Common genetic origins for EEG, alcoholism and anxiety: the role of CRH-BP.
- Authors
- Enoch, Mary-Anne; Shen, Pei-Hong; Ducci, Francesca; Yuan, Qiaoping; Liu, Jixia; White, Kenneth V; Albaugh, Bernard; Hodgkinson, Colin A; Goldman, David
- Year
- 2008
- Journal
- PloS one
- PMID
- 18974851
- DOI
- 10.1371/journal.pone.0003620
- PMCID
- PMC2575401
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.
Chromosome 5q13-14: Convergence of Linkage Peaks for Alpha (8–13 Hz) and Beta (13–30 Hz) EEG power.Only linkage peaks with LOD scores>3.0 are shown here. CRH-BP = corticotropin releasing hormone-binding protein gene. O1 = occipital electrode; P3, PZ, P4 = parietal electrodes.
CRH-BP Gene Map and Haplotype Block Structure in Plains Indians and U.S. Caucasians. CRH-BP: corticotropin releasing hormone-binding protein gene. 2A: The 7 CRH-BP exons are indicated by rectangles. An alternative isoform (CRH-BP alt) expressed in the brain has exon 7 spliced out. The positions of the genotyped SNPs are indicated and the 4 SNPs with significant associations with EEG power are highlighted. The haplotype block structures of the three HapMap populations: CEU (Caucasian); YRI (African) and ASN (Chinese/Japanese) are provided. Conservation across 17 vertebrate species, from zebrafish to humans is indicated (www.genome.ucsc.edu). 2B, 2C: haplotype block structure across the two populations. The numbers are D′ values (linkage disequilibrium between SNP pairs).
CRH-BP Peptide Sequence Conservation.The sequence of the human alternate isoform (H_Alt) is shown in the top line: the terminal 52 amino acids are deleted and replaced by 18 novel amino acids. Line 2 downward through line 8 shows strong sequence conservation between: human/chimp/macaque/dog/cow/rat/mouse/chicken respectively.
| # | Section | Preview |
|---|---|---|
| 60 | Materials and Methods — There were three phases to this study — Verification of linkage results by quantitative trait simulation | Empirical p values for the linkage peaks were obtained by performing 10,000 simulations using SOLAR.… |
| 61 | Materials and Methods — There were three phases to this study — Candidate gene selection | All genes under linkage peaks with a LOD score ≥2 were located by converting genetic map (deCODE)… |
| 62 | Materials and Methods — There were three phases to this study — Candidate gene association study: CRH-BP | A 1,536 tag SNP addiction array has been developed within the Laboratory of Neurogenetics, NIAAA,… |
| 63 | Materials and Methods — There were three phases to this study — Candidate gene association study: CRH-BP | can be generated conditional on the user-specified frequencies using the gene-drop method within… |
| 64 | Materials and Methods — There were three phases to this study — Candidate gene association study: CRH-BP — CRH-BP haplotype analyses | Haplotype frequencies were estimated using a Bayesian approach implemented with PHASE [58].… |
| 65 | Materials and Methods — There were three phases to this study — Assessment of population stratification using ancestry informative markers (AIMS) | The Plains Indian and U.S. Caucasian samples were genotyped for 186 ancestry markers that were on… |
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