Polygenic Scores and Mood Disorder Onsets in the Context of Family History and Early Psychopathology

Kathryn Freeman; Alyson Zwicker; Janice M Fullerton; Danella M Hafeman; Neeltje E M van Haren; John Merranko; Benjamin I Goldstein; Emma K Stapp; Elena de la Serna; Dolores Moreno; Gisela Sugranyes; Sergi Mas; Gloria Roberts; Claudio Toma; Peter R Schofield; Howard J Edenberg; Holly C Wilcox; Melvin G McInnis; Lukas Propper; Barbara Pavlova; Samuel A Stewart; Eileen M Denovan-Wright; Guy A Rouleau; Josefina Castro-Fornieles; Manon H J Hillegers; Boris Birmaher; Philip B Mitchell; Martin Alda; John I Nurnberger; Rudolf Uher

doi:10.1001/jamanetworkopen.2025.5331

Polygenic Scores and Mood Disorder Onsets in the Context of Family History and Early Psychopathology

Kathryn Freeman, Alyson Zwicker, Janice M Fullerton, Danella M Hafeman, Neeltje E M van Haren, John Merranko, Benjamin I Goldstein, Emma K Stapp, Elena de la Serna, Dolores Moreno, Gisela Sugranyes, Sergi Mas, Gloria Roberts, Claudio Toma, Peter R Schofield, Howard J Edenberg, Holly C Wilcox, Melvin G McInnis, Lukas Propper, Barbara PavlovaSamuel A Stewart, Eileen M Denovan-Wright, Guy A Rouleau, Josefina Castro-Fornieles, Manon H J Hillegers, Boris Birmaher, Philip B Mitchell, Martin Alda, John I Nurnberger, Rudolf Uher

Psychiatry

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

IMPORTANCE: Bipolar disorder (BD) and major depressive disorder (MDD) aggregate within families, with risk often first manifesting as early psychopathology, including attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders.

OBJECTIVE: To determine whether polygenic scores (PGS) are associated with mood disorder onset independent of familial high risk for BD (FHR-BD) and early psychopathology.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from 7 prospective cohorts enriched in FHR-BD from Australia, Canada, the Netherlands, Spain, and the US. Participants with FHR-BD, defined as having at least 1 first-degree relative with BD, were compared with participants without FHR for any mood disorder. Participants were repeatedly assessed with variable follow-up intervals from July 1992 to July 2023. Data were analyzed from August 2023 to August 2024.

EXPOSURES: PGS indexed genetic liability for MDD, BD, anxiety, neuroticism, subjective well-being, ADHD, self-regulation, and addiction risk factor. Semistructured diagnostic interviews with relatives established FHR-BD. ADHD or anxiety disorder diagnoses before mood disorder onset constituted early psychopathology.

MAIN OUTCOMES AND MEASURES: The outcome of interest, mood disorder onset, was defined as a consensus-confirmed new diagnosis of MDD or BD. Cox regression examined associations of PGS, FHR-BD, ADHD, and anxiety with mood disorder onset. Kaplan-Meier curves and log-rank tests evaluated the probability of onset by PGS quartile and familial risk status.

RESULTS: A total of 1064 participants (546 [51.3%] female; mean [SD] age at last assessment, 21.7 [5.1] years), including 660 with FHR-BD and 404 without FHR for any mood disorder, were repeatedly assessed for mental disorders. A total of 399 mood disorder onsets occurred over a variable mean (SD) follow-up interval of 6.3 (5.7) years. Multiple PGS were associated with onset after correcting for FHR-BD and early psychopathology, including PGS for ADHD (hazard ratio [HR], 1.19; 95% CI, 1.06-1.34), self-regulation (HR, 1.19; 95% CI, 1.06-1.34), neuroticism (HR, 1.18; 95% CI, 1.06-1.32), MDD (HR, 1.17; 95% CI, 1.04-1.31), addiction risk factor (HR, 1.16; 95% CI, 1.04-1.30), anxiety (HR, 1.15; 95% CI, 1.02-1.28), BD (HR, 1.14; 95% CI, 1.02-1.28), and subjective well-being (HR, 0.89; 95% CI, 0.79-0.99). High PGS for addiction risk factor, anxiety, BD, and MDD were associated with increased probability of onset in the control group. High PGS for ADHD and self-regulation increased rates of onset among participants with FHR-BD. PGS for self-regulation, ADHD, and addiction risk factors showed stronger associations with onsets of BD than MDD.

