Family Health Patterns: A Study Across Generations

PROJECT SUMMARY
Individuals with a family history of alcoholism (FH+) are 4 to 8 times more likely to develop an alcohol use
disorder (AUD) compared to individuals with no such family histories. We developed the Family Health
Patterns project to characterize risk-related phenotypic characteristics of FH+ young adults. During our recent
funding period, we have identified robust links between increased early life adversity (ELA) in FH+ and their (a)
blunted stress reactivity, (b) increased antisocial tendencies, (c) poor affect regulation, and (d) impaired
cognitive performance. In our neuroimaging studies, we identified diffusivity changes in frontal white matter
tracts in both FH+ young adults and children, suggesting decreased myelination and axon damage in
underlying neural circuitry. We interpret these collective findings to suggest that increased ELA in FH+
individuals induces lasting neurobiological changes and consequent behavioral effects that increase AUD risk.
To guide the present proposal, we developed a heuristic model of how ELA contributes to risk-related
phenotypic characteristics in FH+ persons. We propose that convergent epigenetic and transcriptomic
dysregulation of immune genes increase inflammation and immunoreactivity, thereby impairing myelination
and/or damaging axons in developing frontal white matter tracts. The resulting impaired communication to and
from the prefrontal cortex contributes to phenotypic characteristics of increased antisocial tendencies and
poorer affect regulation and cognitive performance, increasing AUD risk. Here we propose to test this model by
examining inflammatory gene expression, functional changes in immunoreactivity, and cerebral white matter
myelin levels and axon damage markers in FH+ and FH– young adults. We will then examine relationships of
these variables with ELA exposure and risk-related phenotypic characteristics. This proposal rigorously builds
on our extensive findings on FH+ behavioral and biological phenotypes by testing a novel, overarching model
of AUD risk. While extensive preclinical evidence exists illustrating ELA induces long-lasting dysregulation of
the immune system and resulting neural and behavioral sequela, our proposal breaks new ground by
comprehensively examining these relationships in humans using advanced immunology and multimodal
neuroimaging together with in-depth behavioral and clinical assessments.

Grant Number: 5R01AA012207-21
NIH Institute/Center: NIH
Principal Investigator: ASHLEY ACHESON