Genetics, behavior, and aging.

This program announcement (PA) solicits novel research integrating genetics, behavior and aging. Human and non-human studies are needed to advance our understanding of the genetic and environmental influences and processes affecting variability in behavior and its functional sequelae with age. This includes studies that help elucidate the relationships of levels and change in behavior to health, functional competence, and quality of life of older adults. This PA is framed around two broad categories of questions: (1) gene-to-behavior questions concerning the nature and role of genetic influences on behaviors at older ages, and how these genetic effects vary with age; and (2) questions about dynamic processes including gene-environment interactions, gene-environment covariation, age-related genetic effects, and how behaviors interact with and affect genetic expression. The behaviors that are eligible for study under this PA should be critical to quality of life among the aged, either as outcomes or as mediators of physical or cognitive health and function. Examples of relevant behavioral domains include, but are not limited to, social behaviors, resilience, vitality, adaptivity, personality, vulnerability to stress, health behaviors, social cognition, human and social capital accumulation, economic savings for retirement, risk-taking, happiness, coping, caregiving, cognitive abilities, cognitive flexibility, cognitive reserve, learning, and functional abilities. This PA is intended to stimulate methodologically rigorous research integrating genetics, other biological sciences, and the behavioral and social sciences. To be considered responsive to this announcement, interdisciplinary perspectives must be unambiguous, the relationship between the behaviors or social processes under study and healthy aging should be articulated, and the proposed study should be embedded within a well articulated set of questions or hypotheses generated from social science and behavioral research. This announcement updates and replaces a previous PA, Behavior Genetics in Adulthood and Old Age (PAS-98-076, issued May 21, 1998).

Behavior and age-related changes in behavioral processes are integral to how well we age. Many behavioral phenotypes, such as resilience, cognitive and functional abilities, social connectedness, happiness, longevity and loneliness are intrinsic to maintaining health and quality of life. Behavior also plays a critical mediating role (e.g. smoking, alcohol use, exercise, risk taking behaviors, adherence, social engagement) in health and disease. Understanding the causes of variation in behavioral development, plasticity, stability, adaptation and change with age is essential to maintaining and enhancing quality of life throughout old age.

Family and twin studies on aging have demonstrated the importance of genetic influences for variation in a large array of behavioral phenotypes related to personality, well-being, functional abilities, cognitive aging, longevity and health. More recent findings based on the longitudinal twin design indicate the importance of genetic influences on functional stability and the importance of environments for change. To move beyond these findings innovative studies are needed that investigate genetic effects within the context of the dynamic aging processes in which they are expressed. This will involve diverse approaches that: integrate molecular and quantitative methods, focus on behavioral systems for which known or candidate genes are identified, explore social processes that affect individual environments, include measures of biological intermediaries of the behaviors, and use non-linear analytic approaches to study genes, social factors and environments in developmentally dynamic ways.

The underlying conceptual model is multifactorial, highlighting the combined action of multiple genetic and environmental influences where phenotypic variation arises as a function of genotypic and environmental differences between people within a particular population. Features of this model are an assumption that environmental influences, ranging from intracellular conditions to larger socio/cultural effects, and genetic influences operate through the same causal field of biological structures and processes. The intricacies of this causal field can lead to complex relationships between genetic factors, environmental influences, and phenotypic outcomes. These complexities include time-related changes in the relative influence of genetic and environmental factors, non-linear interactions among genes, interactions and correlations between genes and environments and environmentally induced gene expression.

The need to examine genetic and environmental influences and behaviors in the context of dynamism of interactive aging systems is increasingly apparent, and unprecedented opportunities to do so are now available. Dramatic advances have been made by molecular geneticists in the explication of hereditary phenomena, by quantitative geneticists in the assessment of aggregate effects of genes and environments, by behavioral and social scientists in identifying intermediary phenotypes (endophenotypes) and in defining and measuring complex behavioral domains, and by statisticians in the measurement of change. Progress in understanding gene-behavior relationships in aging will rely on integrating the theoretical models and methodologies of these research domains to provide powerful tools for combining reductionist approaches (that explore the nature of specific genetic and environmental influences) and integrationist approaches (that explore effects within the larger context of complex systems). Among many examples, improved strategies now exist to identify genes and map quantitative trait loci (QTL); to assess specific genetic and environmental sources of variation; to quantify these specific effects relative to background variation due to the aggregate influence of still-anonymous genes and environments; to conceptualize and examine non-linear and dynamic processes such as epistasis, gene-environment interaction, gene-environment correlation, and behaviorally or environmentally induced genetic expression; to investigate how social worlds and behavioral factors modulate gene expression; to characterize population differences according to sequence (SNP) and haplotype diversity; to detail the structure of behavioral domains; to measure phenotypic change; and to assess age-related changes in influence of both specific and aggregate genetic and environmental domains.

A wide range of designs is relevant to the objectives of this PA, including augmented family studies with combinations of twins, parents, siblings, children and adoptees; sibling studies using highly selected samples for phenotypic indices of similarity/dissimilarity; extended pedigrees; special populations (i.e. inbred groups, cultural and genetic isolates); sub-populations such as the oldest-old; studies that utilize the extensive genome databases and genetic analyses resources that are becoming available; and animal model studies using cross-fostering, selective breeding, inbred strains, recombinant inbred strains or specific genotypic manipulations (e.g. transgenic, knockouts, knock-ins). Research is also encouraged that builds upon ongoing studies of aging cohorts whereby supplemental data collection would allow new hypotheses to be addressed at the intersection of genetics, behavioral and social science and research.