CONCLUSIONS AND RELEVANCE: In this cohort study, multiple PGS were associated with mood disorder onset independent of family history of BD and premorbid diagnoses of ADHD or anxiety. The association between PGS and mood disorder risk varied depending on family history status.

Original language	English
Article number	e255331
Number of pages	14
Journal	JAMA network open
Volume	8
Issue number	4
DOIs	https://doi.org/10.1001/jamanetworkopen.2025.5331
Publication status	Published - 1 Apr 2025

Keywords

Adult
Anxiety Disorders/genetics
Attention Deficit Disorder with Hyperactivity/genetics
Australia/epidemiology
Bipolar Disorder/genetics
Depressive Disorder, Major/genetics
Female
Genetic Predisposition to Disease
Humans
Male
Middle Aged
Mood Disorders/genetics
Multifactorial Inheritance/genetics
Netherlands/epidemiology
Prospective Studies
Psychopathology
Risk Factors
Young Adult

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Freeman, K., Zwicker, A., Fullerton, J. M., Hafeman, D. M., van Haren, N. E. M., Merranko, J., Goldstein, B. I., Stapp, E. K., de la Serna, E., Moreno, D., Sugranyes, G., Mas, S., Roberts, G., Toma, C., Schofield, P. R., Edenberg, H. J., Wilcox, H. C., McInnis, M. G., Propper, L., ... Uher, R. (2025). Polygenic Scores and Mood Disorder Onsets in the Context of Family History and Early Psychopathology. JAMA network open, 8(4), Article e255331. https://doi.org/10.1001/jamanetworkopen.2025.5331

@article{7d9f2bc3671e4dd399016c9afc6b4a36,

title = "Polygenic Scores and Mood Disorder Onsets in the Context of Family History and Early Psychopathology",

abstract = "IMPORTANCE: Bipolar disorder (BD) and major depressive disorder (MDD) aggregate within families, with risk often first manifesting as early psychopathology, including attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders.OBJECTIVE: To determine whether polygenic scores (PGS) are associated with mood disorder onset independent of familial high risk for BD (FHR-BD) and early psychopathology.DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from 7 prospective cohorts enriched in FHR-BD from Australia, Canada, the Netherlands, Spain, and the US. Participants with FHR-BD, defined as having at least 1 first-degree relative with BD, were compared with participants without FHR for any mood disorder. Participants were repeatedly assessed with variable follow-up intervals from July 1992 to July 2023. Data were analyzed from August 2023 to August 2024.EXPOSURES: PGS indexed genetic liability for MDD, BD, anxiety, neuroticism, subjective well-being, ADHD, self-regulation, and addiction risk factor. Semistructured diagnostic interviews with relatives established FHR-BD. ADHD or anxiety disorder diagnoses before mood disorder onset constituted early psychopathology.MAIN OUTCOMES AND MEASURES: The outcome of interest, mood disorder onset, was defined as a consensus-confirmed new diagnosis of MDD or BD. Cox regression examined associations of PGS, FHR-BD, ADHD, and anxiety with mood disorder onset. Kaplan-Meier curves and log-rank tests evaluated the probability of onset by PGS quartile and familial risk status.RESULTS: A total of 1064 participants (546 [51.3%] female; mean [SD] age at last assessment, 21.7 [5.1] years), including 660 with FHR-BD and 404 without FHR for any mood disorder, were repeatedly assessed for mental disorders. A total of 399 mood disorder onsets occurred over a variable mean (SD) follow-up interval of 6.3 (5.7) years. Multiple PGS were associated with onset after correcting for FHR-BD and early psychopathology, including PGS for ADHD (hazard ratio [HR], 1.19; 95% CI, 1.06-1.34), self-regulation (HR, 1.19; 95% CI, 1.06-1.34), neuroticism (HR, 1.18; 95% CI, 1.06-1.32), MDD (HR, 1.17; 95% CI, 1.04-1.31), addiction risk factor (HR, 1.16; 95% CI, 1.04-1.30), anxiety (HR, 1.15; 95% CI, 1.02-1.28), BD (HR, 1.14; 95% CI, 1.02-1.28), and subjective well-being (HR, 0.89; 95% CI, 0.79-0.99). High PGS for addiction risk factor, anxiety, BD, and MDD were associated with increased probability of onset in the control group. High PGS for ADHD and self-regulation increased rates of onset among participants with FHR-BD. PGS for self-regulation, ADHD, and addiction risk factors showed stronger associations with onsets of BD than MDD.CONCLUSIONS AND RELEVANCE: In this cohort study, multiple PGS were associated with mood disorder onset independent of family history of BD and premorbid diagnoses of ADHD or anxiety. The association between PGS and mood disorder risk varied depending on family history status.",

