Hostname: page-component-78c5997874-v9fdk Total loading time: 0 Render date: 2024-11-05T02:32:28.780Z Has data issue: false hasContentIssue false
  • English
  • Français

Discriminating bipolar depression from major depressive disorder with polygenic risk scores

Published online by Cambridge University Press:  17 February 2020

David T. Liebers ,
Mehdi Pirooznia ,
Andrea Ganna ,
Fernando S. Goes Open the ORCID record for Fernando S. Goes [Opens in a new window]  and
Bipolar Genome Study (BiGS)
David T. Liebers
Affiliation:
Harvard Medical School, Boston, MA 02115, USA
Mehdi Pirooznia
Affiliation:
Department of Psychiatry and Behavioral Sciences, Johns Hopkins Institute of Medicine, Baltimore, MD 21205, USA
Andrea Ganna
Affiliation:
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Fernando S. Goes*
Affiliation:
Department of Psychiatry and Behavioral Sciences, Johns Hopkins Institute of Medicine, Baltimore, MD 21205, USA
*
Author for correspondence: Fernando S. Goes, E-mail: [email protected]
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Although accurate differentiation between bipolar disorder (BD) and unipolar major depressive disorder (MDD) has important prognostic and therapeutic implications, the distinction is often challenging based on clinical grounds alone. In this study, we tested whether psychiatric polygenic risk scores (PRSs) improve clinically based classification models of BD v. MDD diagnosis.

Methods

Our sample included 843 BD and 930 MDD subjects similarly genotyped and phenotyped using the same standardized interview. We performed multivariate modeling and receiver operating characteristic analysis, testing the incremental effect of PRSs on a baseline model with clinical symptoms and features known to associate with BD compared with MDD status.

Results

We found a strong association between a BD diagnosis and PRSs drawn from BD (R2 = 3.5%, p = 4.94 × 10−12) and schizophrenia (R2 = 3.2%, p = 5.71 × 10−11) genome-wide association meta-analyses. Individuals with top decile BD PRS had a significantly increased risk for BD v. MDD compared with those in the lowest decile (odds ratio 3.39, confidence interval 2.19–5.25). PRSs discriminated BD v. MDD to a degree comparable with many individual symptoms and clinical features previously shown to associate with BD. When compared with the full composite model with all symptoms and clinical features PRSs provided modestly improved discriminatory ability (ΔC = 0.011, p = 6.48 × 10−4).

Conclusions

Our study demonstrates that psychiatric PRSs provide modest independent discrimination between BD and MDD cases, suggesting that PRSs could ultimately have utility in subjects at the extremes of the distribution and/or subjects for whom clinical symptoms are poorly measured or yet to manifest.

