
a centralized laboratory and statistical analyses, as well as
budgeted genotyping and analysis costs. It is expected that the
time frame and costs for their genomic scan and statistical
analyses will be generally comparable to what could be achieved at
CIDR or at academic or commercial facilities. A time frame for
completion of a genome wide scan within one year, at a cost of $1 -
 $1.5 per genotype, appears reasonable. It is anticipated that
technologies will improve and the rate of work and associated cost
will change.

7) Data and Biological Materials Dissemination

The sharing of materials, data, and software in a timely manner has
been an essential element in the rapid progress that has been made
in the genetic analysis of human diseases. PHS policy requires that
investigators make unique research resources readily available for
research purposes to qualified individuals within the scientific
community when they have been published (PHS Grants Policy
Statement in the July 12, 1996 issue of the NIH Guide to Grants and
Contracts). Providing access to data collected in human genetic
studies for qualified investigators in the wider scientific
community has been a guiding principle of the NIMH Human Genetics
Initiative, which funded data collection and genetic analysis for
schizophrenia, bipolar disorder, and late-onset Alzheimer disease.
Information for this Initiative is available on the Web at
http://zork.wustl.edu/nimh/NIMH_initiative/NIMH_initiative_link.html.
Data and materials collected and produced in projects funded by this RFA
will be distributed to qualified scientific investigators in the wider
research community, and will augment these existing resources.

To address the joint interests of the government in the
availability of, and access to, the results of publicly funded
research and in the opportunity for economic development based on
these results, NIMH requires applicants who respond to this RFA to
develop and propose detailed plans for sharing the data and
materials generated through the grant. It is expected that the
information to be shared includes all clinical, diagnostic, and
pedigree structure information, in addition to cell lines and DNA.
For this purpose, it is the opinion of the NIH that dissemination
of such data and materials via individual laboratories and Web
sites is not sufficient, as it would force interested investigators
to have to search several different data collections to make use of
the results of this initiative. In addition, differences in
protocols across projects for creating databases, establishing cell
lines, and extracting DNA may make it impossible for researchers to
combine information for integrated genetic analyses. It is
preferable that data and materials generated in grants funded under
this RFA should be placed in common, public cell repositories and
databases that are widely accessible by investigators in the
scientific community. The data management facility and cell
repository supported by NIMH contractors are such resources.

The NIMH Human Genetics Initiative employs procedures by which data
and biological materials are widely disseminated to qualified
investigators in the scientific community. These are described on
the Web at http://zork.wustl.edu/nimh/NIMH_initiative/
NIMH%20Human%20Genetics%20Initiative%20Access%20Information.htm. It is
preferable that the procedures for determining access and for
disseminating data and materials are comparable to those currently
employed in the NIMH Human Genetics Initiative. This is essential
to pooling of data and materials collected and produced in grants
funded under this RFA with existing resources widely distributed to
the scientific community.

It is expected that the investigatorþs data sharing plan will
specify the following elements: (1) the creation of comprehensive
and verified databases that contain all clinical, diagnostic,
pedigree structure, and genotypic information collected and
produced in the grant; (2) the establishment of cell lines, from
which DNA will be extracted and stored, for all subjects studied
from whom blood samples have been obtained; (3) mechanisms by which
all databases and biological materials (DNA samples, cell lines)
are widely distributed to qualified investigators in the scientific
community; (4) a protocol and criteria for wide dissemination of
these data and materials; (5) a timetable for distribution; and (6)
an assurance that data and biological materials are disseminated in
a manner comparable to existing protocols and procedures for
distributing such data and materials in the NIMH Human Genetics
Initiative. The Initial review group will comment on the proposed
plan for sharing and data access. The plan will be considered part
of the methodology for carrying out the research and, as such, the
adequacy of the plan will be considered by NIMH staff in
determining whether the grant shall be awarded. The sharing plan as
approved, after negotiation with the applicant when necessary, will
be a condition of the award. Evaluation of renewal applications
will include assessment of the effectiveness of data and biological
material release.

