Polygenic Scores and Onset of Major Mood or Psychotic Disorders Among Offspring of Affected Parents

Alyson Zwicker; Janice M Fullerton; Niamh Mullins; Frances Rice; Danella M Hafeman; Neeltje E M van Haren; Nikita Setiaman; John A Merranko; Benjamin I Goldstein; Alessandra G Ferrera; Emma K Stapp; Elena de la Serna; Dolores Moreno; Gisela Sugranyes; Sergio Mas Herrero; Gloria Roberts; Claudio Toma; Peter R Schofield; Howard J Edenberg; Holly C Wilcox; Melvin G McInnis; Victoria Powell; Lukas Propper; Eileen Denovan-Wright; Guy Rouleau; Josefina Castro-Fornieles; Manon H J Hillegers; Boris Birmaher; Anita Thapar; Philip B Mitchell; Cathryn M Lewis; Martin Alda; John I Nurnberger; Rudolf Uher

doi:10.1176/appi.ajp.20220476

Polygenic Scores and Onset of Major Mood or Psychotic Disorders Among Offspring of Affected Parents

Am J Psychiatry. 2023 Apr 1;180(4):285-293. doi: 10.1176/appi.ajp.20220476. Epub 2023 Feb 22.

Authors

Alyson Zwicker¹, Janice M Fullerton¹, Niamh Mullins¹, Frances Rice¹, Danella M Hafeman¹, Neeltje E M van Haren¹, Nikita Setiaman¹, John A Merranko¹, Benjamin I Goldstein¹, Alessandra G Ferrera¹, Emma K Stapp¹, Elena de la Serna¹, Dolores Moreno¹, Gisela Sugranyes¹, Sergio Mas Herrero¹, Gloria Roberts¹, Claudio Toma¹, Peter R Schofield¹, Howard J Edenberg¹, Holly C Wilcox¹, Melvin G McInnis¹, Victoria Powell¹, Lukas Propper¹, Eileen Denovan-Wright¹, Guy Rouleau¹, Josefina Castro-Fornieles¹, Manon H J Hillegers¹, Boris Birmaher¹, Anita Thapar¹, Philip B Mitchell¹, Cathryn M Lewis¹, Martin Alda¹, John I Nurnberger¹, Rudolf Uher¹

Affiliation

¹ Department of Psychiatry (Zwicker, Propper, Denovan-Wright, Alda, Uher) and Department of Pharmacology (Denovan-Wright), Dalhousie University, Halifax, Nova Scotia, Canada; Nova Scotia Health, Halifax (Zwicker, Alda, Uher); Dalhousie Medicine New Brunswick, Saint John, New Brunswick, Canada (Zwicker); Neuroscience Research Australia, Randwick, New South Wales, Australia (Fullerton, Toma, Schofield); School of Medical Sciences, University of New South Wales, Kensington, Australia (Fullerton, Toma, Schofield); Department of Genetics and Genomic Sciences and Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York (Mullins); Wolfson Centre for Young People's Mental Health, Section of Child and Adolescent Psychiatry, Division of Psychological Medicine and Clinical Neurosciences, and MRC Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, U.K. (Rice, Powell, Thapar); Western Psychiatric Hospital, University of Pittsburgh School of Medicine, Pittsburgh (Hafeman, Merranko, Birmaher); Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, the Netherlands (van Haren, Setiaman, Hillegers); Department of Psychiatry, University Medical Center Utrecht Brain Center, Utrecht, the Netherlands (van Haren, Setiaman, Hillegers); Center for Addiction and Mental Health, University of Toronto Faculty of Medicine, Ontario (Goldstein); Department of Psychiatry (Ferrera, Nurnberger) and Stark Neurosciences Research Institute (Nurnberger), Indiana University School of Medicine, Indianapolis; NIMH, Bethesda, Md. (Stapp); Institut d'Investigacions Biomèdiques Agustí Pi i Sunyer (IDIBAPS), Barcelona, Spain (de la Serna, Sugranyes, Castro-Fornieles); Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain (de la Serna, Moreno, Sugranyes, Castro-Fornieles); Department of Child and Adolescent Psychiatry and Psychology, Institute of Neuroscience, Hospital Clinic of Barcelona, Spain (de la Serna, Sugranyes, Castro-Fornieles); Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, Madrid (Moreno); Department of Psychiatry, Universitat de Barcelona, Spain (Herrero); School of Psychiatry, University of New South Wales, Randwick, New South Wales, Australia (Roberts, Mitchell); Centro de Biología Molecular "Severo Ochoa," Universidad Autónoma de Madrid/CSIC, Madrid (Toma); Department of Biochemistry and Molecular Biology, Indiana University, Indianapolis (Edenberg); Department of Psychiatry and Behavioral Sciences, Division of Child Psychiatry and Public Health, Johns Hopkins Medicine, and Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore (Wilcox); Department of Psychiatry, University of Michigan, Ann Arbor (McInnis); IWK Health Centre, Halifax (Propper); Montreal Neurological Institute and Department of Neurology, McGill University, Montreal (Rouleau); Department of Medicine, University of Barcelona, Barcelona, Spain (Castro-Fornieles); Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Lewis).

PMID: 36856707
DOI: 10.1176/appi.ajp.20220476

Abstract

Objective: Family history is an established risk factor for mental illness. The authors sought to investigate whether polygenic scores (PGSs) can complement family history to improve identification of risk for major mood and psychotic disorders.

Methods: Eight cohorts were combined to create a sample of 1,884 participants ages 2-36 years, including 1,339 offspring of parents with mood or psychotic disorders, who were prospectively assessed with diagnostic interviews over an average of 5.1 years. PGSs were constructed for depression, bipolar disorder, anxiety, attention deficit hyperactivity disorder (ADHD), schizophrenia, neuroticism, subjective well-being, p factor, and height (as a negative control). Cox regression was used to test associations between PGSs, family history of major mental illness, and onsets of major mood and psychotic disorders.

Results: There were 435 onsets of major mood and psychotic disorders across follow-up. PGSs for neuroticism (hazard ratio=1.23, 95% CI=1.12-1.36), schizophrenia (hazard ratio=1.15, 95% CI=1.04-1.26), depression (hazard ratio=1.11, 95% CI=1.01-1.22), ADHD (hazard ratio=1.10, 95% CI=1.00-1.21), subjective well-being (hazard ratio=0.90, 95% CI=0.82-0.99), and p factor (hazard ratio=1.14, 95% CI=1.04-1.26) were associated with onsets. After controlling for family history, neuroticism PGS remained significantly positively associated (hazard ratio=1.19, 95% CI=1.08-1.31) and subjective well-being PGS remained significantly negatively associated (hazard ratio=0.89, 95% CI=0.81-0.98) with onsets.

Conclusions: Neuroticism and subjective well-being PGSs capture risk of major mood and psychotic disorders that is independent of family history, whereas PGSs for psychiatric illness provide limited predictive power when family history is known. Neuroticism and subjective well-being PGSs may complement family history in the early identification of persons at elevated risk.

Keywords: Bipolar and Related Disorders; Depressive Disorders; Genetics/Genomics; Major Depressive Disorder; Schizophrenia Spectrum and Other Psychotic Disorders.

Publication types

Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Bipolar Disorder* / diagnosis
Bipolar Disorder* / genetics
Bipolar Disorder* / psychology
Child
Child, Preschool
Humans
Parents
Psychotic Disorders* / diagnosis
Psychotic Disorders* / genetics
Risk Factors
Schizophrenia* / diagnosis
Schizophrenia* / genetics
Young Adult

Abstract

Publication types

MeSH terms

Grants and funding