Please cite this article as follows: Potash JB, Buervenich S, Cox NJ, Zandi PP, Akula N, Steele J, Rathe JA, Avramopoulos D, Detera-Wadleigh SD, Gershon ES, NIMH Genetics Initiative Bipolar Disorder Consortium, DePaulo JR Jr, Feinberg AP, McMahon FJ. 2007. Gene-Based SNP Mapping of a Psychotic Bipolar Affective Disorder Linkage Region on 22q12.3: Association With HMG2L1 and TOM1. Am J Med Genet Part B 147B:59–67.
Gene-based SNP mapping of a psychotic bipolar affective disorder linkage region on 22q12.3: Association with HMG2L1 and TOM1†
Article first published online: 1 AUG 2007
Copyright © 2007 Wiley-Liss, Inc.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics
Volume 147B, Issue 1, pages 59–67, 5 January 2008
How to Cite
Potash, J. B., Buervenich, S., Cox, N. J., Zandi, P. P., Akula, N., Steele, J., Rathe, J. A., Avramopoulos, D., Detera-Wadleigh, S. D., Gershon, E. S., DePaulo, J. R., Feinberg, A. P. and McMahon, F. J. (2008), Gene-based SNP mapping of a psychotic bipolar affective disorder linkage region on 22q12.3: Association with HMG2L1 and TOM1. Am. J. Med. Genet., 147B: 59–67. doi: 10.1002/ajmg.b.30574
- Issue published online: 14 DEC 2007
- Article first published online: 1 AUG 2007
- Manuscript Accepted: 9 MAY 2007
- Manuscript Received: 20 FEB 2007
- NIMH. Grant Numbers: R01 MH042243, U01 MH46282, U01 MH46280, U01 MH46274
- Stanley Medical Research Institute
- NIMH Intramural Research Program
- bipolar disorder;
- linkage disequilibrium;
- Wnt signaling;
Genetic linkage studies in both bipolar affective disorder (BPAD) and schizophrenia have implicated overlapping regions of chromosome 22q. We previously reported that BPAD pedigrees containing multiple members with psychotic symptoms showed suggestive linkage to chromosome 22q12.3. Now we have tested 189 single nucleotide polymorphisms (SNPs) spanning a 3 Mb region around the linkage peak for association with BPAD in 305 families, unrelated cases, and controls. SNPs were selected in or near genes, resulting in coverage at a density of 1 SNP per 6.7 kb across the 22 annotated genes in the region. The strongest signal emerged from family-based association analysis of an 11-SNP, 54 kb haplotype straddling the gene HMG2L1 and part of TOM1. A 3-marker haplotype of SNPs within TOM1 was associated with BPAD (allele-wise P = 0.0011) and with psychotic BPAD (allele-wise P = 0.00049). As hypothesized, the mean odds ratio for the risk alleles across the region was 1.39 in the psychotic but only 0.96 in the non-psychotic subset. Genotype-wise analyses yielded similar results, but the psychotic/non-psychotic distinction was more pronounced with mean odds ratios of 1.91 versus 0.8. Permutation of genotype-wise results for rs2413338 in HMG2L1 showed an empirical P = 0.037 for the difference between subsets. HMG2L1 is a negative regulator of Wnt signaling, a pathway of interest in psychotic BPAD as it is activated by both mood stabilizer and anti-psychotic medications. Further work is needed to confirm these results and uncover the functional variation underlying the association signal. © 2007 Wiley-Liss, Inc.