After extensive discussion with mental health and human genetics
researchers and advocacy members, the Genetics Workgroup of the
National Advisory Mental Health Council (NAMHC) recommended that
NIMH should draft a policy that provides for the sharing of genetic
materials after a 12- to 18-month proprietary period. It was also
recommended that this policy include all elements of the guidelines
developed by the NIH and the Department of Energy (DOE) to address
the special needs of genome research. These guidelines call for
material and information from genome research to be made available
within six months of the time the data or materials are collected,
and are available on the Web at
http://www.nhgri.nih.gov/Grant_info/Funding/Statements/data_release.html.

Adherence with the time frame recommended by the NAMHCþs Genetics
Workgroup is highly desirable. This is expected to result in all
data being released to the scientific community by the end of the
four-year award period, even if a competing renewal application is
submitted. More rapid sharing is encouraged.  Requests for
exemptions or extensions will require compelling justification and
will be fully evaluated through peer review and by program staff.

8) Quality Control

The verification of family structure and updating of diagnostic and
other clinical information is essential to the conduction of
genetic analyses. Applicants are expected to maintain an electronic
database of clinical, family structure, and diagnostic information
that will be verified and updated throughout the project. Rigorous
quality control procedures will permit the applicant to create up-
to-date diagnostic and pedigree structure information. An essential
element of the quality control procedure is to verify this family
structure and diagnostic information. Final information -
consisting of family structure information obtained after
genotyping, updated final best estimate diagnostic data, and other
updated clinical information - is expected to be included in the
investigatorþs data sharing plan. In addition, high-quality cell
lines and DNA are expected to be included in the investigatorþs
data sharing plan.

9) Human Subjects Issues

Proper safeguards are required to protect the welfare and rights of
subjects who participate in genetic research. Subjects who
participate in research projects funded under this RFA need to be
fully informed that data collected from them will be rendered
anonymous and will be distributed by NIMH to qualified scientific
investigators in the wider research community. Subjects also need
to be informed that some of these qualified investigators may have
commercial interests. As a result of research supported under this
RFA and of research subsequently conducted on these data, it is
possible that enough information eventually might be developed to
allow individuals to be identified and, consequently, become
subject to any risk(s) that might arise as a result of that
identification. Applicants should address any special human
subjects issues that arise as a result of the proposed research.
NIH is currently working to develop a model consent form for human
genetic research, and this will be provided to applicants whose
projects are funded under this RFA. This may then serve as a
template that is subject to modification and/or approval by local
institutional review boards.

Post-Award Management

During the course of the project period, while the original
approved scope of work will be maintained, it is anticipated that
technologies will improve and the rate of progress and focus of
work supported by the grant(s) may change. Accordingly, it is
expected that the principal investigator(s) will make many 
necessary adjustments in scientific direction to accommodate such
changes. Most importantly, it is essential to the achievement of
the study aims for recruitment to proceed as rapidly and
efficiently as possible. Thus, principal investigators may need to
be flexible in modifying recruitment strategies to assure that the
targeted sample size is achieved within a three-year period. During
the course of the award period, the principal investigators will be
invited to meet with NIMH program staff in the Washington, D.C.
area, to review scientific progress. Other scientists external to
and knowledgeable about these studies may also be invited to
participate. Budget requests should include travel funds for the
principal investigator to meet annually in the Washington, D.C.
area, should such meetings be advisable.

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, who may also provide additional
relevant information.

LETTER OF INTENT

Prospective applicants are encouraged to discuss their research
objectives with NIMH staff early in their planning process. 
Prospective applicants are asked to submit, by April 14, 1998, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the principal
investigator, the identities of other key personnel and
participating institutions, and the number and title of the RFA in
response to which the application may be submitted.  Although a
letter of intent is not required, is not binding, and does not
enter into the review of a subsequent application, the information
that it contains allows NIMH staff to estimate the potential review
workload and avoid conflicts of interest in the review.

Investigators who submit an individual R01 application requesting
direct costs of $500,000 or more for any one year, and
investigators as a group who submit a collaborative R01 application
requesting an overall total direct cost budget of $500,000 or more
for any one year, are strongly encouraged to submit a letter of
intent.

The letter of intent is to be sent to:

Dr. Steven O. Moldin
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

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be
used in applying for these grants. These forms are available at
most institutional offices of sponsored research or from the
Division of Extramural Outreach and Information Resources, National
Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD
20892-7910; telephone (301) 435-0714; fax (301) 480-0525; email:
asknih@od.nih.gov.

