Transdiagnostic risk of mental disorders in offspring of affected parents: a meta-analysis of family high-risk and registry studies

Rudolf Uher; Barbara Pavlova; Joaquim Radua; Umberto Provenzani; Sara Najafi; Lydia Fortea; Maria Ortuño; Anna Nazarova; Nader Perroud; Lena Palaniyappan; Katharina Domschke; Samuele Cortese; Paul D Arnold; Jehannine C Austin; Michael M Vanyukov; Myrna M Weissman; Allan H Young; Manon H J Hillegers; Andrea Danese; Merete Nordentoft; Robin M Murray; Paolo Fusar-Poli

doi:10.1002/wps.21147

Transdiagnostic risk of mental disorders in offspring of affected parents: a meta-analysis of family high-risk and registry studies

World Psychiatry. 2023 Oct;22(3):433-448. doi: 10.1002/wps.21147.

Authors

Rudolf Uher^{1

2}, Barbara Pavlova^{1

2}, Joaquim Radua³, Umberto Provenzani⁴, Sara Najafi^{1

2}, Lydia Fortea³, Maria Ortuño³, Anna Nazarova^{1

2}, Nader Perroud^{5

6}, Lena Palaniyappan^{7

8

9}, Katharina Domschke¹⁰, Samuele Cortese^{11

12

13

14}, Paul D Arnold¹⁵, Jehannine C Austin¹⁶, Michael M Vanyukov¹⁷, Myrna M Weissman^{18

19

20}, Allan H Young²¹, Manon H J Hillegers²², Andrea Danese^{23

24}, Merete Nordentoft^{25

26}, Robin M Murray²⁷, Paolo Fusar-Poli^{4

28

29}

Affiliations

¹ Dalhousie University, Department of Psychiatry, Halifax, NS, Canada.
² Nova Scotia Health Authority, Halifax, NS, Canada.
³ Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBERSAM, Instituto de Salud Carlos III, University of Barcelona, Barcelona, Spain.
⁴ Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.
⁵ Service of Psychiatric Specialties, Department of Psychiatry, University Hospitals of Geneva, Geneva, Switzerland.
⁶ Department of Psychiatry, University of Geneva, Geneva, Switzerland.
⁷ Douglas Mental Health University Institute, Department of Psychiatry, McGill University, Montreal, QB, Canada.
⁸ Robarts Research Institute, Western University, London, ON, Canada.
⁹ Department of Medical Biophysics, Western University, London, ON, Canada.
¹⁰ Department of Psychiatry and Psychotherapy, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
¹¹ School of Psychology, and Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK.
¹² Solent NHS Trust, Southampton, UK.
¹³ Division of Psychiatry and Applied Psychology, University of Nottingham, Nottingham, UK.
¹⁴ Hassenfeld Children's Hospital at NYU Langone, New York, NY, USA.
¹⁵ Mathison Centre for Mental Health Research & Education, University of Calgary, Calgary, AL, Canada.
¹⁶ Departments of Psychiatry and Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
¹⁷ Departments of Pharmaceutical Sciences, Psychiatry, and Human Genetics, University of Pittsburgh, Pittsburgh, PA, USA.
¹⁸ Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
¹⁹ Division of Translational Epidemiology, New York State Psychiatric Institute, New York, NY, USA.
²⁰ Mailman School of Public Health, Columbia University, New York, NY, USA.
²¹ Centre for Affective Disorders, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, UK.
²² Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
²³ Social, Genetic and Developmental Psychiatry Centre and Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
²⁴ National and Specialist CAMHS Clinic for Trauma, Anxiety, and Depression, South London and Maudsley NHS Foundation Trust, London, UK.
²⁵ Copenhagen Research Center for Mental Health, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark.
²⁶ Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
²⁷ Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
²⁸ Early Psychosis: Intervention and Clinical-detection (EPIC) lab, Department of Psychosis Studies, King's College London, London, UK.
²⁹ Outreach and Support in South-London (OASIS) NHS Foundation Trust, South London and Maudsley NHS Foundation Trust, London, UK.

Abstract

The offspring of parents with mental disorders are at increased risk for developing mental disorders themselves. The risk to offspring may extend transdiagnostically to disorders other than those present in the parents. The literature on this topic is vast but mixed. To inform targeted prevention and genetic counseling, we performed a comprehensive, PRISMA 2020-compliant meta-analysis. We systematically searched the literature published up to September 2022 to retrieve original family high-risk and registry studies reporting on the risk of mental disorders in offspring of parents with any type of mental disorder. We performed random-effects meta-analyses of the relative risk (risk ratio, RR) and absolute risk (lifetime, up to the age at assessment) of mental disorders, defined according to the ICD or DSM. Cumulative incidence by offspring age was determined using meta-analytic Kaplan-Meier curves. We measured heterogeneity with the I² statistic, and risk of bias with the Quality In Prognosis Studies (QUIPS) tool. Sensitivity analyses addressed the impact of study design (family high-risk vs. registry) and specific vs. transdiagnostic risks. Transdiagnosticity was appraised with the TRANSD criteria. We identified 211 independent studies that reported data on 3,172,115 offspring of parents with psychotic, bipolar, depressive, disruptive, attention-deficit/hyperactivity, anxiety, substance use, eating, obsessive-compulsive, and borderline personality disorders, and 20,428,575 control offspring. The RR and lifetime risk of developing any mental disorder were 3.0 and 55% in offspring of parents with anxiety disorders; 2.6 and 17% in offspring of those with psychosis; 2.1 and 55% in offspring of those with bipolar disorder; 1.9 and 51% in offspring of those with depressive disorders; and 1.5 and 38% in offspring of those with substance use disorders. The offspring's RR and lifetime risk of developing the same mental disorder diagnosed in their parent were 8.4 and 32% for attention-deficit/hyperactivity disorder; 5.8 and 8% for psychosis; 5.1 and 5% for bipolar disorder; 2.8 and 9% for substance use disorders; 2.3 and 14% for depressive disorders; 2.3 and 1% for eating disorders; and 2.2 and 31% for anxiety disorders. There were 37 significant transdiagnostic associations between parental mental disorders and the RR of developing a different mental disorder in the offspring. In offspring of parents with psychosis, bipolar and depressive disorder, the risk of the same disorder onset emerged at 16, 5 and 6 years, and cumulated to 3%, 19% and 24% by age 18; and to 8%, 36% and 46% by age 28. Heterogeneity ranged from 0 to 0.98, and 96% of studies were at high risk of bias. Sensitivity analyses restricted to prospective family high-risk studies confirmed the pattern of findings with similar RR, but with greater absolute risks compared to analyses of all study types. This study demonstrates at a global, meta-analytic level that offspring of affected parents have strongly elevated RR and lifetime risk of developing any mental disorder as well as the same mental disorder diagnosed in the parent. The transdiagnostic risks suggest that offspring of parents with a range of mental disorders should be considered as candidates for targeted primary prevention.

Keywords: Familial risk; anxiety disorders; bipolar disorder; depression; eating disorders; mental disorders; psychosis; substance use disorders; targeted primary prevention; transdiagnostic risk.