title: 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.
authors.affiliation: Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA. maenoch@niaaa.nih.gov
authors.forename: Mary-Anne
authors.initials: MA
authors.lastname: Enoch
authors.forename: Pei-Hong
authors.initials: PH
authors.lastname: Shen
authors.forename: Francesca
authors.initials: F
authors.lastname: Ducci
authors.forename: Qiaoping
authors.initials: Q
authors.lastname: Yuan
authors.forename: Jixia
authors.initials: J
authors.lastname: Liu
authors.forename: Kenneth V
authors.initials: KV
authors.lastname: White
authors.forename: Bernard
authors.initials: B
authors.lastname: Albaugh
authors.forename: Colin A
authors.initials: CA
authors.lastname: Hodgkinson
authors.forename: David
authors.initials: D
authors.lastname: Goldman
mesh_terms: 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
chemical_list: D002352:Carrier Proteins; C067133:corticotropin releasing factor-binding protein