Keywords

Bipolar disordergeneticsGWASmajor depressive disordermood disorderspolygenic risk scores
Type
Original Articles
Information
Psychological Medicine , Volume 51 , Issue 9 , July 2021 , pp. 1451 - 1458
Check for updates
Copyright
Copyright © The Author(s) 2020. Published by Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Altshuler, L. L., Post, R. M., Leverich, G. S., Mikalauskas, K., Rosoff, A., & Ackerman, L. (1995). Antidepressant-induced mania and cycle acceleration: A controversy revisited. The American Journal of Psychiatry, 152, 1130–1138.Google ScholarPubMed
Baldessarini, R. J., Faedda, G. L., Offidani, E., Vázquez, G. H., Marangoni, C., Serra, G., & Tondo, L. (2013). Antidepressant-associated mood-switching and transition from unipolar major depression to bipolar disorder: A review. Journal of Affective Disorders, 148, 129–135.CrossRefGoogle ScholarPubMed
Bauer, M., Andreassen, O. A., Geddes, J. R., Vedel Kessing, L., Lewitzka, U., Schulze, T. G., & Vieta, E. (2018). Areas of uncertainties and unmet needs in bipolar disorders: Clinical and research perspectives. The Lancet Psychiatry, 5, 930–939.CrossRefGoogle ScholarPubMed
Chang, C. C., Chow, C. C., Tellier, L. C., Vattikuti, S., Purcell, S. M., & Lee, J. J. (2015). Second-generation PLINK: Rising to the challenge of larger and richer datasets. GigaScience, 4, 7.CrossRefGoogle ScholarPubMed
Das, A. K., Olfson, M., Gameroff, M. J., Pilowsky, D. J., Blanco, C., Feder, A., … Weissman, M. M. (2005). Screening for bipolar disorder in a primary care practice. Journal of the American Medical Association, 293, 956–963.CrossRefGoogle Scholar
Frankland, A., Roberts, G., Holmes-Preston, E., Perich, T., Levy, F., Lenroot, R., … Mitchell, P. B. (2018). Clinical predictors of conversion to bipolar disorder in a prospective longitudinal familial high-risk sample: Focus on depressive features. Psychological Medicine, 48, 1713–1721.CrossRefGoogle Scholar
Gan, Z., Diao, F., Wei, Q., Wu, X., Cheng, M., Guan, N., … Zhang, J. (2011). A predictive model for diagnosing bipolar disorder based on the clinical characteristics of major depressive episodes in Chinese population. Journal of Affective Disorders, 134, 119–125.CrossRefGoogle ScholarPubMed
Howard, D. M., Adams, M. J., Clarke, T.-K., Hafferty, J. D., Gibson, J., Shirali, M., … McIntosh, A. M. (2018). Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nature Neuroscience, 22, 343–352.CrossRefGoogle Scholar
International Consortium on Lithium Genetics (ConLi+Gen), Amare, A. T., Schubert, K. O., Hou, L., Clark, S. R., Papiol, S., … Baune, B. T. (2018). Association of polygenic score for schizophrenia and HLA antigen and inflammation genes with response to lithium in bipolar affective disorder: A genome-wide association study. JAMA Psychiatry, 2018, 75, 65–74.Google ScholarPubMed
Kessler, R. C. (2012). The costs of depression. Psychiatric Clinics of North America, 35, 1–14.CrossRefGoogle ScholarPubMed
Khera, A. V., Chaffin, M., Aragam, K. G., Haas, M. E., Roselli, C., Choi, S. H., … Kathiresan, S. (2018). Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nature Genetics, 50, 1219–1224.CrossRefGoogle ScholarPubMed
Khera, A. V., Chaffin, M., Wade, K. H., Zahid, S., Brancale, J., Xia, R., … Kathiresan, S. (2019). Polygenic prediction of weight and obesity trajectories from birth to adulthood. Cell, 177, 587–596.e9.CrossRefGoogle ScholarPubMed
Lee, A., Mavaddat, N., Wilcox, A. N., Cunningham, A. P., Carver, T., Hartley, S., … Antoniou, A. C. (2019). BOADICEA: A comprehensive breast cancer risk prediction model incorporating genetic and nongenetic risk factors. Genetics in Medicine, 21, 1708–1718.CrossRefGoogle ScholarPubMed
