# Using transmitted and untransmitted gene networks to identify molecular pathways to substance use & misuse in genetically controlled twins

> **NIH NIH R01** · VIRGINIA COMMONWEALTH UNIVERSITY · 2021 · $588,299

## Abstract

Project Summary
 Multiple genetic risks cause alcohol, nicotine and cannabis substance use (SU) and substance use disorders
(SUDs). However, genetic studies alone cannot explain the cascade of molecular changes between SNPs and
SU and SUDs. Nor can current approaches correctly measure the causal impact of genetic differences on
parental and home environments linked to SU and SUDs. Molecular studies that link GWAS results to gene
expression data via eQTL findings have increased our understanding of the etiology of SU and SUDs. Yet, they
fail to capture complex gene interactions that are the hallmark of complex traits including SU and SUDs, or are
mostly underpowered (especially from brain tissues). Another limitation is that genetic and molecular studies
neglect environmental confounding. We know that parents create and influence children’s environments and that
certain parental and home environments are more associated with SU and SUDs. Not only do genetic risks vary
with environments, but environments themselves are also heritable, and are thus confounded by parental
genetics. We and others argue that unconfounding the impact of parent-to-offspring molecular genetics on SU
and SUDs from the parental and home environments is the central task of genetics. Here, we rely on recent
methodological advances to address these limitations. First, we have developed a novel and proven method of
measuring the impact of untransmitted parental genomes. This method identifies the indirect impact of
untransmitted parental genomes on complex behaviours. A significant impact of untransmitted genomes is
evidence of genetically nurtured environments that are unconfounded by the direct parent-to-offspring genetics.
Second, we can now perform gene expression (GE) imputation using existing GWAS. We can, therefore,
estimate heritable, genome-wide individual differences in imputed GE networks in very large samples. This
substantially increases our power to identify molecular pathways underlying SU and SUD aetiology. In summary,
we are proposing to i) use existing GWAS data from large population-based family samples, ii) apply our method
of assembling untransmitted parental genomes, iii) impute parentally transmitted and untransmitted GE, iv) apply
network analyses to identify transmitted and untransmitted GE networks that are associated with SU and SUDs,
and v) identify parental and home environments mediating these networks. This will enable us to identify the GE
networks involved in SU and SUDs while identifying risky and protective parental and home environments that
are genetically ‘nurtured’ within a unified theoretical framework.

## Key facts

- **NIH application ID:** 10298865
- **Project number:** 1R01DA052453-01A1
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** Nathan Alexander Gillespie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $588,299
- **Award type:** 1
- **Project period:** 2021-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10298865

## Citation

> US National Institutes of Health, RePORTER application 10298865, Using transmitted and untransmitted gene networks to identify molecular pathways to substance use & misuse in genetically controlled twins (1R01DA052453-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10298865. Licensed CC0.

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