Notice of Special Interest: Genetics of Alcohol Sensitivity and Tolerance
Notice Number:

Key Dates

Release Date:

June 25, 2021

First Available Due Date:
October 05, 2021
Expiration Date:
May 08, 2024

Related Announcements

PAR-21-250 - Mechanisms of Alcohol Tolerance (R21/R33 - Clinical Trial Optional)

PA-19-055 - NIH Research Project Grant (Parent R01 Clinical Trial Required)

PA-19-056 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

PA-19-091 – NIH Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)

Issued by

National Institute on Alcohol Abuse and Alcoholism (NIAAA)


The purpose of this notice of special interest (NOSI) is to provide enhanced understanding of genetic, genomic, and epigenetic factors contributing to biological processes for individual variation in sensitivity, the development of tolerance, and progression to AUD. NIAAA is interested in projects that will develop innovative strategies integrating both experimental and bioinformatics approaches to establish causality for candidate genes from GWAS and linkage studies and to provide insights into genetic mechanisms of alcohol sensitivity and the development of tolerance through investigation of genomic, epigenetic, or transcriptional variation, and gene network and pathway analyses. Applicants are encouraged to consider model systems in which these complex relationships can be better studied under defined genetic backgrounds and well-controlled environmental conditions.


While many Americans drink alcohol, for some, drinking becomes problematic, potentially leading to an alcohol use disorder (AUD). Initial response to alcohol ingestion, sometimes known as sensitivity, may predict AUD development later in life. Low sensitivity is associated with high probability of developing an AUD. Following initial exposure, responses to alcohol change with subsequent drinking. Alcohol tolerance is a complex phenomenon in which increased alcohol intake is required to achieve a given effect, e.g., the feeling of intoxication, and is a defining feature of AUD. Stated in another way, tolerance decreases the effect of a defined alcohol dose, and reflects individual differences in sensitivity to pharmacologic effects of alcohol and physiological adaptation to alcohol exposure.

Responses to alcohol and the propensity to develop AUD vary significantly within and across populations, and are greatly influenced by family history of AUD. Family linkage and genome-wide association studies identified numerous candidate genes and genetic variations implicated in and contributing to alcohol sensitivity and tolerance. Candidate genes include gamma-aminobutyric acid (GABA) receptors, serotonin transporter, opioid receptor, and nicotinic acetylcholine receptor, as well as those for alcohol-metabolizing enzymes. Yet, their contribution to individual variation in alcohol sensitivity and tolerance and their contribution to underlying biological mechanisms remain largely unknown. This is in part because: 1) study cohorts vary in age, sex, previous alcohol exposure history, drinking context, and 2) response variables are often subjective, while objective measures are not comparable between studies.

Mechanisms underlying sensitivity and tolerance to alcohol are not well known, since alcohol responses are complex, multifactorial, and influenced both by genetic factors and environmental variables such as drinking context and stress exposure. Various studies have revealed different aspects of the genetic underpinnings of alcohol effects. Combining and integrating our knowledge from human genetic studies with information from studies of model organisms will be a productive strategy for investigating gene x gene (G x G), gene x environment (G x E) interactions, and epigenetic contributions to the underlying genetic mechanisms.

Specific Areas of Research Interest

Examples of potential research topics include, but are not limited to:

  • minimal standardization of methodologies used to search for genes that contribute to alcohol sensitivity and tolerance to facilitate combining multiple data sets within and across studies for meta-analysis
  • meta-analyses of large-scale genomic resources incorporating GWAS, transcriptional profiling studies, and epigenetic studies on humans and model organisms to gain insights into the genetic bases of alcohol sensitivity and tolerance
  • studies of candidate genes, loci and genetic variants identified through GWAS and sequencing of relevant genes that focus on in-depth evaluations of multiple generations of human families and pedigrees in animals
  • studies of candidate genes/loci and genetic variants for regulatory roles for tissue-specific gene expression, and for contributions to biological pathways and networks
  • translational research in model organisms utilizing state-of-the-art gene-editing and gene delivery approaches for in vivo validation of candidate genes, genetic variations, and gene networks from studies in humans
  • studies on epigenetic modifications and underlying mechanisms in mediating alcohol effects, for example, heritable gene expression changes in specific brain regions and organ systems that govern the behavioral consequences related to tolerance and AUD.

Notes on priorities

The following will be considered non-responsive to this NOSI:

  • Applications on genetics of cross-tolerance effects of alcohol with other drugs of abuse or multiple substances
  • Studies that include a focus on environmental moderators of sensitivity or stress
  • Proposal of the generation of new rodent lines through selective breeding strategies

The use of standardized models and transgenic animals especially for translational research is preferred.

Applicants are strongly encouraged to consult the Scientific/Research Contact listed below to discuss the alignment of their proposed work with the objectives of this FOA.

Note on NIAAA's interest in diversity

Research shows that diverse teams working together outperform homogenous teams. Scientists and trainees from diverse backgrounds and with different life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. Diverse teams of scientists will lead the way to develop more innovative inclusive research that will more broadly enhance public health. Fostering diversity by addressing underrepresentation in the scientific research workforce is a key component of the NIH strategy to identify, develop, support, and maintain the quality of our scientific workforce. It is expected that the research program will include a diverse group of scientists, including individuals from underrepresented backgrounds as per NOT-OD-20-031 (Notice of NIH's Interest in Diversity). NIAAA is especially interested in enhancing diversity representation including, but not to the exclusion of others, from racial, ethnic and gender minorities and early-stage investigators.

Application and Submission Information

This notice applies to due dates on or after October 5, 2021 and subsequent receipt dates through May 8, 2024. 

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

  • PAR-21-250 - Mechanisms of Alcohol Tolerance (R21/R33 - Clinical Trial Optional)
  • PA-19-055 - NIH Research Project Grant (Parent R01 Clinical Trial Required)
  • PA-19-056  - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
  • PA-19-091 – NIH Research Project Grant (Parent R01 Basic Experimental Studies with Humans Required)

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

  • For funding consideration, applicants must include “NOT-AA-21-029” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.


Please direct all inquiries to the contacts in Section VII of the listed funding opportunity announcements with the following additions/substitutions:

Scientific/Research Contact(s)

Hemin Chin, PhD
Division of Neuroscience and Behavior
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-1282

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Financial/Grants Management Contact(s)

Judy Fox
National Institute on Alcohol Abuse and Alcoholism

Telephone: 301 -443-4704


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