keywords = "Adult, Anxiety Disorders/genetics, Attention Deficit Disorder with Hyperactivity/genetics, Australia/epidemiology, Bipolar Disorder/genetics, Depressive Disorder, Major/genetics, Female, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mood Disorders/genetics, Multifactorial Inheritance/genetics, Netherlands/epidemiology, Prospective Studies, Psychopathology, Risk Factors, Young Adult",

author = "Kathryn Freeman and Alyson Zwicker and Fullerton, {Janice M} and Hafeman, {Danella M} and {van Haren}, {Neeltje E M} and John Merranko and Goldstein, {Benjamin I} and Stapp, {Emma K} and {de la Serna}, Elena and Dolores Moreno and Gisela Sugranyes and Sergi Mas and Gloria Roberts and Claudio Toma and Schofield, {Peter R} and Edenberg, {Howard J} and Wilcox, {Holly C} and McInnis, {Melvin G} and Lukas Propper and Barbara Pavlova and Stewart, {Samuel A} and Denovan-Wright, {Eileen M} and Rouleau, {Guy A} and Josefina Castro-Fornieles and Hillegers, {Manon H J} and Boris Birmaher and Mitchell, {Philip B} and Martin Alda and Nurnberger, {John I} and Rudolf Uher",

note = "Publisher Copyright: Copyright {\textcopyright} 2025 Freeman K et al.",

year = "2025",

month = apr,

day = "1",

doi = "10.1001/jamanetworkopen.2025.5331",

language = "English",

volume = "8",

number = "4",

}

Freeman, K, Zwicker, A, Fullerton, JM, Hafeman, DM, van Haren, NEM, Merranko, J, Goldstein, BI, Stapp, EK, de la Serna, E, Moreno, D, Sugranyes, G, Mas, S, Roberts, G, Toma, C, Schofield, PR, Edenberg, HJ, Wilcox, HC, McInnis, MG, Propper, L, Pavlova, B, Stewart, SA, Denovan-Wright, EM, Rouleau, GA, Castro-Fornieles, J, Hillegers, MHJ, Birmaher, B, Mitchell, PB, Alda, M, Nurnberger, JI & Uher, R 2025, 'Polygenic Scores and Mood Disorder Onsets in the Context of Family History and Early Psychopathology', JAMA network open, vol. 8, no. 4, e255331. https://doi.org/10.1001/jamanetworkopen.2025.5331

TY - JOUR

T1 - Polygenic Scores and Mood Disorder Onsets in the Context of Family History and Early Psychopathology

