Polygenic Liability and Recurrence of Depression in Patients With First-Onset Depression Treated in Hospital-Based Settings | Depressive Disorders | JAMA Psychiatry | JAMA Network
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Figure.  Relative and Absolute Risks of Recurrent Depressive Episode by Polygenic Risk Score (PRS)
Relative and Absolute Risks of Recurrent Depressive Episode by Polygenic Risk Score (PRS)

A, Hazard ratios (HRs) represent the increase in the hazard of experiencing at least 1 recurrent depressive episode during the 20-year follow-up period per 1-SD increase in PRSs for major depression (PRS-MD), bipolar disorder (PRS-BD), schizophrenia (PRS-SZ), and attention-deficit/hyperactivity disorder (PRS-AD). HRs that were not mutually adjusted were obtained from Cox regression models adjusted for the first 5 ancestral principal components and sex, and stratified by genotyping wave to control for batch effects. Mutually adjusted HRs were obtained from Cox regression models including all covariates listed above as well as the other 4 PRS variables. B, The probability of recurrence as a function of time since the end date of the first depression episode, P(t), at a given PRS level was obtained using the Nelson-Aalen estimator C(t) and calculated as P(t) = 1 − exp(−C[t] × exp[PRS × β]), where β is estimated in the Cox regression model.

Table.  Sample Characteristics for Patients With Major Depression With and Without Recurrent Episodes
Sample Characteristics for Patients With Major Depression With and Without Recurrent Episodes
1.
Sullivan  PF, Neale  MC, Kendler  KS.  Genetic epidemiology of major depression: review and meta-analysis.   Am J Psychiatry. 2000;157(10):1552-1562. doi:10.1176/appi.ajp.157.10.1552PubMedGoogle ScholarCrossref
2.
Wray  NR, Ripke  S, Mattheisen  M,  et al; eQTLGen; 23andMe; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium.  Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.   Nat Genet. 2018;50(5):668-681. doi:10.1038/s41588-018-0090-3PubMedGoogle ScholarCrossref
3.
Pedersen  CB, Bybjerg-Grauholm  J, Pedersen  MG,  et al.  The iPSYCH2012 case-cohort sample: new directions for unravelling genetic and environmental architectures of severe mental disorders.   Mol Psychiatry. 2018;23(1):6-14. doi:10.1038/mp.2017.196PubMedGoogle ScholarCrossref
4.
Vilhjálmsson  BJ, Yang  J, Finucane  HK,  et al; Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study.  Modeling linkage disequilibrium increases accuracy of polygenic risk scores.   Am J Hum Genet. 2015;97(4):576-592. doi:10.1016/j.ajhg.2015.09.001PubMedGoogle ScholarCrossref
5.
Kessing  LV, Andersen  PK, Mortensen  PB, Bolwig  TG.  Recurrence in affective disorder. I. case register study.   Br J Psychiatry. 1998;172:23-28. doi:10.1192/bjp.172.1.23PubMedGoogle ScholarCrossref
6.
Musliner  KL, Krebs  MD, Albiñana  C,  et al.  Polygenic risk and progression to bipolar or psychotic disorders among individuals diagnosed with unipolar depression in early life.   Am J Psychiatry. 2020;177(10):936-943. doi:10.1176/appi.ajp.2020.19111195PubMedGoogle ScholarCrossref
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    Research Letter
    May 12, 2021

    Polygenic Liability and Recurrence of Depression in Patients With First-Onset Depression Treated in Hospital-Based Settings

    Author Affiliations
    • 1National Centre for Register-Based Research, Department of Economics and Business Economics, Aarhus University, Aarhus, Denmark
    • 2The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark
    • 3Centre for Integrated Register-Based Research at Aarhus University (CIRRAU), Aarhus, Denmark
    • 4Department of Biomedicine, Aarhus University, Aarhus, Denmark
    • 5Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
    • 6Department of Affective Disorders, Aarhus University Hospital-Psychiatry, Aarhus, Denmark
    JAMA Psychiatry. 2021;78(7):792-795. doi:10.1001/jamapsychiatry.2021.0701