Leonhard, K., Korff, I., & Schulz, H. (1962). Temperament in families with monopolar and bipolar phasic psychoses. Psychiatria et Neurologia, 143, 416–434.CrossRefGoogle ScholarPubMed
Leonpacher, A. K., Liebers, D., Pirooznia, M., Jancic, D., MacKinnon, D. F., Mondimore, F. M., … Goes, F. S. (2015). Distinguishing bipolar from unipolar depression: The importance of clinical symptoms and illness features. Psychological Medicine, 45, 2437–2446.CrossRefGoogle ScholarPubMed
Lish, J. D., Dime-Meenan, S., Whybrow, P. C., Price, R. A., & Hirschfeld, R. M. A. (1994). The National Depressive and Manic-depressive Association (DMDA) survey of bipolar members. Journal of Affective Disorders, 31, 281–294.CrossRefGoogle ScholarPubMed
Martin, A. R., Kanai, M., Kamatani, Y., Okada, Y., Neale, B. M., & Daly, M. J. (2019). Clinical use of current polygenic risk scores may exacerbate health disparities. Nature Genetics, 51, 584–591.CrossRefGoogle ScholarPubMed
Mavaddat, N., Michailidou, K., Dennis, J., Lush, M., Fachal, L., Lee, A., … Easton, D. F. (2019). Polygenic risk scores for prediction of breast cancer and breast cancer subtypes. The American Journal of Human Genetics, 104, 21–34.CrossRefGoogle ScholarPubMed
Mega, J. L., Stitziel, N. O., Smith, J. G., Chasman, D. I., Caulfield, M., Devlin, J. J., … Sabatine, M. S. (2015). Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: An analysis of primary and secondary prevention trials. Lancet, 385, 2264–2271.CrossRefGoogle ScholarPubMed
Mitchell, P. B., Frankland, A., Hadzi-Pavlovic, D., Roberts, G., Corry, J., Wright, A., … Breakspear, M. (2011). Comparison of depressive episodes in bipolar disorder and in major depressive disorder within bipolar disorder pedigrees. British Journal of Psychiatry, 199, 303–309.CrossRefGoogle ScholarPubMed
Nurnberger, J. I., Blehar, M. C., Kaufmann, C. A., York-Cooler, C., Simpson, S. G., Harkavy-Friedman, J., … Reich, T. (1994). Diagnostic interview for genetic studies. Rationale, unique features, and training. NIMH Genetics Initiative. Archives of General Psychiatry, 51, 849–859.CrossRefGoogle ScholarPubMed
Pacchiarotti, I., Bond, D. J., Baldessarini, R. J., Nolen, W. A., Grunze, H., Licht, R. W., … Vieta, E. (2013). The International Society for Bipolar Disorders (ISBD) task force report on antidepressant use in bipolar disorders. American Journal of Psychiatry, 170, 1249–1262.CrossRefGoogle ScholarPubMed
Pardiñas, A. F., Holmans, P., Pocklington, A. J., Escott-Price, V., Ripke, S., Carrera, N., … CRESTAR Consortium. (2018). Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Nature Genetics, 50, 381–389.CrossRefGoogle ScholarPubMed
Purcell, S. M., Wray, N. R., Stone, J. L., Visscher, P. M., O'Donovan, M. C., Sullivan, P. F., … Sklar, P. (2009). Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature, 460, 748–752.Google ScholarPubMed
Regier, D. A., Narrow, W. E., Clarke, D. E., Kraemer, H. C., Kuramoto, S. J., Kuhl, E. A., & Kupfer, D. J. (2013). DSM-5 field trials in the United States and Canada, Part II: Test–retest reliability of selected categorical diagnoses. The American Journal of Psychiatry, 170, 59–70.CrossRefGoogle ScholarPubMed
Sachs, G. S., Nierenberg, A. A., Calabrese, J. R., Marangell, L. B., Wisniewski, S. R., Gyulai, L., … Thase, M. E. (2007). Effectiveness of adjunctive antidepressant treatment for bipolar depression. New England Journal of Medicine, 356, 1711–1722.CrossRefGoogle ScholarPubMed
