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Selecting cases of major psychiatric and substance use disorders in Swedish national registries on the basis of clinical features to maximize the strength or specificity of the genetic risk

Molecular Psychiatry volume 28, pages 5195–5205 (2023)Cite this article

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Abstract

We investigate how selection of psychiatric cases by phenotypic criteria can alter the strength and specificity of their genetic risk by examining samples from national Swedish registries for five disorders: major depression (MD, N = 158,557), drug use disorder (DUD, N = 69,841), bipolar disorder (BD, N = 13,530)) ADHD (N = 54,996) and schizophrenia (N = 11,227)). We maximized the family genetic risk score (FGRS) for each disorder and then the specificity of the FGRS in six disorder pairs by univariable and multivariable regression. We use split-half methods to divide our cases for each disorder into deciles for prediction of genetic risk magnitude and quintiles for prediction of specificity by FGRS differences between two disorders. We utilized seven predictor groups: demography/sex, # registrations, site of diagnosis, severity, comorbidity, treatment, and educational/social variables. The ratio of the FGRS in the upper vs two lower deciles from our multivariable prediction model was, in order, DUD – 12.6, MD – 4.9, BD – 4.5, ADHD – 3.3 and schizophrenia 1.4. From the lowest to highest quintile, our measures of genetic specificity increased more than five-fold for i) MD vs. Anxiety Disorders, ii) MD vs BD, iii) MD versus alcohol use disorder (AUD), iv) BD vs schizophrenia and v) DUD vs AUD. This increase was nearly two-fold for ADHD vs DUD. We conclude that the level of genetic liability for our psychiatric disorders could be substantially enriched by selection of cases with our predictors. Specificity of genetic risk could also be substantially impacted by these same predictors.

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Fig. 1: The relationship between the decile of Family-Genetic Risk Score (FGRS) from our multivariable analyses (using a split-half training and test sample) predicting the strength of the genetic risk for, respectively (from upper left to lower right) major depression (MD), drug use disorder (DUD), bipolar disorder (BD), ADHD and schizophrenia (SZ).
Fig. 2: The relationship between the quintile of the Family-Genetic Risk Score (FGRS) difference from our multivariable analyses (using a split-half training and test sample) predicting the difference in genetic risk for, the following six pairs of disorders (from upper left to lower right): Major Depression vs. Anxiety Disorders (MD vs AD), Major Depression vs. Bipolar Disorder (MD vs BD), Major Depression vs. Alcohol Use Disorder (MD vs. AUD), Bipolar Disorder vs Schizophrenia (BD vs SZ), Drug Use Disorder vs. Alcohol Use Disorder (DUD vs AUD) and ADHD vs. Drug Use Disorder.

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KS MD PhD had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Funding

Funding

This project was supported by grants AA023534 and DA030005 from the National Institutes of Health and the Swedish Research Council (2020–01175).

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Authors and Affiliations

  1. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    Kenneth S. Kendler

  2. Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA

    Kenneth S. Kendler

  3. Center for Primary Health Care Research, Lund University, Malmö, Sweden

    Henrik Ohlsson, Jan Sundquist & Kristina Sundquist

  4. Departments of Family Medicine, Community Health and Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, USA

    Jan Sundquist & Kristina Sundquist

  5. Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Jan Sundquist & Kristina Sundquist

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  4. Kristina Sundquist
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Contributions

KSK developed the hypothesis and HO performed the statistical analyses. KSK drafted the manuscript with input from JS, KS, and HO who all reviewed the MS. JS and KS oversaw and kept updated the registry resources needed for these analyses.

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Correspondence to Kenneth S. Kendler.

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Kendler, K.S., Ohlsson, H., Sundquist, J. et al. Selecting cases of major psychiatric and substance use disorders in Swedish national registries on the basis of clinical features to maximize the strength or specificity of the genetic risk. Mol Psychiatry 28, 5195–5205 (2023). https://doi.org/10.1038/s41380-023-02156-2

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