Association of Polygenic Liabilities for Major Depression, Bipolar Disorder, and Schizophrenia with Risk for Depression in the Danish Population

Katherine L. Musliner; Preben B. Mortensen; John J. McGrath; Nis P. Suppli; David M. Hougaard; Jonas Bybjerg-Grauholm; Marie Bækvad-Hansen; Ole Andreassen; Carsten B. Pedersen; Marianne G. Pedersen; Ole Mors; Merete Nordentoft; Anders D. Børglum; Thomas Werge; Esben Agerbo

doi:10.1001/jamapsychiatry.2018.4166

Association of Polygenic Liabilities for Major Depression, Bipolar Disorder, and Schizophrenia with Risk for Depression in the Danish Population

Katherine L. Musliner^*, Preben B. Mortensen, John J. McGrath, Nis P. Suppli, David M. Hougaard, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Ole Andreassen, Carsten B. Pedersen, Marianne G. Pedersen, Ole Mors, Merete Nordentoft, Anders D. Børglum, Thomas Werge, Esben Agerbo

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin

30 Citationer (Scopus)

Abstract

Importance: Although the usefulness of polygenic risk scores as a measure of genetic liability for major depression (MD) has been established, their association with depression in the general population remains relatively unexplored. Objective: To evaluate whether polygenic risk scores for MD, bipolar disorder (BD), and schizophrenia (SZ) are associated with depression in the general population and explore whether these polygenic liabilities are associated with heterogeneity in terms of age at onset and severity at the initial depression diagnosis. Design, Setting, and Participants: Participants were drawn from the Danish iPSYCH2012 case-cohort study, a representative sample drawn from the population of Denmark born between May 1, 1981, and December 31, 2005. The hazard of depression was estimated using Cox regressions modified to accommodate the case-cohort design. Case-only analyses were conducted using linear and multinomial regressions. The data analysis was conducted from February 2017 to June 2018. Exposures: Polygenic risk scores for MD, BD, and SZ trained using the most recent genome-wide association study results from the Psychiatric Genomics Consortium. Main Outcomes and Measures: The main outcome was first depressive episode (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code F32) treated in hospital-based psychiatric care. Severity at the initial diagnosis was measured using the ICD-10 code severity specifications (mild, moderate, severe without psychosis, and severe with psychosis) and treatment setting (inpatient, outpatient, and emergency). Results: Of 34573 participants aged 10 to 31 years at censoring, 68% of those with depression were female compared with 48.9% of participants without depression. Each SD increase in polygenic liability for MD, BD, and SZ was associated with 30% (hazard ratio [HR], 1.30; 95% CI, 1.27-1.33), 5% (HR, 1.05; 95% CI, 1.02-1.07), and 12% (HR, 1.12; 95% CI, 1.09-1.15) increases in the hazard of depression, respectively. Among cases, a higher polygenic liability for BD was associated with earlier depression onset (β = -.07; SE =.02; P =.002). Conclusions and Relevance: Polygenic liability for MD is associated with first depression in the general population, which supports the idea that these scores tap into an underlying liability for developing the disorder. The fact that polygenic risk for BD and polygenic risk for SZ also were associated with depression is consistent with prior evidence that these disorders share some common genetic overlap. Variations in polygenic liability may contribute slightly to heterogeneity in clinical presentation, but these associations appear minimal.

Originalsprog	Engelsk
Tidsskrift	JAMA Psychiatry
Vol/bind	76
Udgave nummer	5
Sider (fra-til)	516-525
Antal sider	10
ISSN	2168-622X
DOI	https://doi.org/10.1001/jamapsychiatry.2018.4166
Status	Udgivet - 2019

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10.1001/jamapsychiatry.2018.4166

jamapsychiatry_musliner_2019_oi_180103.pdfForlagets udgivne version, 390 KB

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Musliner, K. L., Mortensen, P. B., McGrath, J. J., Suppli, N. P., Hougaard, D. M., Bybjerg-Grauholm, J., Bækvad-Hansen, M., Andreassen, O., Pedersen, C. B., Pedersen, M. G., Mors, O., Nordentoft, M., Børglum, A. D., Werge, T., & Agerbo, E. (2019). Association of Polygenic Liabilities for Major Depression, Bipolar Disorder, and Schizophrenia with Risk for Depression in the Danish Population. JAMA Psychiatry, 76(5), 516-525. https://doi.org/10.1001/jamapsychiatry.2018.4166

