Common genetic origins for EEG, alcoholism and anxiety: the role of CRH-BP.
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.
Enoch
Mary-Anne
MA
Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA. maenoch@niaaa.nih.gov
Shen
Pei-Hong
PH
Ducci
Francesca
F
Yuan
Qiaoping
Q
Liu
Jixia
J
White
Kenneth V
KV
Albaugh
Bernard
B
Hodgkinson
Colin A
CA
Goldman
David
D
D000437:Alcoholism / Q000208:ethnology / Q000235:genetics*; D001007:Anxiety / Q000208:ethnology / Q000235:genetics*; D001921:Brain / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002895:Chromosomes, Human, Pair 5; D004569:Electroencephalography; D004777:Environment; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D012146:Rest / Q000502:physiology
D002352:Carrier Proteins; C067133:corticotropin releasing factor-binding protein