Elizabeth Powell, Ph.D.

February 08, 2024

Purpose

The purpose of the Collaborative Study on the Genetics of Alcoholism (COGA) is to advance knowledge about the complex influences of gene and environment on development and progression of alcohol use disorder (AUD). From its inception, COGA has generated and utilized extensive arrays of genotypic and phenotypic data from families densely affected by AUD and from comparison families to identify genes and understand their role in susceptibility to (or protection from) developing AUD and related phenotypes. New genetic variants have been identified, refined endophenotypes have been characterized, and functional information has begun to emerge on known genetic variants that influence risk for and protection from AUD. 

The goals of this renewal concept are to continue to integrate and share COGA data and to continue to add data across the lifecycle, specifically in the adolescent and young adult (Prospective Study) and older adult (Lifespan Study) cohorts. The initiative will advance the understanding of the complexity of the genotypes and phenotypes that contribute to the heterogeneity of AUD, integrate the analysis of multiple data sources, and generate mechanistic hypothesis to understand the contributions of genetic, behavioral, and environmental factors on the development of (or resilience from) AUD.

Scope/Objectives

The scope of the concept is to understand how previously identified genes and gene variants act to affect the risk for AUD or support recovery in current COGA cohorts, particularly the studies on adolescent and young adults in Prospective Study and on older subjects (participants 50+ years in the Lifespan Study). Examination of the influences of environmental factors continues to be essential for delineating the heterogeneity and underlying biological mechanisms of AUD phenotypes. This initiative is expected to:

• Advance the understanding of the complexity of AUD leveraging existing multi-generational COGA genetic and genomic data, including utilizing state-of-the-art genomic, epigenomic and multi-omic technologies, such as WGS (whole genome sequencing), RNA-seq, methylome, metabolome, and proteome analyses.
• Identify genes with a causal role in AUD based on genome-wide significant loci from genome-wide association studies.
• Generate of a web-based portal to make COGA research findings and publications accessible to the scientific community and to communicate the key COGA findings with public health implications and relevance to the public.
• Share all past and new COGA genetic and genomic data with related comprehensive phenotypic data widely with the broader research community.
• Establish an integrated COGA database resource for a wide variety of analyses that is available to researchers interested in AUD. The resource will include basic processing, harmonization, imputation, and integration of multi-modal past and new COGA datasets, so that data are FAIR (Findable, Accessible, Interoperable and Reusable).
• Generate tools and methodology, in collaboration with geneticists and data scientists, to perform current, integrative, comprehensive analyses leveraging the entire COGA and other large-scale datasets (e.g. genetics and genomics, transcriptomics, and epigenomics) across the alcohol addiction cycle and life cycle, providing mechanistic hypotheses for follow-up studies.
• Provide biological reagents and bioinformatic analysis tools to researchers outside of COGA.
• Facilitate the field to move from identification of genetic loci to understanding mechanisms underlying chronic AUD and associated comorbidities (using functional genomics approaches, and social-environmental contributions).
• Develop an integrated model of risk, resilience, and recovery of AUD that includes genomic, physiological, and socio-environmental factors over the lifespan.
• Continue to collect genetic and phenotype data on COGA adolescents and young adults and aging families focusing on the understudied period of later life to investigate lifespan perspective. This includes longitudinal course of chronic AUD through late life, and medical, neurocognitive, and mental health correlates and consequences of AUD (including cognitive decline, dementia, liver disease, premature death and other medical and mental health comorbidities).

Justification

The previous COGA studies have provided critical information to better understand the genetic and biological underpinnings of AUD. However, there is a need for a framework to unify the findings and provide the data to the community for additional analysis and discovery. The initiative will facilitate identification of therapeutic targets and development of prevention strategies for AUD, supported by data generation, curation and bioinformatic analyses. The environment for data sharing has changed dramatically in the past 5 years. The establishment of the NIAAA Data Archive and the Final NIH Data Management and Sharing Policy (NOT-OD-21-013) provide an ecosystem and structure for the sharing of future and past (legacy) data from the COGA studies. The initiative will require analysis of all the COGA results. While the adult data in COGA are extensive, two family cohorts, adolescent and young adults in Prospective Study and older participants in Lifespan Study, will benefit from additional participants and data collection. The COGA initiative is focused on optimizing the use of the past COGA data and completing data collection across the lifespan. New pilot studies or experimental directions are not anticipated.