Identifying Potential Causal Risk Factors for Self-Harm: A Polygenic Risk Scoring and Mendelian Randomisation Approach

Abstract

BackgroundMultiple individual vulnerabilities and traits are phenotypically associated with suicidal and non-suicidal self-harm. However, associations between these risk factors and self-harm are subject to confounding. We implemented genetically informed methods to better identify individual risk factors for self-harm.\n\nMethodsUsing genotype data and online Mental Health Questionnaire responses in the UK Biobank sample (N = 125,925), polygenic risk scores (PRS) were generated to index 24 plausible individual risk factors for self-harm in the following domains: mental health vulnerabilities, substance use phenotypes, cognitive traits, personality traits and physical traits. PRS were entered as predictors in binomial regression models to predict self-harm. Multinomial regressions were used to model suicidal and non-suicidal self-harm. To further probe the causal nature of these relationships, two-sample Mendelian Randomisation (MR) analyses were conducted for significant risk factors identified in PRS analyses.\n\nOutcomesSelf-harm was predicted by PRS indexing six individual risk factors, which are major depressive disorder (MDD), attention deficit/hyperactivity disorder (ADHD), bipolar disorder, schizophrenia, alcohol dependence disorder (ALC) and lifetime cannabis use. Effect sizes ranged from {beta} = 0.044 (95% CI: 0.016 to 0.152) for PRS for lifetime cannabis use, to {beta} = 0.179 (95% CI: 0.152 to 0.207) for PRS for MDD. No systematic distinctions emerged between suicidal and non-suicidal self-harm. In follow-up MR analyses, MDD, ADHD and schizophrenia emerged as plausible causal risk factors for self-harm.\n\nInterpretationAmong a range of potential risk factors leading to self-harm, core predictors were found among psychiatric disorders. In addition to MDD, liabilities for schizophrenia and ADHD increased the risk for self-harm. Detection and treatment of core symptoms of these conditions, such as psychotic or impulsivity symptoms, may benefit self-harming patients.\n\nFundingLim is funded by Kings International Postgraduate Research Scholarship. Dr Pingault is funded by grant MQ16IP16 from MQ: Transforming Mental Health. Dr Coleman is supported by the UK National Institute of Health Research Maudsley Biomedical Research Centre. MRC grant MR/N015746/1 to CML and PFOR. Dr Hagenaars is funded by the Medical Research Council (MR/S0151132). Kylie P. Glanville is funded by the UK Medical Research Council (PhD studentship; grant MR/N015746/1). This paper represents independent research part-funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and Kings College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.\n\nResearch in ContextO_ST_ABSEvidence before this studyC_ST_ABSA search was conducted on PubMed for literature from inception until 1st May 2019 using terms related to suicidal self-harm (SSH) and non-suicidal self-harm (NSSH), as well as polygenic risk scores (PRS), (\"self-harm\"[All Fields] OR \"self-injurious\"[All Fields] OR \"self-mutilation\"[All Fields] OR \"suicide\"[All Fields]) AND (\"polygenic\"[All Fields] OR \"multifactorial inheritance\"[All Fields]). Similar search was done for Mendelian Randomisation (MR), replacing \"multifactorial inheritance\" and \"polygenic\" with \"Mendelian Randomisation/Randomization\". Evidence was included only if the study had used PRS or MR method to predict self-harm phenotypes using risk factors of self-harm. Ten papers for PRS and no paper for MR were identified.\n\nThere were mixed results for PRS studies. PRS for MDD predicted SSH in two studies but not in another two studies. PRS for depressive symptoms predicted SSH but not NSSH. PRS for schizophrenia predicted SSH in one but not in another two studies. PRS for bipolar disorder predicted SSH in one study but did not predict SSH nor NSSH in another two studies.\n\nAdded value of this studyBy using a large population-based sample, we systematically studied individual vulnerabilities and traits that can potentially lead to self-harm, including mental health vulnerabilities, substance use phenotypes, cognitive traits, personality traits and physical traits, summing up to 24 PRS as genetic proxies for 24 risk factors. We conducted MR to strengthen causal inference. We further distinguished non-suicidal self-harm (NSSH) and suicidal self-harm (SSH).\n\nApart from PRS for schizophrenia, MDD and bipolar disorder, novel PRS were also identified to be associated with self-harm, which are PRS for attention-deficit hyperactivity disorder (ADHD), cannabis use and alcohol dependence. A larger sample size allowed us to confirm positive findings from the previously mixed literature regarding the associations between PRS for MDD, bipolar disorder, and schizophrenia with self-harm. Multivariate analyses and MR analyses strengthened the evidence implicating MDD, ADHD and schizophrenia as plausible causal risk factors for self-harm.\n\nImplications of all the available evidenceAmong the 24 risk factors considered, plausible causal risk factors for self-harm were identified among psychiatric conditions. Using PRS and MR methods and a number of complementary analyses provided higher confidence to infer causality and nuanced insights into the aetiology of self-harm. From a clinical perspective, detection and treatment of core symptoms of these conditions, such as psychotic or impulsivity symptoms, may prevent individuals from self-harming.