Whole-Exome Sequencing to Identify Potential Genetic Risk in Substance Use Disorders: A Pilot Feasibility Study

Abstract

Genetics intersects with environmental, cultural, and social factors in the development of addictive disorders. This study reports the feasibility of whole-exome sequencing of trios (subject and two family members) to discover potential genetic variants in the development of substance use disorders (SUD). Family trios were recruited from the National Addictions Management Service in Singapore during the 2016–2018 period. Recruited subjects had severe alcohol use disorder (AUD) or opioid use disorder (OUD), with nicotine dependence (ND) and a family history of addictive disorders. Demographic characteristics and severity of addiction were captured. Whole-exome sequencing (WES) and analysis were performed on salivary samples collected from the trios. WES revealed variants in several genes in each individual and disruptive protein mutations in most. Variants were identified in genes previously associated with SUDs, such as Pleckstrin homology domain-containing family M member 3 (PLEKHM3), coiled-coil serine-rich protein 1 (CCSER1), LIM and calponin homology domains-containing protein 1 (LIMCH1), dynein axonemal heavy chain 8 (DNAH8), and the taste receptor type 2 member 38 (TAS2R38) involved in the perception of bitterness. The feasibility study suggests that subjects with a severe addiction profile, polysubstance use, and family history of addiction may often harbor gene variants that may predispose them to SUDs. This study could serve as a model for future precision medicine-based personalized interventional strategies for behavioral addictions and SUDs and for the discovery of potentially pathogenic genetic variants.

Contingent stimulus delivery assay for zebrafish reveals a role for CCSER1 in alcohol preference

“…One way to improve our understanding of the neurogenetics of addiction is to perform functional analyses of candidate genes discovered in human genetic studies using animal models. In a pilot study, we identified missense variants predicted to damage protein function in the gene CCSER1 by whole exome study (WES) of family trios where at least one family member had been diagnosed with a substance use disorder (SUD), including AUD 34 . Intronic variants in CCSER1 have previously been associated with the methadone dose in opioid‐dependent individuals and with alcohol dependence in genome‐wide gene‐by‐environment interaction studies of risky behavior 53,54 .…”

“…In a pilot study, we identified missense variants predicted to damage protein function in the gene CCSER1 by whole exome study (WES) of family trios where at least one family member had been diagnosed with a substance use disorder (SUD), including AUD. 34 Intronic variants in CCSER1 have F I G U R E 4 Preference for alcohol does not change with pre-exposure Both nacre À/À (E,F) and AB WT (E,F) strains showed a similar preference for (A) and (C) 5% alcohol and avoidance of (B) and (f) 10% alcohol. The mean difference is depicted as a black dot, and the 95% confidence intervals are shown as vertical error bars.…”

“…The gene previously known as FAM190A has been studied extensively for its role in cell division and tumorigenesis. 69 As the intronic variants in this gene were associated with multiple SUDs and risky behavior, 53,54 and the disruptive exonic variants associated with AUD were discovered in WES study, 34 it made for a good candidate for examination in a model system. Linkage analysis of selectively bred rats had identified potentially damaging missense mutation in the CCSER1 gene (P82L) in alcohol-non-preferring rats in a previous study.…”

“…The sensitivity and the utility of this assay system to conduct neurogenetic studies became apparent when the responses to two genetic mutant lines were examined. Among these, the mutants generated in the Coiled‐Coil Serine Rich Protein ( CCSER1 ; HUGO gene ID HGNC:29349) gene for this study also demonstrated a way to evaluate the potential pathogenicity of candidate genes discovered in human genetic association studies 34 rapidly using an animal model.…”

Coordination among frequent genetic variants imparts substance use susceptibility and pathogenesis

“…Therefore, high-resolution sequencing is required to investigate causal variants for a phenotype as complex as SUDs. Though studies performing whole exome sequencing in SUDs are scant, more studies are required to expand the spectrum of SUDs variants ( AshaRani et al, 2021 ). Therefore, the present study was taken up to identify gene variants by re-assessing the exome sequences of SUDs probands.…”