Musliner, KL, Mortensen, PB, McGrath, JJ, Suppli, NP, Hougaard, DM, Bybjerg-Grauholm, J, Bækvad-Hansen, M, Andreassen, O, Pedersen, CB, Pedersen, MG, Mors, O, Nordentoft, M, Børglum, AD, Werge, T & Agerbo, E 2019, 'Association of Polygenic Liabilities for Major Depression, Bipolar Disorder, and Schizophrenia with Risk for Depression in the Danish Population', JAMA Psychiatry, bind 76, nr. 5, s. 516-525. https://doi.org/10.1001/jamapsychiatry.2018.4166

@article{2c5b528d074c4a03bd19be3f3c4fe4dc,

title = "Association of Polygenic Liabilities for Major Depression, Bipolar Disorder, and Schizophrenia with Risk for Depression in the Danish Population",

abstract = "Importance: Although the usefulness of polygenic risk scores as a measure of genetic liability for major depression (MD) has been established, their association with depression in the general population remains relatively unexplored. Objective: To evaluate whether polygenic risk scores for MD, bipolar disorder (BD), and schizophrenia (SZ) are associated with depression in the general population and explore whether these polygenic liabilities are associated with heterogeneity in terms of age at onset and severity at the initial depression diagnosis. Design, Setting, and Participants: Participants were drawn from the Danish iPSYCH2012 case-cohort study, a representative sample drawn from the population of Denmark born between May 1, 1981, and December 31, 2005. The hazard of depression was estimated using Cox regressions modified to accommodate the case-cohort design. Case-only analyses were conducted using linear and multinomial regressions. The data analysis was conducted from February 2017 to June 2018. Exposures: Polygenic risk scores for MD, BD, and SZ trained using the most recent genome-wide association study results from the Psychiatric Genomics Consortium. Main Outcomes and Measures: The main outcome was first depressive episode (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code F32) treated in hospital-based psychiatric care. Severity at the initial diagnosis was measured using the ICD-10 code severity specifications (mild, moderate, severe without psychosis, and severe with psychosis) and treatment setting (inpatient, outpatient, and emergency). Results: Of 34573 participants aged 10 to 31 years at censoring, 68% of those with depression were female compared with 48.9% of participants without depression. Each SD increase in polygenic liability for MD, BD, and SZ was associated with 30% (hazard ratio [HR], 1.30; 95% CI, 1.27-1.33), 5% (HR, 1.05; 95% CI, 1.02-1.07), and 12% (HR, 1.12; 95% CI, 1.09-1.15) increases in the hazard of depression, respectively. Among cases, a higher polygenic liability for BD was associated with earlier depression onset (β = -.07; SE =.02; P =.002). Conclusions and Relevance: Polygenic liability for MD is associated with first depression in the general population, which supports the idea that these scores tap into an underlying liability for developing the disorder. The fact that polygenic risk for BD and polygenic risk for SZ also were associated with depression is consistent with prior evidence that these disorders share some common genetic overlap. Variations in polygenic liability may contribute slightly to heterogeneity in clinical presentation, but these associations appear minimal.",

author = "Musliner, {Katherine L.} and Mortensen, {Preben B.} and McGrath, {John J.} and Suppli, {Nis P.} and Hougaard, {David M.} and Jonas Bybjerg-Grauholm and Marie B{\ae}kvad-Hansen and Ole Andreassen and Pedersen, {Carsten B.} and Pedersen, {Marianne G.} and Ole Mors and Merete Nordentoft and B{\o}rglum, {Anders D.} and Thomas Werge and Esben Agerbo",

year = "2019",

doi = "10.1001/jamapsychiatry.2018.4166",

language = "English",

volume = "76",

pages = "516--525",

journal = "JAMA Psychiatry",

issn = "2168-622X",

publisher = "The JAMA Network",

number = "5",

}

TY - JOUR

T1 - Association of Polygenic Liabilities for Major Depression, Bipolar Disorder, and Schizophrenia with Risk for Depression in the Danish Population

AU - Musliner, Katherine L.

AU - Mortensen, Preben B.

AU - McGrath, John J.

AU - Suppli, Nis P.

AU - Hougaard, David M.

AU - Bybjerg-Grauholm, Jonas

AU - Bækvad-Hansen, Marie

AU - Andreassen, Ole

AU - Pedersen, Carsten B.

AU - Pedersen, Marianne G.

AU - Mors, Ole

AU - Nordentoft, Merete

AU - Børglum, Anders D.

