Polygenic dissection of diagnosis and clinical dimensions of bipolar disorder and schizophrenia
Open accessAbstract
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.
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Genetic correlation between SCZ and BD is remarkably high (rg = 0.67).
“Given that genetic correlation between SCZ and BD is remarkably high (rg = 0.67)46,53,54, these findings suggest cellular substrates for molecular convergence (Ex7 and In6 are shared between two disorders) and divergence (Ex1 is BD-specific, while Ex2 is SCZ-specific) among two highly genetically correlated disorders.”
From Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders (2021) · cites this paper as [54]
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- Authors
- Ruderfer, D. M., Fanous, A. H., Ripke, S., McQuillin, A., Amdur, R. L., Schizophrenia Working Group of the Psychiatric Genomics Consortium, Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, Cross-Disorder Working Group of the Psychiatric Genomics Consortium, Gejman, P. V., O'Donovan, M. C., Andreassen, O. A., Djurovic, S., Hultman, C. M., Kelsoe, J. R., Jamain, S., Landén, M., Leboyer, M., Nimgaonkar, V, Nurnberger, J., Smoller, J. W., Craddock, N., Corvin, A., Sullivan, P. F., Holmans, P., Sklar, P., & Kendler, K. S.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Georgetown University (US)
- Broad Institute (US)
- University College London (GB)
- Washington DC VA Medical Center (US)
- Endeavor Health (US)
- Oslo University Hospital (NO)
- Karolinska Institutet (SE)
- University of California San Diego (US)
- Inserm (FR)
- University of Pittsburgh (US)
- Trinity College Dublin (IE)
- University of North Carolina at Chapel Hill (US)
- Virginia Commonwealth University (US)
- Corresponding author
- Sklar, P
- Kendler, K S
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2013-11-26
- Volume
- 19
- Issue
- 9
- Pages
- 1017-1024
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC4033708
- OpenAlex
- W1970528899
- Cited by
- 364
- References
- 47
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 17 · 2023: 24 · 2022: 26 · 2021: 22 · 2020: 36 · 2019: 42 · 2018: 50 · 2017: 44 · 2016: 35 · 2015: 24 · 2014: 20
- FWCI
- 18.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Worcester Research and Publications (University of Worcester) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- HAL (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- IUScholarWorks (Indiana University) (submittedVersion)
- Purdue University Indianapolis (Indiana University) (submittedVersion)
- Funders
- National Institutes of Health (5u01mh094432-04)
- National Institute of Mental Health (U01 MH094432, R01MH097276)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Keywords
- bipolar disorder, schizophrenia, polygenic risk score, shared genetic risk loci, CACNA1C, IFI44L, major histocompatibility complex, MAD1L1, PIK3C2A, mania
- MeSH terms
- Bipolar Disorder, Factor Analysis, Statistical, Humans, Nuclear Proteins, Phenotype, Schizophrenia, Schizophrenic Psychology, Odds Ratio, Case-Control Studies, Cell Cycle Proteins, Phosphatidylinositol 3-Kinases, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Calcium Channels, L-Type, Genome-Wide Association Study
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