Longitudinal effects and environmental moderation of ALDH2 and ADH1B gene variants on substance use from age 14 to 40

Abstract

Alcohol use and dependence are strongly affected by variation in aldehyde dehydrogenase (ALDH2) and, to a lesser extent, alcohol dehydrogenase (ADH1B) genes. We use this genetic variation with an adoption design to test the causal role of alcohol use on other drug use, as well as the moderating role of adoptive parent, sibling, and peer alcohol use. Longitudinal models were run on 412 genotyped adopted individuals of East Asian ancestry with multiple assessments between ages 14 and 40. We found robust associations between alcohol frequency, quantity, and maximum drinks and ALDH2, but not ADH1B, status. The magnitude of the ALDH2 protective effect increased with age, particularly for maximum drinks, though estimates were smaller than previously reported in ancestrally similar individuals in East/North-East Asian countries. These results suggest that sociocultural factors in Minnesota may reduce the protective effects of ALDH2. We found that peer alcohol use, but not parent or sibling use, predicted adopted offspring’s use, and that these environmental influences did not vary by ALDH2 status. Finally, we did not find strong evidence of associations between ALDH2 status and tobacco, marijuana, or illegal drug use, contrary to expectation if alcohol serves as a gateway to use of other drugs.

Special Issue editorial: Leveraging genetically informative study designs to understand the development and familial transmission of psychopathology

“…Results were largely null and there was little support for this hypothesis except that higher father-child relationship quality was associated with later age of alcohol initiation, and greater social competence was associated with lower resistance to heavy episodic alcohol use. Saunders et al (2022) took a Mendelian randomization approach that leveraged natural and random variation in the ALDH2 and ADH1B genes (common only in East/North-East Asian ancestry populations) and the adoption study design in the Sibling Interaction and Behavior Study. They found robust evidence that one ALDH2 variant is associated with lower alcohol use (but not later age of initiation) in adolescence, but not protective against other substance use, inconsistent with the gateway hypothesis.…”