Genetic liability to major psychiatric disorders contributes to multi-faceted quality of life outcomes in children and adults

Importance Psychiatric disorders can have an immense impact on socioeconomic, physical, and social-psychological facets of life. Psychiatric disorders are also highly heritable. Under a liability threshold model, an important question arises as to what extent genetic liability for psychiatric disorders relates to, and possibly impacts on, different aspects of quality of life in the general population. Objective To characterize the link between psychiatric genetic liability and diverse aspects of quality of life in childhood and adulthood. Design, setting, and participants We used data from two multi-site, population-based cohorts, i.e. preadolescent children in the USA enrolled at age 9-10 years from the Adolescent Brain Cognitive Development (ABCD) study (N=4,645) and white British adults between age 40-69 years from the UK Biobank (UKB) study (N=377,664). Due to the current limitations of our genetic methods, only data from unrelated individuals of European descent could be included. Main outcomes and measures To derive robust measures capturing multiple domains of quality of life in each of the cohorts, we integrated an array of measurements of academic, economic, and physical status, as well as social well-being, in a second-level three-factor confirmatory factor analysis. The genetic liabilities to seven major psychiatric disorders were quantified by a set of polygenic scores (PGSs) derived from the largest genome-wide association studies to date, independent of the target cohorts, of major depressive disorder (MDD, N=142k-173k), anxiety disorders (ANX, N=22k-144k), attention-deficit/hyperactivity disorder (ADHD, N=226k), autism spectrum disorder (ASD, N=55k), schizophrenia (SCZ, N=130k), bipolar disorder (BIP, N=353k-414k), and cannabis use disorder (CUD, N=384k). Using general linear models we assessed associations between PGSs and the estimated latent factors, controlling for age, sex, site, genotyping batch, plate, and genetic ancestry. Results In each cohort, three latent factors indexing distinct but correlated quality of life domains, (1) educational performance and cognition (Edu, in ABCD) / social economic status (SES, in UKB), (2) physical health (Hea), (3) adverse social experience (Adv, in ABCD) / social well-being (Soc, in UKB), were estimated with excellent model fit indices. In addition, a general factor was derived that captured the covariances between the three latent factors (QoL). In the ABCD cohort, ADHD-PGS was significantly associated with Edu (β = -0.13, t = -8.29, p = 1.53e-16), Adv (β = -0.09, t = -5.79, p = 7.81e-09), and general QoL (β = -0.14, t = -8.74, p = 3.37e-18) factors. In the UKB cohort, all examined disorder PGSs were significantly associated with the general QoL latent factor and at least one first-order subdomain, with ADHD-PGS (β = -0.06 ∼ -0.10, t = -29.1 ∼ -52.5, p < 5.91e-186) and MDD-PGS (β = -0.04 ∼ -0.07, t = -23.8 ∼ -36.3, p < 3.63e-125) showing the largest effects. Conclusions and relevance The present study reveals an inverse relationship between psychiatric genetic liabilities and multiple quality of life metrics, with ADHD-associated genetic risk being the main contributor in both children and adults, and MDD additionally showing effects in adults. All effect sizes observed were small, as expected. Understanding potential real-world outcomes of quantitative measures of disorder-related genetic risks in the general population can provide a scientific foundation for societal intervention and policy-making processes, with profound implications for promoting a flourishing society. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research has been conducted using data from UK Biobank (http://www.ukbiobank.ac.uk/), under application 23668. UK Biobank is supported by its founding funders the Wellcome Trust and UK Medical Research Council, as well as the Department of Health, Scottish Government, the Northwest Regional Development Agency, British Heart Foundation and Cancer Research UK. The data from the ABCD Study (https://abcdstudy.org/) were obtained under request 11315. This study is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, U24DA041147. A full list of supporters is available at https://abcdstudy.org/federal-partners/. A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/consortium_members/. ABCD consortium investigators designed and implemented the study and/or provided data but did not participate in the analysis or writing of this report. This work was carried out on the Dutch national e-infrastructure with the support of SURF Cooperative (Grant no. EINF1824). YS is funded by the junior researcher PhD grant from Donders Center for Medical Neuroscience at Radboudumc. ES is funded by a NARSAD Young Investigator from the Brain and Behavior Research Foundation (Grant no. 25034), and a Hypatia Tenure Track Grant (Radboudumc). BF has received educational speaking fees from Medice GmbH. NRM and BF have received funding from the European Community's Horizon 2020 research and innovation programme under grant agreement no. 847879 (PRIME). Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health under Award Number R01MH124851. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Institutional Review Board (IRB) at the University of California, San Diego, approved all aspects of the ABCD Study. The UK Biobank study was conducted under generic approval from the NHS National Research Ethics Service (approval letter dated 17th June 2011, Ref 11/NW/0382). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Data from the ABCD Study is available at the NIMH Data Archive (NDA). The UK Biobank resource is open to all bona fide researchers under request. Genome-wide association summary statistics are publicly available from psychiatric genomics consortium.