An endophenotype approach to the genetics of alcohol dependence: a genome wide association study of fast beta EEG in families of African ancestry

Abstract

Fast beta (20–28 Hz) electroencephalogram (EEG) oscillatory activity may be a useful endophenotype for studying the genetics of disorders characterized by neural hyperexcitability, including substance use disorders (SUDs). However, the genetic underpinnings of fast beta EEG have not previously been studied in a population of African-American ancestry (AA). In a sample of 2382 AA individuals from 482 families drawn from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a genome-wide association study (GWAS) on resting-state fast beta EEG power. To further characterize our genetic findings, we examined the functional and clinical/behavioral significance of GWAS variants. Ten correlated single-nucleotide polymorphisms (SNPs) (r2>0.9) located in an intergenic region on chromosome 3q26 were associated with fast beta EEG power at P<5 × 10−8. The most significantly associated SNP, rs11720469 (β: − 0.124; P<4.5 × 10−9), is also an expression quantitative trait locus for BCHE (butyrylcholinesterase), expressed in thalamus tissue. Four of the genome-wide SNPs were also associated with Diagnostic and Statistical Manual of Mental Disorders Alcohol Dependence in COGA AA families, and two (rs13093097, rs7428372) were replicated in an independent AA sample (Gelernter et al.). Analyses in the AA adolescent/young adult (offspring from COGA families) subsample indicated association of rs11720469 with heavy episodic drinking (frequency of consuming 5+ drinks within 24 h). Converging findings presented in this study provide support for the role of genetic variants within 3q26 in neural and behavioral disinhibition. These novel genetic findings highlight the importance of including AA populations in genetics research on SUDs and the utility of the endophenotype approach in enhancing our understanding of mechanisms underlying addiction susceptibility.

Genome‐wide association analysis links multiple psychiatric liability genes to oscillatory brain activity

“…This bodes well for future GWAS of additional EEG parameters. For example, two recently published GWASs of bipolar EEG from families of African and European ancestry reported genome-wide signal at 3q26 and 6q22, respectively [Meyers et al, 2017a; Meyers et al, 2017b]. Bipolar EEG derivations show more localized activity than other EEG derivations and remove volume conduction effects, and have been particularly successful as a biomarker of alcohol dependence.…”

“…The first genome-wide association study of EEG oscillation strength showed an association between SGIP1 and theta oscillations in both Native American and European Ancestry samples. Two recent studies from the Collaborative Study on the Genetics of Alcoholism (COGA) associated several intergenic SNPs at 6q22 in a European sample [Meyers et al, 2017a], and at 3q26 in African American ancestry [Meyers et al, 2017b] for >20 Hz fast beta oscillations.…”

Genome‐wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward‐related ventral striatum activity in African‐ and European‐Americans

“…Multiple genome-wide arrays were used to genotype the COGA sample 23,[39][40][41] Text) using SHAPEIT2 42 and Minimac3. 43 Imputed SNPs with R 2 < 0.30 were excluded, and genotype probabilities were converted to best-guess genotypes if ≥0.90.…”

Conflict-related medial frontal theta as an endophenotype for alcohol use disorder

“…Given the current state of the psychiatric/endophenotype behavioral genetics field, it is difficult to speculate on the specific genetic mechanisms that give rise to the AUD-theta genetic correlation. The search to identify specific genetic variants of several task-based EEG-based endophenotypes, including midfrontal theta power, has so far proven largely unsuccessful (Iacono et al., 2017; Malone, McGue, & Iacono, 2017; although see Smit et al, 2018, and Meyers et al, 2017, for genomewide association studies [GWAS] of resting state EEG oscillatory power). Evidence suggests that psychophysiological endophenotypes, like psychiatric phenotypes, are highly polygenic and genetically complex, with individual common variants explaining a very small fraction of the phenotypic variance.…”