Intergenerational transmission of substance use and substance use disorders: disentangling phenotypic, transmitted and non-transmitted genetic effects

Substance use disorders (SUDs) including alcohol, nicotine and cannabis have a significant impact 
on global health. Excessive alcohol use causes approximately 880,000 deaths among working-age 
adults in the U.S. at the cost of $224 billion annually. Nicotine use is responsible for about 480,0000 
deaths in the U.S. or $300 billion annually. By 2010, cannabis misuse accounted for two million 
disability-adjusted life years globally, a 22% increase since 1990. Changes in the legal status of cannabis 
are likely to exacerbate these trends. 
Substance use and SUDs tend to run in families. Offspring of parents with SUDs have an increased 
risk to develop SUDs as compared to offspring of parents without SUDs. To understand the 
intergenerational transmission of SUDs, prospective studies that follow different generations within 
families over the life course are needed. Further, siblings comparison in SUDs could also help 
understand the familiar transmission of SUDs. In addition, it is important to understand the 
developmental trajectories of substance use and disorders over time.
However, these phenotypic associations between parents and offspring can be confounded by 
genetic effects. We know that parents have genes that influence their risk of disease, some of which 
will be randomly transmitted to their offspring. Without taking account for the genetic transmission, 
these parent-offspring associations could be misinterpreted as causal. Besides a direct genetic effect, 
another pathway of familial transmission is "genetic nurture". Specifically, nontransmitted genes may 
influence parental phenotypes (environmental exposure), which in turn affects the offspring’s risk, 
independent of the genetic risk transmitted from parent to offspring. However, the mechanisms of 
intergenerational transmission of SUDs, in particular genetic nurture effects, remain unclear. 
Proposal number: OV (to be completed by Lifelines)
Application form data, biomaterials and linkage
Date 15-7-2019
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Recently, novel methods have been developed leveraging the opportunities of GWAS data to 
quantify transmitted and nontransmitted alleles, thereby testing genetic nurture effects on offspring 
traits directly. Previous studies have demonstrated that parental nontransmitted alleles independently 
predicted their offspring's educational achievements through 'genetic nurture'. In the current study, 
we aim to investigate the impact of nontransmitted parental genetics in the offspring’s risk of SUDs
using these novel methods.
GWAS studies have begun identifying multiple loci for SU and SUD phenotypes. Despite these 
advances, it is poorly understood how genetic risk variants for SUDs contributes to disease pathology.
Expression quantitative trait loci (eQTLs), which are responsible for a substantial proportion of gene 
expression variance, have been suggested as functional links and biological underpinnings between 
GWAS loci and disease. However, the majority of molecular studies are either underpowered or still 
fail to capture complex gene interactions. In this study, we will resolve this by performing gene 
expression (GE) imputation with existing GWAS samples. This substantially increases our power to 
identify molecular pathways underlying SU and SUD etiology. 
By integrating phenotypic, genetic and environmental perspectives, our goal is to provide a 
comprehensive framework to describe how the risks of substance use (SU) and substance use disorders 
(SUDs) emerge and are transmitted in families.