The RFA label available in the PHS 398 (rev. 5/95) application form
must be affixed to the bottom of the face page of the application.
Failure to use this label could result in delayed processing of the
application such that it may not reach the review committee in time
for review. In addition, the RFA title and number, "Molecular
Genetics of Mental Disorders: MH-98-010," must be typed in section
2 of the face page of the application form and the YES box marked.

Applicants submitting a collaborative R01 application must follow
the instructions and application procedures described in
PAR-98-017, "Collaborative R01s for Clinical Studies of Mental
Disorders," which appeared in the December 19, 1997 issue of the
NIH Guide on the Web at http://grants.nih.gov/grants/guide/pa-files/PAR-98-017.html.
In these cases, this program announcement title and number must also be
typed in section 2 of the face page of the application form.

Submit a signed, typewritten original of the application, including
the Checklist, and four 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)

At the time of submission, one additional copy of the application
must be sent to:

Dr. Steven O. Moldin
Division of Basic and Clinical Neuroscience Research
National Institute of Mental Health
5600 Fishers Lane, Room 10C-26
Rockville, MD  20857

Applications must be received by May 19, 1998. If an application is
received after that date, it will be returned to the applicant
without review. The Center for Scientific Review (CSR) will not
accept any application in response to this RFA 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 substantial
revisions of applications already reviewed, but such applications
must include an introduction addressing the previous critique. The
applicants should also ensure that their revised applications
respond to the review criteria by which applications in response to
this RFA will be evaluated.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR
and for responsiveness to this RFA by NIMH staff. Incomplete
applications will be returned to the applicant without further
consideration. If the application is not responsive to the RFA, NIH
staff will contact the applicant to determine whether to return the
application to the applicant or submit it for review in competition
with unsolicited applications at the next review cycle.

Those applications that are complete and responsive to this RFA
will be evaluated for scientific and technical merit in accordance
with the criteria stated below by an appropriate peer review group.
As part of the initial merit review, all applications will receive
a written critique and may undergo a process in which only those
applications deemed to have the highest scientific merit will be
discussed and assigned a priority score. All applications will
receive a second level of review by the NIMH National Advisory
Council.

Review Criteria

The criteria to be used in the evaluation of grant applications are
listed below. To put those criteria in context the following
information is contained in instructions to peer reviewers.

The goals of NIH-supported research are to advance our
understanding of biological systems, improve the control of
disease, and enhance health. The reviewers will comment on the
following aspects of the application in their written critiques in
order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals. Each of the
criteria will be addressed and considered by the reviewers in
assigning the overall score weighting them as appropriate for each
application. Note that the application does not need to be strong
in all categories to be judged likely to have a major scientific
impact and thus deserve a high priority score. For example, an
investigator may propose to carry out important work that by its
nature is not innovative but is essential to move a field forward.

o  Significance: Does this study specify the large-scale data
collection effort needed to determine the chromosomal localization
of genes that confer susceptibility to schizophrenia, bipolar
disorder, or early-onset recurrent unipolar depression? Does the
applicant propose to collect a new pedigree sample, and not one
that has been previously studied? Is the scope of work for the
molecular genetic studies focused exclusively on efforts to
establish the chromosomal locations of susceptibility loci, and not
focused on fine mapping, sequencing, or mutation analyses?

o  Approach: Are the conceptual framework, design, ascertainment
strategy, assessment/ diagnostic procedures, and targeted sample
size adequate, appropriate, and feasible to accomplish the specific
aims of the project? Does the applicant have access to sufficient
resources to obtain the targeted sample size? Is the sample size
sufficient to identify chromosomal regions that harbor genes
conferring susceptibility to the disorder under investigation? Does
the applicant acknowledge potential problems in recruitment and
consider alternatives? Is the scientific and technical merit of the
proposed research sufficient to advance the objectives of the RFA?
Is phenotyping being done in a highly reliable, rigorous and
comprehensive fashion, permitting the establishment of diagnoses in
multiple systems? Is the applicant collecting data on a broad range
of psychopathology, which may form the basis for future studies
that correlate phenotypic characteristics (and not just existing
diagnoses) to underlying genotypes? Will genotyping be accomplished
in a rapid and cost-effective fashion?