    Risk of major depression (MD) is determined partly by genetic factors, and evidence from family studies suggests that individuals who experience recurrent MD might have a higher genetic loading.1 Studies have demonstrated that MD is polygenic, meaning multiple genetic variants contribute to risk of MD.2 Wray et al2 found an association between polygenic liability for MD and odds of recurrent MD vs single-episode MD; however, to our knowledge, no study has examined whether polygenic risk scores (PRSs) can prospectively predict recurrence among individuals with first-onset depression. Furthermore, to our knowledge, no study has evaluated whether PRS could potentially be useful for predicting recurrence in a clinical setting. Therefore, our goal was to examine whether higher PRS for MD (PRS-MD) was associated with increased risk of recurrence in individuals diagnosed with unipolar depression in hospital-based settings and to estimate the absolute risk of recurrence based on polygenic risk. As a secondary goal, we examined the specificity of the association between PRS-MD and recurrence by assessing whether PRS for bipolar disorder (PRS-BD), schizophrenia (PRS-SZ), and attention-deficit/hyperactivity disorder (PRS-AD) were also associated with increased risk of recurrence.

    Methods

    Data were drawn from the iPSYCH2012 case-cohort sample3 (eMethods in the Supplement). The study sample consisted of 16 180 individuals with no prior bipolar or schizophrenia spectrum diagnoses who were diagnosed with a single depressive episode (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10], code F32) and aged 10 to 32 years in inpatient, outpatient, or emergency department settings in publicly funded psychiatric hospitals in Denmark from January 1, 1995, to December 31, 2016. Data were analyzed from September 2019 to November 2020. PRS variables were calculated using LDpred version 1.4 A subsequent depression diagnosis was defined as a recurrent episode if it occurred at least 8 weeks after the end date of the first contact5; thus follow-up began 57 days after the end of the first depression episode and ended at the date of contact of the second depression episode (ICD-10 codes F32 or F33), death, emigration, or December 31, 2016, whichever came first. Hazard ratios and absolute risks were estimated using Cox regression, with 2-tailed significance set at P < .05. Models were adjusted for sex and the first 5 ancestral principal components, and stratified by genotyping wave to control for batch effects. This study was approved by the Danish Data Protection Agency. In Denmark, informed consent is not required for register-based studies.

    Results

    Of 16 180 individuals, 11 044 (68.3%) were female. The mean (SD) age at first depression diagnoses was 19.1 (4.1) years. Sample characteristics are shown in the Table. Follow-up ranged from 1 day to 20 years, with a median (interquartile range) of 5.6 (3.4-8.4) years. Among patients who experienced a recurrent episode, time to recurrence ranged from 2 months to 17 years. Probabilities of recurrence at 2, 5, 10, 15, and 20 years following the first depression diagnosis were 16.5% (95% CI, 15.9-17.0), 24.0% (95% CI, 23.4-24.7), 31.7% (95% CI, 30.9-32.6), 35.8% (95% CI, 34.5-37.1), and 37.9% (95% CI, 35.1-40.8), respectively.

    The Figure shows the relative and absolute risks of recurrence by PRS. There was a significant association between PRS-MD and hazard of recurrence, which persisted after controlling for the other PRSs (adjusted hazard ratio per 1-SD increase, 1.07; 95% CI, 1.04-1.10; P < .001) (Figure, A). None of the other PRSs were associated with recurrence. The absolute risk of recurrence across the follow-up period, stratified by PRS-MD, is illustrated in Figure, B. After 20 years, an individual with PRS-MD 2 SDs below the mean had a 34.4% (95% CI, 31.4-37.6) risk of recurrence, while an individual 2 SDs above the mean had a 41.6% (95% CI, 38.2-45.2) risk of recurrence.

    Discussion

    This population-based cohort study found that higher polygenic liability for MD was associated with increased risk of recurrent depressive episodes. These results are consistent with prior studies1,2 and lend support to the hypothesis that individuals with recurrent depression may have, on average, a higher genetic loading than individuals with a single episode of depression. This association appears to be specific to PRS-MD, as we found no evidence that polygenic liability for other psychiatric disorders was associated with recurrence risk.6 These results may not be generalizable outside of Denmark or to patients with MD who do not receive hospital-based care. Further research is needed to determine if PRS-MD can inform clinical practice.

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    Article Information

    Accepted for Publication: March 10, 2021.

    Published Online: May 12, 2021. doi:10.1001/jamapsychiatry.2021.0701

    Corresponding Author: Katherine L. Musliner, MPH, PhD, National Centre for Register-based Research, Department of Economics and Business Economics, Aarhus University, Fuglesangs Alle 26, Bldg R, Room 235, 8210 Aarhus V, Denmark (klm@econ.au.dk).

