Identification of novel genome-wide associations for suicidality in UK Biobank, genetic correlation with psychiatric disorders and polygenic association with completed suicide

Rona J Strawbridge, Joey Ward, Amy Ferguson, Nicholas Graham, Richard J Shaw, Breda Cullen, Robert Pearsall, Laura M Lyall, Keira J A Johnston, Claire L Niedzwiedz, Jill P Pell, Daniel Mackay, Julie Langan Martin, Donald M Lyall, Mark E S Bailey, Daniel J Smith, Rona J Strawbridge, Joey Ward, Amy Ferguson, Nicholas Graham, Richard J Shaw, Breda Cullen, Robert Pearsall, Laura M Lyall, Keira J A Johnston, Claire L Niedzwiedz, Jill P Pell, Daniel Mackay, Julie Langan Martin, Donald M Lyall, Mark E S Bailey, Daniel J Smith

Abstract

Background: Suicide is a major issue for global public health. Suicidality describes a broad spectrum of thoughts and behaviours, some of which are common in the general population. Although suicide results from a complex interaction of multiple social and psychological factors, predisposition to suicidality is at least partly genetic.

Methods: Ordinal genome-wide association study of suicidality in the UK Biobank cohort comparing: 'no suicidality' controls (N = 83,557); 'thoughts that life was not worth living' (N = 21,063); 'ever contemplated self-harm' (N = 13,038); 'act of deliberate self-harm in the past' (N = 2498); and 'previous suicide attempt' (N = 2666).

Outcomes: We identified three novel genome-wide significant loci for suicidality (on chromosomes nine, 11 and 13) and moderate-to-strong genetic correlations between suicidality and a range of psychiatric disorders, most notably depression (rg 0·81).

Interpretation: These findings provide new information about genetic variants relating to increased risk of suicidal thoughts and behaviours. Future work should assess the extent to which polygenic risk scores for suicidality, in combination with non-genetic risk factors, may be useful for stratified approaches to suicide prevention at a population level. FUND: UKRI Innovation-HDR-UK Fellowship (MR/S003061/1). MRC Mental Health Data Pathfinder Award (MC_PC_17217). MRC Doctoral Training Programme Studentship at the University of Glasgow (MR/K501335/1). MRC Doctoral Training Programme Studentship at the Universities of Glasgow and Edinburgh. UKRI Innovation Fellowship (MR/R024774/1).

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
Manhattan plot of GWAS of ordinal suicidality in UK Biobank (N = 122,935): A) adjusted for age, sex, genotyping chip and population structure, B) adjusted for age, sex, genotyping chip, population structure and psychiatric disorders. Dashed red line = genome wide significance threshold. Inset: QQ plot for genome-wide association with ordinal suicidality. Red line = theoretical distribution under the null hypothesis of no association. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 2
Fig. 2
Regional plots for GWAS significant loci and CNTN5 tissue expression: A) ZCCHC7 locus on Chr9, B) CNTN5 locus on Chr11, C) Chr13 locus, where: SNPs (each point) are aligned according to position (X axis) and strength of association (Y Axis, left); Purple colouring indicates the index SNP, with other colours representing linkage disequilibrium (r2) with the index SNP, as per the colour key; Recombination rate is presented as a pale blue line graph in the background (Y axis, right); Genes are presented below the association plot by location (X axis) and direction of transcription (arrows). D) Tissue expression profile of CNTN5, where tissues are arranged alphabetically along the X-axis and expression level is (TPM; standardised transcripts per million reads) provided on the Y-axis. Box plots represent median and interquartile range, with error bars demonstrating 1.5× the interquartile range and dots representing outliers. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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