o  Innovation and originality: Does the project employ novel and
creative concepts and approaches for large-scale pedigree
collection? Does the applicant employ novel methods for integrating
data from multiple sources to establish best estimate psychiatric
diagnoses? Does the project foster new analytic approaches for
identifying chromosomal regions of interest?

o  Investigator: Are the principal investigator and staff
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? Is there a
multidisciplinary research effort that includes representation of
the scientists needed for large-scale data collection and genetic
analysis (e.g., clinicians, diagnosticians, molecular geneticist,
statistical geneticist, bioinformatics specialist)?

o  Scalability: What is the likelihood that the data collected in
the project will be rapidly collected and available for analysis by
a broad range of biomedical investigators?

o  Integration with other resources: Are the plans adequate to
integrate the data and materials collected with those collected in
the NIMH Human Genetics Initiative?  Are comprehensive diagnostic
assessment instruments and software currently available utilized in
the project?  Are DSM-IV criteria used to define a minimum number
of affected individuals with the core phenotype, for the purpose of
pedigree ascertainment?

o  Exportability and accessibility: Will the applicantþs data
management plans permit creation of a highly efficient and
organized electronic database? Will these plans facilitate the
creation of databases containing final best estimate diagnostic
data, family structure information, and clinical data, as well as
the establishment of cell lines and DNA samples, that will be
widely disseminated to qualified investigators in the scientific
community? Will data provided to the data management facility and
cell repository be in a highly exportable format that will permit
rapid integration with comparable resources maintained by NIMH?
Does the investigatorþs quality control plans assure that databases
provided to the scientific community are accurate and up-to-date,
and that cell lines and DNA samples are of high-quality?

o  Environment: Does the scientific environment in which the work
will be done contribute to the probability of success? Do the
proposed methods take advantage of unique features of the
scientific environment or employ useful collaborative arrangements?
Is there evidence of institutional support? Does the applicant have
access to sufficient clinical resources to obtain the targeted
sample size?

o  Budget and duration: Are the proposed budget and duration
appropriate in relation to the proposed research? Are the costs and
time frames for molecular and statistical analyses generally
comparable to those at CIDR and other high-throughput genotyping
facilities? Are the costs, time frames, and abilities to widely
distribute data and materials to qualified investigators in the
scientific community for the cell repository and data management
facility chosen by the applicant to create databases, establish
cell lines, and extract DNA generally comparable to those that
would be obtained by using existing NIMH resources?

o  Adequacy of plans to include both genders and minorities and
their subgroups: Are both genders and minority groups represented,
or is their exclusion scientifically justified?

The initial review group will also examine the provisions for the
protection of human and animal subjects, the safety of the research
environment, and conformance with the NIH Guidelines for the
Inclusion of Women and Minorities as Subjects in Clinical Research.

The availability of special opportunities for furthering methods
development through the use of unusual talent resources or
environmental conditions in other countries which are not readily
available in the United States, or which provide augmentation of
existing U.S. resources, will be considered in the review.

AWARD CRITERIA

The earliest anticipated date of award is September 30, 1998.
Subject to the availability of funds, and consonant with the
priorities of this RFA, NIMH will provides funds for a project
period not to exceed 4 years. Factors that will be used to make
award decisions are as follows:

o  Quality of the proposed project, as determined by rigorous
scientific peer review;

o  Feasibility of the proposed large-scale data collection effort,
within a three-year time frame;

o  Cost effectiveness and rapidity of the proposed genotyping work
and genetic analyses;

o  Adequacy of plan to assure that data and biological materials
collected and produced in the project can be easily integrated with
comparable data and materials collected in the NIMH Human Genetics
Initiative;

o  Adequacy of plans to make all data and biological materials
collected and produced as a result of the proposed research widely
accessible in a timely manner to the biomedical research community;

o  Availability of funds.

INQUIRIES

Written, telephone, and e-mail inquiries concerning this RFA are
strongly encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. Steven O. Moldin
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

Direct inquiries regarding fiscal matters to:

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

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.242. 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. Awards will be administered under PHS grants policy
as stated in the Public Health Service Grants Policy Statement
(April 1, 1994).

PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the nonuse 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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