Major methodological considerations should be well articulated, including the implications for aging of the behavioral phenotypes being studied, documentation of solid measurement characteristics, presentation of power analyses to reveal that sample sizes suffice for analyzing the genetic effects being studied, and clear descriptions of the analytical procedures to be employed must be provided. The research team should be multidisciplinary and, at a minimum, reflect expertise in genetics (molecular and/or quantitative), and the social/behavioral sciences.

Among the many research avenues pertinent to studying the behaviors of relevance to this PA are 1) Studies that explore the genetics of behavioral interventions and address how genetic differences moderate responses among the elderly to health promoting behaviors (e.g. exercise, social connectedness, cognitive training); 2) Studies to elucidate behavior-gene (i.e. individuate loci and QTLs) relationships for behaviors affecting quality of life with aging. Novel, hypothesis-driven research is needed to: a) investigate how genes or QTLs implicated in aging processes (e.g. oxidative stress) affect behavioral function and change, and b) explore age effects in the genes or QTLs implicated in behavioral functioning (e.g. DRD4 and novelty-seeking, APOE and cognitive function); 3) Behavioral genetic designs (using human or animal models) that combine quantitative and molecular techniques to resolve variance and covariance structures more finely than has previously been accomplished by quantifying the influences of specific genes, QTLs and specific measured environments; 4) Behavioral genetic studies (using human or animal models) that investigate genetic variation and QTLs affecting rates and shapes of change in behavioral functioning; 5) Studies of specific environmental influences in genetically informative research on aging. Despite the importance of dynamic processes involving gene-environment interaction and covariation, measured environments are rarely included in human studies. Research is needed that incorporates critical features of diverse environments (i.e. social, economic, physical and cultural environments) into behavioral genetic studies of aging for the purpose of analyzing gene-environment dynamics; 6) Studies (using human or animal models) to investigate gene by environment interaction. Examples include research exploring whether and how social environments or enriched experiences (quality of education, etc.) mediate progression to disease among those with genetic predispositions to disease; studies investigating the effects of socially or experientially enriched or restricted environments on genetic expression; research testing whether protective health effects conferred by education prevail in the presence of genetic risk, and genetic research that builds upon and bridges findings from established fields of environmental inquiry (e.g. health disparities) to explore gene by environment interactions; 7) Studies elucidating the genetic regulation of neural mechanisms, and their modulation by environmental circumstances, that impact upon cognitive function, cognitive reserve and flexibility, learning, and memory; 8) Studies to investigate gene by environmental covariation. Individuals shape and select their environments throughout development, and these processes are affected by many factors including age, and aging transitions such as retirement, chronic care giving, bereavement, isolation and functional loss. Research is needed that develops analytical models by which to study gene-environment covariation in the context of these age-related changes in abilities to define and select one's environment.

This PA will use the NIH R01 award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project.

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

The National Institute on Aging (NIA) intends to commit at least $2 million for an initial round of funding of applications of high scientific merit in FY 2004. An applicant may request a project period of up to 5 years. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIA provides support for this program, awards pursuant to this PA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

An overarching goal of this PA is to encourage innovative research integrating knowledge and methodologies from genetics, gerontology, and the behavioral and social sciences. Applications should articulate the interdisciplinary dimensions and components of the proposed research, and explain how the collective expertise of the research team meets these interdisciplinary requirements with regards to the specific aims to be investigated.

The sharing of unique resources such as phenotypic data, DNA, and genome scans in a timely manner contributes greatly to progress in understanding the genetics of complex phenotypes. The NIH encourages data sharing (http:// grants.nih.gov/grants/guide/notice-files/NOTOD-03-032.html) and requires all applications from October 1, 2003 that request $500,000 or more in direct costs in any single year to address data sharing. For this PA, investigators are encouraged to submit a data-sharing plan regardless of the size of the requested budget. The NIH data sharing and implementation guidelines policies can be found at http:// grants.nih.gov/grants/policy/data_sharing/ data_sharing_guidance.htm. NIH staff will evaluate the adequacy of the proposed data sharing and access plan, and consider it in making award decisions. Staff will also consider waivers as appropriate to the conditions of data collection. Also, except under circumstances where the data are likely to be of unique value and importance to other investigators, staff will accept requested costs under $500,000 a year as sufficient reason for a waiver. The sharing plan approved by NIH staff, after negotiation with the applicant when necessary, will become part of the terms and conditions of the award. NIH staff will also evaluate compliance with the sharing plan and scientific progress in the non-competing continuation of the grant award application.

Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/ phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, 301-435-0714, e-mail: [e-mail].

Applications submitted in response to this PA will be accepted at the standard application deadlines, which are available at http:// grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. Submit a signed, typewritten original of the application, including the checklist, and five signed photocopies in one package to: Center for Scientific Review, National Institutes of Health, 6701 Rockledge Drive, Room 1040, MSC 7710, Bethesda, MD 20892-7710, USA, Bethesda, MD 20817 (for express/ courier service)

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

Contact: Angie Chon-Lee, Behavioral and Social Research Program, NIA, Gateway Building, Room 533, Bethesda, MD 20892-9205, USA, 301-594 5943, fax: [phone], e-mail: [e-mail]; Marilyn M. Miller, Neuroscience and Neuropsychology of Aging Program, National Institute on Aging, Gateway Building, Suite 350, 7201 Wisconsin Avenue, Bethesda, MD 20892-9205, USA, 301-496-9350, fax: [phone], e-mail: [e-mail]. Reference: PA No. PAS-03-128