This review presents a comprehensive evaluation of genetic methodologies and findings stemming from the family-centered Collaborative Study on the Genetics of Alcoholism (COGA). COGA’s primary objective was to identify genes influencing the susceptibility to alcohol use disorder (AUD) and its related complications. Notably, COGA was an early adopter of genome-wide association studies (GWAS) while also focusing on the hereditary aspects of AUD and associated conditions within familial contexts, incorporating rigorous clinical and neurophysiological data. Investigations cover genetic predispositions, developmental pathways toward substance use disorders, phenome-wide association studies, loci of interest, pleiotropy, social genomics, genetic nurture, and within-family analyses. This research initiative also stands out for its amplification of a diverse dataset.
COGA’s research design has transitioned from an initial focus on linkage studies to more recent use in extensive meta-analyses. This shift mirrors the evolving understanding of the genetic basis of alcohol use disorder (AUD) and psychiatric disorders in general. Moreover, while common genetic risk variants were initially expected to be located within gene-coding regions, GWAS research has shown that most of these variants are located in non-coding regions, influencing regulatory functions.
In parallel with the drive to increase sample sizes for gene discovery, there is a growing appreciation for the value of family-based datasets like COGA. These datasets encompass deep phenotyping, longitudinal perspectives, diverse ages, and ancestral diversity. The family-based design of COGA is well-suited to address scientific questions that are difficult to explore in very large datasets of unrelated individuals. This includes investigating direct and indirect genetic effects, assessing the robustness of identified genetic locations and polygenic signals through within-family comparisons, and conducting in-depth examinations of how genetic predispositions for AUD evolve over time and their effects on other traits and disorders. To advance our knowledge of the genetic basis of AUD, detailed, family-based designs in data-rich samples like COGA, alongside large collaborative meta-analyses that combine data from COGA with numerous other cohorts, will be crucial.
Johnson EC, Salvatore JE, Lai D, Merikangas AK, Nurnberger JI, Tischfield JA, Xuei X, Kamarajan C, Wetherill L, Collaborators C, Rice JP, Kramer JR, Kuperman S, Foroud T, Slesinger PA, Goate AM, Porjesz B, Dick DM, Edenberg HJ, Agrawal A (2023) The collaborative study on the genetics of alcoholism: Genetics. Genes, Brain and Behavior, e12856. PMID: 37387240. DOI: 10.1111/gbb.12856
