- The current goal of the COGA Genomics project is to move from identification of loci that affect risk for alcohol use disorder (AUD) and related conditions to understanding the biological pathways, neurobehavioral and molecular mechanisms involved, and how they are expressed throughout the life course.
- Genome-Wide Association Studies (GWAS): We have carried out GWAS on 8,038 individuals of European descent and 3,655 individuals of African descent.
- To go beyond finding loci to understanding the underlying biology we generate genomic data on functional differences in brain regions and also integrate genomic and functional data from many outside sources (e.g., GTeX, Common Mind)
- We are also testing the effects of the variants and genes that we identify in human induced Pluripotent Stem Cells (iPSC-derived cells). We examine effects on the transcriptome and on neuronal signaling in iPSC-derived neurons in 2D cultures and 3D brain organoids, and use CRISPR/Cas9 genome editing to test effects of variants. We use a strategy of generating neurons from individuals with extreme polygenic risk scores (high and low risk for AUD) to see effects in different genomic contexts.
Brain Function Project
A central part of COGA has been to study brain function in people with alcohol use disorder (AUD) and in their relatives including their children. We have recorded brain waves (also called “brain oscillations”), electrical signals produced in the brain, detected with harmless sensors inside a cap using the electroencephalogram, or EEG, in thousands of people as they sit still (resting state) or perform simple tasks such as pressing a button only for a specific image shown on a computer screen while ignoring other images/
We have recorded brain waves in family members with and without alcohol problems, often more than once, during their lifetime, including in their children, who have been retested every two years during adolescence and young adulthood. We also measure skills such as attention, memory, and problem solving.
COGA applies novel data analyses that allow us to evaluate different aspects of brain function, such as identifying specific images or sounds, decision making, or evaluating the outcomes of a decision. Some of these methods show how different areas of the brain communicate and work together, like musicians in an orchestra; when this synchrony is disrupted, performance of tasks may be impaired.
We use these measures of brain function to detect and understand both risk and protective factors for the development of AUD, as well as for the consequences of heavy drinking on the brain, including the impact on cognitive functions. We have also examined genetic and environmental influences on these brain function measures and the trajectories of their development during adolescence, young adulthood, and continuing changes throughout the lifespan.
Environmental influences can also impact brain development. Individuals exposed to childhood sexual trauma had brain wave activity that differed from individuals who didn’t experience trauma, which put them at increased risk for the development of alcohol use disorder.
COGA has found that brain wave activity differs in individuals with alcohol use disorders – and in their unaffected children. These brain wave abnormalities observed in young children may be a marker of risk for developing AUD, and not simply a consequence of excessive drinking. We can use these brain waves to help us find the genes involved in why some people are more at risk.
The goal of the lifespan project is to understand how risk and resilience for alcohol and related problems unfolds across the lifespan. There have been multiple waves of data collection, which focused on different parts of the lifespan.
Original COGA participants included “probands” and their family members. The probands were people who were in treatment for alcohol dependence at one of six treatment facilities in the U.S. (San Diego, CA; St. Louis, MO; Iowa City, IA; Hartford, CT, New York, NY; and San Diego, CA.) when they were invited to join the study. Their family members were also invited to join the study, whether or not they had alcohol problems. Probands and their family members participated in a comprehensive interview that included questions about alcohol and drug use and physical and mental health. Families with 2 or more 1st-degree relatives who had alcohol dependence also participated in testing to measure brain function and provided blood samples for genetic analysis. Comparison families were recruited from various sources, including dental clinics and driver’s license registries, also completed interviews.
Prospective COGA participants are descendents of the original COGA participants, described above, who were born in 1982 or later and who have at least one parent who was interviewed in the original COGA study. They were recruited into the prospective study beginning in 2004 when they were between the ages of 12 and 22. This part of the COGA study is called the “prospective cohort” because the participants were interviewed every 2 years to see how they changed over time. This allows researchers to examine how genes and environment work together to influence drinking initiation and the course of drinking – whether a person remains a light drinker throughout adolescence and early adulthood, for example, or begins as a light or moderate drinker but becomes a heavy drinker. Members of the prospective cohort participated in interviews very similar to the one used in the original sample, which allows comparison of characteristics in several generations.
The lifespan project is a combination and continuation of both of these efforts. It is called “lifespan” because it is designed to cover the years of great changes in many peoples’ lives: from childhood through adolescence, when alcohol use is often initiated; the early and middle adult years when work, romantic partnerships, and children are paramount concerns; and the older adult years, when alcohol habits may change but when the cumulative effects of lifetime alcohol use are most likely to manifest in problems like liver disease.
The next phase of the lifespan project will take place from 2019-2023. During this period, we will focus on interviewing people who participated in the prospective study who are entering their 30s and 40s, and will also interview people from the original COGA study who are entering their 50s, 60s, and 70s. This will give us an overall picture of the life occurrences and alcohol habits throughout the adult years to complement the information we gathered over the last decade of the project on adolescents and young adults. The data we gather from participants in the next phase of the lifespan project will help us to:
- Characterize the course of alcohol use and alcohol use disorders in early, middle, and late adulthood
- Examine how genes and environment work together to influence the course of alcohol use, including non-problem use, heavy and chronic use, periods of remission and relapse, sustained recovery, and resistance to developing alcohol problems despite having high familial or environmental risk
- Understand how alcohol use over the life course influences social, psychological, cognitive, and general health outcomes and mortality, and whether periods of remission or recovery from alcohol problems have an effect on those outcomes.