School of Medicine Publications and Presentations
Document Type
Article
Publication Date
1-1-2019
Abstract
Genome-wide association studies of case-control status have advanced the understanding of the genetic basis of psychiatric disorders. Further progress may be gained by increasing sample size but also by new analysis strategies that advance the exploitation of existing data, especially for clinically important quantitative phenotypes. The functionally-informed efficient region-based test strategy (FIERS) introduced herein uses prior knowledge on biological function and dependence of genotypes within a powerful statistical framework with improved sensitivity and specificity for detecting consistent genetic effects across studies. As proof of concept, FIERS was used for the first genome-wide single nucleotide polymorphism (SNP)-based investigation on bipolar disorder (BD) that focuses on an important aspect of disease course, the functional outcome. FIERS identified a significantly associated locus on chromosome 15 (hg38: chr15:48965004 – 49464789 bp) with consistent effect strength between two independent studies (GAIN/TGen: European Americans, BOMA: Germans; n = 1592 BD patients in total). Protective and risk haplotypes were found on the most strongly associated SNPs. They contain a CTCF binding site (rs586758); CTCF sites are known to regulate sets of genes within a chromatin domain. The rs586758 – rs2086256 – rs1904317 haplotype is located in the promoter flanking region of the COPS2 gene, close to microRNA4716, and the EID1, SHC4, DTWD1 genes as plausible biological candidates. While implication with BD is novel, COPS2, EID1, and SHC4 are known to be relevant for neuronal differentiation and function and DTWD1 for psychopharmacological side effects. The test strategy FIERS that enabled this discovery is equally applicable for tag SNPs and sequence data.
Recommended Citation
Budde, M., Friedrichs, S., Alliey-Rodriguez, N., Ament, S., Badner, J. A., Berrettini, W. H., Bloss, C. S., Byerley, W., Cichon, S., Comes, A. L., Coryell, W., Craig, D. W., Degenhardt, F., Edenberg, H. J., Foroud, T., Forstner, A. J., Frank, J., Gershon, E. S., Goes, F. S., Greenwood, T. A., … Malzahn, D. (2019). Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 29(1), 156–170. https://doi.org/10.1016/j.euroneuro.2018.10.005
Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-No Derivative Works 4.0 International License.
First Page
156
Last Page
170
Publication Title
European Neuropsychopharmacology
DOI
10.1016/j.euroneuro.2018.10.005
Academic Level
faculty
Mentor/PI Department
Neuroscience
Comments
http://creativecommons.org/licenses/by-nc-nd/4.0/