A genome-wide association study of interhemispheric theta EEG coherence: implications for neural connectivity and alcohol use behavior.
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- Authors
- Meyers, Jacquelyn L; Zhang, Jian; Chorlian, David B; Pandey, Ashwini K; Kamarajan, Chella; Wang, Jen-Chyong; Wetherill, Leah; Lai, Dongbing; Chao, Michael; Chan, Grace; Kinreich, Sivan; Kapoor, Manav; Bertelsen, Sarah; McClintick, Jeanette; Bauer, Lance; Hesselbrock, Victor; Kuperman, Samuel; Kramer, John; Salvatore, Jessica E; Dick, Danielle M; Agrawal, Arpana; Foroud, Tatiana; Edenberg, Howard J; Goate, Alison; Porjesz, Bernice
- Year
- 2021
- Journal
- Molecular psychiatry
- PMID
- 32433515
- DOI
- 10.1038/s41380-020-0777-6
- PMCID
- PMC8503860
Aberrant connectivity of large-scale brain networks has been observed among individuals with alcohol use disorders (AUDs) as well as in those at risk, suggesting deficits in neural communication between brain regions in the liability to develop AUD. Electroencephalographical (EEG) coherence, which measures the degree of synchrony between brain regions, may be a useful measure of connectivity patterns in neural networks for studying the genetics of AUD. In 8810 individuals (6644 of European and 2166 of African ancestry) from the Collaborative Study on the Genetics of Alcoholism (COGA), we performed a Multi-Trait Analyses of genome-wide association studies (MTAG) on parietal resting-state theta (3-7βHz) EEG coherence, which previously have been associated with AUD. We also examined developmental effects of GWAS findings on trajectories of neural connectivity in a longitudinal subsample of 2316 adolescent/young adult offspring from COGA families (ages 12-30) and examined the functional and clinical significance of GWAS variants. Six correlated single nucleotide polymorphisms located in a brain-expressed lincRNA (ENSG00000266213) on chromosome 18q23 were associated with posterior interhemispheric low theta EEG coherence (3-5βHz). These same variants were also associated with alcohol use behavior and posterior corpus callosum volume, both in a subset of COGA and in the UK Biobank. Analyses in the subsample of COGA offspring indicated that the association of rs12954372 with low theta EEG coherence occurred only in females, most prominently between ages 25 and 30 (pβ<β2βΓβ10). Converging data provide support for the role of genetic variants on chromosome 18q23 in regulating neural connectivity and alcohol use behavior, potentially via dysregulated myelination. While findings were less robust, genome-wide associations were also observed with rs151174000 and parieto-frontal low theta coherence, rs14429078 and parieto-occipital interhemispheric high theta coherence, and rs116445911 with centro-parietal low theta coherence. These novel genetic findings highlight the utility of the endophenotype approach in enhancing our understanding of mechanisms underlying addiction susceptibility.
Manhattan plot displaying genome-wide meta-analysis association results for interhemispheric low theta coherence (P3-O1βP4-O2)Genome-wide association results for low theta EEG coherence in the genome-wide meta-analysis of individuals of European and African ancestry. Y axis denotes the βlog10 (P-value) for association. X axis is the physical position of the SNPs across the genome. Note: Red line indicates the threshold of genome-wide significance (P<5 Γ 10β8).
Increased posterior corpus callosum volume was observed among rs12954372 A-allele carriers (B: 0.34, p: 0.038, adjusted for gender, age, total brain volume, PC1-PC3, and genotype array) in COGA participants (Total MRI N=60, A-allele carriers N=7)
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