Identification of novel common variants associated with chronic pain using conditional false discovery rate analysis with major depressive disorder and assessment of pleiotropic effects of LRFN5

Johnston, K. J.A., Adams, M. J., Nicholl, B. I. , Ward, J., Strawbridge, R. , McIntosh, A., Smith, D. J. and Bailey, M. E.S. (2019) Identification of novel common variants associated with chronic pain using conditional false discovery rate analysis with major depressive disorder and assessment of pleiotropic effects of LRFN5. Translational Psychiatry, 9, 310. (doi: 10.1038/s41398-019-0613-4) (PMID:31748543) (PMCID:PMC6868167)

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Abstract

Chronic pain is a complex trait that is moderately heritable and genetically, as well as phenotypically, correlated with major depressive disorder (MDD). Use of the conditional false discovery rate (cFDR) approach, which leverages pleiotropy identified from existing GWAS outputs, has been successful in discovering novel associated variants in related phenotypes. Here, genome-wide association study outputs for both von Korff chronic pain grade and for MDD were used to identify variants meeting a cFDR threshold for each outcome phenotype separately, as well as a conjunctional cFDR (ccFDR) threshold for both phenotypes together. Using a moderately conservative threshold, we identified a total of 11 novel single nucleotide polymorphisms (SNPs), six of which were associated with chronic pain grade and nine of which were associated with MDD. Four SNPs on chromosome 14 were associated with both chronic pain grade and MDD. SNPs associated only with chronic pain grade were located within SLC16A7 on chromosome 12. SNPs associated only with MDD were located either in a gene-dense region on chromosome 1 harbouring LINC01360, LRRIQ3, FPGT and FPGT-TNNI3K, or within/close to LRFN5 on chromosome 14. The SNPs associated with both outcomes were also located within LRFN5. Several of the SNPs on chromosomes 1 and 14 were identified as being associated with expression levels of nearby genes in the brain and central nervous system. Overall, using the cFDR approach, we identified several novel genetic loci associated with chronic pain and we describe likely pleiotropic effects of a recently identified MDD locus on chronic pain.

Item Type:Articles
Additional Information:R.J.S. is supported by a UKRI Innovation- HDR-UK Fellowship (MR/S003061/1). J.W. is supported by the JMAS Sim Fellowship for depression research from the Royal College of Physicians of Edinburgh (173558). K.J.A.J. is supported by an MRC Doctoral Training Programme Studentship at the Universities of Glasgow and Edinburgh (MR/N013166/1). D.J.S. acknowledges the support of the Brain and Behaviour Research Foundation (Independent Investigator Award 1930), a Lister Prize Fellowship (173096) and the MRC Mental Health Data Pathfinder Award (MC_PC_17217). M.J.A. and A.M.M. are supported by Pathfinder Award MC_PC_17209 and by Wellcome Trust Grant 104036/Z/14/Z.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Smith, Professor Daniel and Nicholl, Dr Barbara and Bailey, Dr Mark and Ward, Mr Joey and Johnston, Ms Keira and Strawbridge, Dr Rona
Authors: Johnston, K. J.A., Adams, M. J., Nicholl, B. I., Ward, J., Strawbridge, R., McIntosh, A., Smith, D. J., and Bailey, M. E.S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Public Health
College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Translational Psychiatry
Publisher:Nature Publishing Group
ISSN:2158-3188
ISSN (Online):2158-3188
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Translational Psychiatry 9:310
Publisher Policy:Reproduced under a Creative Commons license

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
3040050MRC Precision Medicine Training GrantMorven BarlassMedical Research Council (MRC)MR/N013166/1-LGH/MS/MED25CAMS - Cardiovascular Science