| Abstract | The last several years have been breakthrough ones in bipolar disorder (BPD) genetics, as the field has identified robust risk variants for the first time. Leading the way have been genome-wide association studies (GWAS) that have assessed common genetic markers across very large groups of patients and controls. These have resulted in findings in genes including ANK3, CACNA1C, SYNE1, ODZ4, and TRANK1. Additional studies have begun to examine the biology of these genes and how risk variants influence aspects of brain and behavior that underlie BPD. For example, carriers of the CACNA1C risk variant have been found to exhibit hippocampal and anterior cingulate dysfunction during episodic memory recall. This work has shed additional light on the relationship of bipolar susceptibility variants to other disorders, particularly schizophrenia. Even larger BPD GWAS are expected with samples now amassed of 21,035 cases and 28,758 controls. Studies have examined the pharmacogenomics of BPD with studies of lithium response, yielding high profile results that remain to be confirmed. The next frontier in the field is the identification of rare bipolar susceptibility variants through large-scale DNA sequencing. While only a couple of papers have been published to date, many studies are underway. The Bipolar Sequencing Consortium has been formed to bring together all of the groups working in this area, and to perform meta-analyses of the data generated. The consortium, with 13 member groups, now has exome data on ~3,500 cases and ~5,000 controls, and on ~162 families. The focus will likely shift within several years from exome data to whole genome data as costs of obtaining such data continue to drop. Gene-mapping studies are now providing clear results that provide insights into the pathophysiology of the disorder. Sequencing studies should extend this process further. Findings could eventually set the stage for rational therapeutic development. |
| Abstract | Bipolar disorder and schizophrenia are two often severe disorders with high heritabilities. Recent studies have demonstrated a large overlap of genetic risk loci between these disorders but diagnostic and molecular distinctions still remain. Here, we perform a combined genome-wide association study (GWAS) of 19?779 bipolar disorder (BP) and schizophrenia (SCZ) cases versus 19?423 controls, in addition to a direct comparison GWAS of 7129 SCZ cases versus 9252 BP cases. In our case-control analysis, we identify five previously identified regions reaching genome-wide significance (CACNA1C, IFI44L, MHC, TRANK1 and MAD1L1) and a novel locus near PIK3C2A. We create a polygenic risk score that is significantly different between BP and SCZ and show a significant correlation between a BP polygenic risk score and the clinical dimension of mania in SCZ patients. Our results indicate that first, combining diseases with similar genetic risk profiles improves power to detect shared risk loci and second, that future direct comparisons of BP and SCZ are likely to identify loci with significant differential effects. Identifying these loci should aid in the fundamental understanding of how these diseases differ biologically. These findings also indicate that combining clinical symptom dimensions and polygenic signatures could provide additional information that may someday be used clinically. |