AU - Freeman, Kathryn

AU - Zwicker, Alyson

AU - Fullerton, Janice M

AU - Hafeman, Danella M

AU - van Haren, Neeltje E M

AU - Merranko, John

AU - Goldstein, Benjamin I

AU - Stapp, Emma K

AU - de la Serna, Elena

AU - Moreno, Dolores

AU - Sugranyes, Gisela

AU - Mas, Sergi

AU - Roberts, Gloria

AU - Toma, Claudio

AU - Schofield, Peter R

AU - Edenberg, Howard J

AU - Wilcox, Holly C

AU - McInnis, Melvin G

AU - Propper, Lukas

AU - Pavlova, Barbara

AU - Stewart, Samuel A

AU - Denovan-Wright, Eileen M

AU - Rouleau, Guy A

AU - Castro-Fornieles, Josefina

AU - Hillegers, Manon H J

AU - Birmaher, Boris

AU - Mitchell, Philip B

AU - Alda, Martin

AU - Nurnberger, John I

AU - Uher, Rudolf

PY - 2025/4/1

Y1 - 2025/4/1

N2 - IMPORTANCE: Bipolar disorder (BD) and major depressive disorder (MDD) aggregate within families, with risk often first manifesting as early psychopathology, including attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders.OBJECTIVE: To determine whether polygenic scores (PGS) are associated with mood disorder onset independent of familial high risk for BD (FHR-BD) and early psychopathology.DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from 7 prospective cohorts enriched in FHR-BD from Australia, Canada, the Netherlands, Spain, and the US. Participants with FHR-BD, defined as having at least 1 first-degree relative with BD, were compared with participants without FHR for any mood disorder. Participants were repeatedly assessed with variable follow-up intervals from July 1992 to July 2023. Data were analyzed from August 2023 to August 2024.EXPOSURES: PGS indexed genetic liability for MDD, BD, anxiety, neuroticism, subjective well-being, ADHD, self-regulation, and addiction risk factor. Semistructured diagnostic interviews with relatives established FHR-BD. ADHD or anxiety disorder diagnoses before mood disorder onset constituted early psychopathology.MAIN OUTCOMES AND MEASURES: The outcome of interest, mood disorder onset, was defined as a consensus-confirmed new diagnosis of MDD or BD. Cox regression examined associations of PGS, FHR-BD, ADHD, and anxiety with mood disorder onset. Kaplan-Meier curves and log-rank tests evaluated the probability of onset by PGS quartile and familial risk status.RESULTS: A total of 1064 participants (546 [51.3%] female; mean [SD] age at last assessment, 21.7 [5.1] years), including 660 with FHR-BD and 404 without FHR for any mood disorder, were repeatedly assessed for mental disorders. A total of 399 mood disorder onsets occurred over a variable mean (SD) follow-up interval of 6.3 (5.7) years. Multiple PGS were associated with onset after correcting for FHR-BD and early psychopathology, including PGS for ADHD (hazard ratio [HR], 1.19; 95% CI, 1.06-1.34), self-regulation (HR, 1.19; 95% CI, 1.06-1.34), neuroticism (HR, 1.18; 95% CI, 1.06-1.32), MDD (HR, 1.17; 95% CI, 1.04-1.31), addiction risk factor (HR, 1.16; 95% CI, 1.04-1.30), anxiety (HR, 1.15; 95% CI, 1.02-1.28), BD (HR, 1.14; 95% CI, 1.02-1.28), and subjective well-being (HR, 0.89; 95% CI, 0.79-0.99). High PGS for addiction risk factor, anxiety, BD, and MDD were associated with increased probability of onset in the control group. High PGS for ADHD and self-regulation increased rates of onset among participants with FHR-BD. PGS for self-regulation, ADHD, and addiction risk factors showed stronger associations with onsets of BD than MDD.CONCLUSIONS AND RELEVANCE: In this cohort study, multiple PGS were associated with mood disorder onset independent of family history of BD and premorbid diagnoses of ADHD or anxiety. The association between PGS and mood disorder risk varied depending on family history status.