    Author Contributions: Dr Musliner had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Musliner, Agerbo, Østergaard.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Musliner, Agerbo.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Musliner, Agerbo, Vilhjálmsson, Albiñana.

    Obtained funding: Musliner, Mortensen.

    Administrative, technical, or material support: Agerbo, Mortensen.

    Supervision: Agerbo, Vilhjálmsson, Østergaard.

    Conflict of Interest Disclosures: Dr Musliner reports grants from the Lundbeck Foundation during the conduct of the study. Dr Østergaard reports grants from the Lundbeck Foundation, the Novo Nordisk Foundation, the Independent Research Fund Denmark, and the Danish Cancer Society during the conduct of the study. No other disclosures were reported.

    Funding/Support: This study was funded by postdoctoral fellowship grant 303-2018-3551 from the Lundbeck Foundation. The iPSYCH2012 sample was funded by grants R102-A9118 and R155-2014-1724 from the Lundbeck Foundation. Genotyping of the iPSYCH2012 sample was conducted by the Broad Institute and supported by grants from the Lundbeck Foundation, the Stanley Foundation, grant SFARI 311789 from the Simons Foundation, and grant NIMH 5U01MH094432-02 from the National Institutes of Mental Health. Dr Østergaard is supported by grants NNF20SA0062874 from the Novo Nordisk Foundation, R358-2020-2341 and R344-2020-1073 from the Lundbeck Foundation, R283-A16461 from the Danish Cancer Society, and 7016-00048B from the Independent Research Fund Denmark.

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Additional Contributions: We thank the Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium, the Schizophrenia Working Group of the Psychiatric Genomics Consortium, and the Attention Deficit Hyperactivity Working Group of the Psychiatric Genomics Consortium for providing the summary statistics used to calculate the polygenic risk scores. We also thank the principal investigators of the iPSYCH project, Anders Børglum, MD, PhD, Department of Biomedicine, Aarhus University, Aarhus, Denmark; David Hougaard, DrMedSci, Department for Congenital Disorders, Danish Center for Neonatal Screening, Statens Serum Institute, Copenhagen, Denmark; Ole Mors, MD, Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark; Merete Nordentoft, PhD, Department of Clinical Medicine, Copenhagen Research Center for Mental Health, Copenhagen University Hospital Copenhagen, Denmark; and Thomas Werge, PhD, Institute of Biological Psychiatry, Mental Health Center Sct. Hans, Mental Health Services, Roskilde, Denmark. These individuals were not compensated for their contributions to this project.

    References
    1.
    Sullivan  PF, Neale  MC, Kendler  KS.  Genetic epidemiology of major depression: review and meta-analysis.   Am J Psychiatry. 2000;157(10):1552-1562. doi:10.1176/appi.ajp.157.10.1552PubMedGoogle ScholarCrossref
    2.
    Wray  NR, Ripke  S, Mattheisen  M,  et al; eQTLGen; 23andMe; Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium.  Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression.   Nat Genet. 2018;50(5):668-681. doi:10.1038/s41588-018-0090-3PubMedGoogle ScholarCrossref
    3.
    Pedersen  CB, Bybjerg-Grauholm  J, Pedersen  MG,  et al.  The iPSYCH2012 case-cohort sample: new directions for unravelling genetic and environmental architectures of severe mental disorders.   Mol Psychiatry. 2018;23(1):6-14. doi:10.1038/mp.2017.196PubMedGoogle ScholarCrossref
    4.
    Vilhjálmsson  BJ, Yang  J, Finucane  HK,  et al; Schizophrenia Working Group of the Psychiatric Genomics Consortium, Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) study.  Modeling linkage disequilibrium increases accuracy of polygenic risk scores.   Am J Hum Genet. 2015;97(4):576-592. doi:10.1016/j.ajhg.2015.09.001PubMedGoogle ScholarCrossref
    5.
    Kessing  LV, Andersen  PK, Mortensen  PB, Bolwig  TG.  Recurrence in affective disorder. I. case register study.   Br J Psychiatry. 1998;172:23-28. doi:10.1192/bjp.172.1.23PubMedGoogle ScholarCrossref
    6.
    Musliner  KL, Krebs  MD, Albiñana  C,  et al.  Polygenic risk and progression to bipolar or psychotic disorders among individuals diagnosed with unipolar depression in early life.   Am J Psychiatry. 2020;177(10):936-943. doi:10.1176/appi.ajp.2020.19111195PubMedGoogle ScholarCrossref
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