Schaffer, A., Isometsä, E. T., Tondo, L., Moreno, D. H., Sinyor, M., Kessing, L. V., … Yatham, L. (2015). Epidemiology, neurobiology and pharmacological interventions related to suicide deaths and suicide attempts in bipolar disorder: Part I of a report of the International Society for Bipolar Disorders Task Force on Suicide in Bipolar Disorder. Australian & New Zealand Journal of Psychiatry, 49, 785–802.CrossRefGoogle ScholarPubMed
Seibert, T. M., Fan, C. C., Wang, Y., Zuber, V., Karunamuni, R., Parsons, J. K., … Practical Consortium. (2018). Polygenic hazard score to guide screening for aggressive prostate cancer: Development and validation in large scale cohorts. BMJ, 360, j5757.CrossRefGoogle ScholarPubMed
Shi, J., Potash, J. B., Knowles, J. A., Weissman, M. M., Coryell, W., Scheftner, W. A., … Levinson, D. F. (2011). Genome-wide association study of recurrent early-onset major depressive disorder. Molecular Psychiatry, 16, 193–201.CrossRefGoogle ScholarPubMed
Smith, D. J., & Craddock, N. (2011). Unipolar and bipolar depression: Different or the same? The British Journal of Psychiatry, 199, 272–274.CrossRefGoogle ScholarPubMed
Smith, E. N., Koller, D. L., Panganiban, C., Szelinger, S., Zhang, P., Badner, J. A., … Kelsoe, J. R. (2011). Genome-wide association of bipolar disorder suggests an enrichment of replicable associations in regions near genes. PLoS Genetics, 7, e1002134.Google ScholarPubMed
Stahl, E. A., Breen, G., Forstner, A. J., McQuillin, A., Ripke, S., Trubetskoy, V., … Bipolar Disorder Working Group of the Psychiatric Genomics Consortium. (2019). Genome-wide association study identifies 30 loci associated with bipolar disorder. Nature Genetics, 51, 793–803.CrossRefGoogle ScholarPubMed
Consortium, T. B., Anttila, V., Bulik-Sullivan, B., Finucane, H. K., Walters, R. K., Bras, J., … Neale, B. M. (2018). Analysis of shared heritability in common disorders of the brain. Science, 360, eaap8757.CrossRefGoogle Scholar
Udler, M. S., McCarthy, M. I., Florez, J. C., & Mahajan, A. (2019). Genetic risk scores for diabetes diagnosis and precision medicine. Endocrine Reviews, 40, 1500–1520.CrossRefGoogle ScholarPubMed
Van Meter, A. R., Burke, C., Youngstrom, E. A., Faedda, G. L., & Correll, C. U. (2016). The bipolar prodrome: Meta-analysis of symptom prevalence prior to initial or recurrent mood episodes. Journal of the American Academy of Child & Adolescent Psychiatry, 55, 543–555.CrossRefGoogle ScholarPubMed
Vassos, E., Di Forti, M., Coleman, J., Iyegbe, C., Prata, D., Euesden, J., … Breen, G. (2017). An examination of polygenic score risk prediction in individuals with first-episode psychosis. Biological Psychiatry, 81, 470–477.CrossRefGoogle ScholarPubMed
Vilhjálmsson, B. J., Yang, J., Finucane, H. K., Gusev, A., Lindström, S., Ripke, S., … Price, A. (2015). Modeling linkage disequilibrium increases accuracy of polygenic risk scores. The American Journal of Human Genetics, 97, 576–592.CrossRefGoogle ScholarPubMed
Wells, J. E., & Horwood, L. J. (2004). How accurate is recall of key symptoms of depression? A comparison of recall and longitudinal reports. Psychological Medicine, 34, 1001–1011.CrossRefGoogle ScholarPubMed
Wray, N. R., Goddard, M. E., & Visscher, P. M. (2007). Prediction of individual genetic risk to disease from genome-wide association studies. Genome Research, 17, 1520–1528.CrossRefGoogle ScholarPubMed
Zhang, J.-P., Robinson, D., Yu, J., Gallego, J., Fleischhacker, W. W., Kahn, R. S., … Lencz, T. (2019). Schizophrenia polygenic risk score as a predictor of antipsychotic efficacy in first-episode psychosis. American Journal of Psychiatry, 176, 21–28.CrossRefGoogle ScholarPubMed
Supplementary material: File

Liebers et al. supplementary material

Tables S1 and S2

Download Liebers et al. supplementary material(File)
File 28.6 KB