AB - IMPORTANCE: Bipolar disorder (BD) and major depressive disorder (MDD) aggregate within families, with risk often first manifesting as early psychopathology, including attention-deficit/hyperactivity disorder (ADHD) and anxiety disorders.OBJECTIVE: To determine whether polygenic scores (PGS) are associated with mood disorder onset independent of familial high risk for BD (FHR-BD) and early psychopathology.DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from 7 prospective cohorts enriched in FHR-BD from Australia, Canada, the Netherlands, Spain, and the US. Participants with FHR-BD, defined as having at least 1 first-degree relative with BD, were compared with participants without FHR for any mood disorder. Participants were repeatedly assessed with variable follow-up intervals from July 1992 to July 2023. Data were analyzed from August 2023 to August 2024.EXPOSURES: PGS indexed genetic liability for MDD, BD, anxiety, neuroticism, subjective well-being, ADHD, self-regulation, and addiction risk factor. Semistructured diagnostic interviews with relatives established FHR-BD. ADHD or anxiety disorder diagnoses before mood disorder onset constituted early psychopathology.MAIN OUTCOMES AND MEASURES: The outcome of interest, mood disorder onset, was defined as a consensus-confirmed new diagnosis of MDD or BD. Cox regression examined associations of PGS, FHR-BD, ADHD, and anxiety with mood disorder onset. Kaplan-Meier curves and log-rank tests evaluated the probability of onset by PGS quartile and familial risk status.RESULTS: A total of 1064 participants (546 [51.3%] female; mean [SD] age at last assessment, 21.7 [5.1] years), including 660 with FHR-BD and 404 without FHR for any mood disorder, were repeatedly assessed for mental disorders. A total of 399 mood disorder onsets occurred over a variable mean (SD) follow-up interval of 6.3 (5.7) years. Multiple PGS were associated with onset after correcting for FHR-BD and early psychopathology, including PGS for ADHD (hazard ratio [HR], 1.19; 95% CI, 1.06-1.34), self-regulation (HR, 1.19; 95% CI, 1.06-1.34), neuroticism (HR, 1.18; 95% CI, 1.06-1.32), MDD (HR, 1.17; 95% CI, 1.04-1.31), addiction risk factor (HR, 1.16; 95% CI, 1.04-1.30), anxiety (HR, 1.15; 95% CI, 1.02-1.28), BD (HR, 1.14; 95% CI, 1.02-1.28), and subjective well-being (HR, 0.89; 95% CI, 0.79-0.99). High PGS for addiction risk factor, anxiety, BD, and MDD were associated with increased probability of onset in the control group. High PGS for ADHD and self-regulation increased rates of onset among participants with FHR-BD. PGS for self-regulation, ADHD, and addiction risk factors showed stronger associations with onsets of BD than MDD.CONCLUSIONS AND RELEVANCE: In this cohort study, multiple PGS were associated with mood disorder onset independent of family history of BD and premorbid diagnoses of ADHD or anxiety. The association between PGS and mood disorder risk varied depending on family history status.

KW - Adult

KW - Anxiety Disorders/genetics

KW - Attention Deficit Disorder with Hyperactivity/genetics

KW - Australia/epidemiology

KW - Bipolar Disorder/genetics

KW - Depressive Disorder, Major/genetics

KW - Female

KW - Genetic Predisposition to Disease

KW - Humans

KW - Male

KW - Middle Aged

KW - Mood Disorders/genetics

KW - Multifactorial Inheritance/genetics

KW - Netherlands/epidemiology

KW - Prospective Studies

KW - Psychopathology

KW - Risk Factors

KW - Young Adult

U2 - 10.1001/jamanetworkopen.2025.5331

DO - 10.1001/jamanetworkopen.2025.5331

M3 - Article

C2 - 40238098

SN - 2574-3805

VL - 8

JO - JAMA network open

JF - JAMA network open

IS - 4

M1 - e255331

ER -

Polygenic Scores and Mood Disorder Onsets in the Context of Family History and Early Psychopathology

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