Common Genetic Origins for EEG, Alcoholism and Anxiety: The Role of CRH-BP

Abstract

The resting EEG is a dynamic index of cortical activation, cognitive function and consciousness and is therefore an intermediate phenotype for many behaviors in which arousal is implicated such as anxiety and alcoholism. We performed a dense whole genome linkage scan using 3878 unlinked SNPs in a large pedigree derived from a population isolate sample of 328 Plains American Indians. Alpha (8–13 Hz), theta (4–8 Hz) and beta (13–30 Hz) EEG power was heritable (0.58–0.27) and stable over a 2 year period (r = 0.82–0.53). Genetic correlations between frequency bands were high (0.75). Linkage peaks for EEG power in all three frequency bands converged on chromosome 5q13-14 with genome-wide significant LOD scores of 3.5 (empirical p<0.0001) for alpha and beta power. A logical candidate gene, corticotropin releasing hormone-binding protein (CRH-BP), was located at the apex of these convergent linkage peaks. CRH-BP was significantly associated with alpha power in the Plains Indians and also in a replication sample of 188 Caucasians. Moreover, the same SNPs and haplotypes, located within the CRH-BP haplotype block, were also associated with anxiety disorders in the Plains Indians and alcohol use disorders in the Caucasians. CRH-BP modulates CRH which influences cortical and hippocampal EEG activity and is the primary mediator of the neuroendocrine stress response. Our results suggest a likely role for CRH-BP in stress-related alcoholism and highlight the use of the resting EEG as an intermediate phenotype for arousal-related behaviors such as anxiety and addiction.

Genome-wide association identifies candidate genes that influence the human electroencephalogram

“…Alleles significant (but subthreshold) for association with increased θ power were underrepresented in individuals with AUD. Reduced θ power in alcoholics had been reported for this dataset (15). The present data indicate a relationship between SGIP1 genotype and AUD.…”

“…SGIP1 and ST6GALNAC3 lie within a linkage peak on chr 1p (95-115 cM), linked to β2 EEG spectral power (16)(17)(18)(19)(20) in the COGA (27,28). UGDH, LIAS, RPL9, and KLB lie in a region of chr 4 previously linked to EEG in this Plains Indian dataset (15), together with an additional Native American population (29) and in the COGA dataset (30). Additionally, the study has identified BICD1 located on chr 12p11 as a candidate gene for resting α power variability.…”

“…We have performed GWAS in a sample of Plains American Indians, in which α (8-13 Hz), β (13-30 Hz), and θ (3-8 Hz) EEG spectral power are moderately heritable with high test-retest correlations over 2 years (15). Notably, this sample represents a population isolate evidencing a small but, as it turned out, useful degree of European admixture, and is genetically distinct from other Native American populations.…”

“…EEG also has moderate predictive value for personality variation and psychiatric disease including depression (7), bipolar disorder (8), attention-deficit/hyperactivity disorder (9), and obsessive-compulsive disorder (10). Increased β power is associated with both alcoholism and family history of alcoholism (11,12), θ power is altered in alcoholics (13)(14)(15), and reduced α power has been associated with a family history of alcoholism and with alcoholism with comorbid anxiety disorders (16,17). However, the EEG is not clinically useful for diagnosis of any specific psychiatric disorder.…”

Comments for Current Interpretation EEG Alpha Activity: A Review and Analysis

“…It is likely, however, that multiple genes contribute to "alpha phenotypes", and a few candidate genes were indeed found to affect alpha oscillations. So, recent genetic polymorphism studies indicated that the gene on chromosome 5q13-14 of corticotrophin releasing hormone-binding protein (CRH-BP) modulates alpha power in isolated Plains American Indians and Caucasians [85]. Moreover, a functional variation in exon 7 of the gene on chromosome 6 encoding the human GABAB receptor (GABABR1) also influences EEG voltage in the alpha range [86].…”