AU - Werge, Thomas

AU - Agerbo, Esben

PY - 2019

Y1 - 2019

N2 - Importance: Although the usefulness of polygenic risk scores as a measure of genetic liability for major depression (MD) has been established, their association with depression in the general population remains relatively unexplored. Objective: To evaluate whether polygenic risk scores for MD, bipolar disorder (BD), and schizophrenia (SZ) are associated with depression in the general population and explore whether these polygenic liabilities are associated with heterogeneity in terms of age at onset and severity at the initial depression diagnosis. Design, Setting, and Participants: Participants were drawn from the Danish iPSYCH2012 case-cohort study, a representative sample drawn from the population of Denmark born between May 1, 1981, and December 31, 2005. The hazard of depression was estimated using Cox regressions modified to accommodate the case-cohort design. Case-only analyses were conducted using linear and multinomial regressions. The data analysis was conducted from February 2017 to June 2018. Exposures: Polygenic risk scores for MD, BD, and SZ trained using the most recent genome-wide association study results from the Psychiatric Genomics Consortium. Main Outcomes and Measures: The main outcome was first depressive episode (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code F32) treated in hospital-based psychiatric care. Severity at the initial diagnosis was measured using the ICD-10 code severity specifications (mild, moderate, severe without psychosis, and severe with psychosis) and treatment setting (inpatient, outpatient, and emergency). Results: Of 34573 participants aged 10 to 31 years at censoring, 68% of those with depression were female compared with 48.9% of participants without depression. Each SD increase in polygenic liability for MD, BD, and SZ was associated with 30% (hazard ratio [HR], 1.30; 95% CI, 1.27-1.33), 5% (HR, 1.05; 95% CI, 1.02-1.07), and 12% (HR, 1.12; 95% CI, 1.09-1.15) increases in the hazard of depression, respectively. Among cases, a higher polygenic liability for BD was associated with earlier depression onset (β = -.07; SE =.02; P =.002). Conclusions and Relevance: Polygenic liability for MD is associated with first depression in the general population, which supports the idea that these scores tap into an underlying liability for developing the disorder. The fact that polygenic risk for BD and polygenic risk for SZ also were associated with depression is consistent with prior evidence that these disorders share some common genetic overlap. Variations in polygenic liability may contribute slightly to heterogeneity in clinical presentation, but these associations appear minimal.

AB - Importance: Although the usefulness of polygenic risk scores as a measure of genetic liability for major depression (MD) has been established, their association with depression in the general population remains relatively unexplored. Objective: To evaluate whether polygenic risk scores for MD, bipolar disorder (BD), and schizophrenia (SZ) are associated with depression in the general population and explore whether these polygenic liabilities are associated with heterogeneity in terms of age at onset and severity at the initial depression diagnosis. Design, Setting, and Participants: Participants were drawn from the Danish iPSYCH2012 case-cohort study, a representative sample drawn from the population of Denmark born between May 1, 1981, and December 31, 2005. The hazard of depression was estimated using Cox regressions modified to accommodate the case-cohort design. Case-only analyses were conducted using linear and multinomial regressions. The data analysis was conducted from February 2017 to June 2018. Exposures: Polygenic risk scores for MD, BD, and SZ trained using the most recent genome-wide association study results from the Psychiatric Genomics Consortium. Main Outcomes and Measures: The main outcome was first depressive episode (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] code F32) treated in hospital-based psychiatric care. Severity at the initial diagnosis was measured using the ICD-10 code severity specifications (mild, moderate, severe without psychosis, and severe with psychosis) and treatment setting (inpatient, outpatient, and emergency). Results: Of 34573 participants aged 10 to 31 years at censoring, 68% of those with depression were female compared with 48.9% of participants without depression. Each SD increase in polygenic liability for MD, BD, and SZ was associated with 30% (hazard ratio [HR], 1.30; 95% CI, 1.27-1.33), 5% (HR, 1.05; 95% CI, 1.02-1.07), and 12% (HR, 1.12; 95% CI, 1.09-1.15) increases in the hazard of depression, respectively. Among cases, a higher polygenic liability for BD was associated with earlier depression onset (β = -.07; SE =.02; P =.002). Conclusions and Relevance: Polygenic liability for MD is associated with first depression in the general population, which supports the idea that these scores tap into an underlying liability for developing the disorder. The fact that polygenic risk for BD and polygenic risk for SZ also were associated with depression is consistent with prior evidence that these disorders share some common genetic overlap. Variations in polygenic liability may contribute slightly to heterogeneity in clinical presentation, but these associations appear minimal.

U2 - 10.1001/jamapsychiatry.2018.4166

DO - 10.1001/jamapsychiatry.2018.4166

M3 - Journal article

C2 - 30698613

AN - SCOPUS:85061012249

SN - 2168-622X

VL - 76

SP - 516

EP - 525

JO - JAMA Psychiatry

JF - JAMA Psychiatry

IS - 5

ER -

Association of Polygenic Liabilities for Major Depression, Bipolar Disorder, and Schizophrenia with Risk for Depression in the Danish Population

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