title: Genetic and Environmental Risk for Chronic Pain and the Contribution of Risk Variants for Major Depressive Disorder: A Family-Based Mixed-Model Analysis.
abstract: Chronic pain is highly prevalent and a significant source of disability, yet its genetic and environmental risk factors are poorly understood. Its relationship with major depressive disorder (MDD) is of particular importance. We sought to test the contribution of genetic factors and shared and unique environment to risk of chronic pain and its correlation with MDD in Generation Scotland: Scottish Family Health Study (GS:SFHS). We then sought to replicate any significant findings in the United Kingdom Biobank study.
  
  
  
  Using family-based mixed-model analyses, we examined the contribution of genetics and shared family environment to chronic pain by spouse, sibling, and household relationships. These analyses were conducted in GS:SFHS (n = 23,960), a family- and population-based study of individuals recruited from the Scottish population through their general practitioners. We then examined and partitioned the correlation between chronic pain and MDD and estimated the contribution of genetic factors and shared environment in GS:SFHS. Finally, we used data from two independent genome-wide association studies to test whether chronic pain has a polygenic architecture and examine whether genomic risk of psychiatric disorder predicted chronic pain and whether genomic risk of chronic pain predicted MDD. These analyses were conducted in GS:SFHS and repeated in UK Biobank, a study of 500,000 from the UK population, of whom 112,151 had genotyping and phenotypic data. Chronic pain is a moderately heritable trait (heritability = 38.4%, 95% CI 33.6% to 43.9%) that is significantly concordant in spouses (variance explained 18.7%, 95% CI 9.5% to 25.1%). Chronic pain is positively correlated with depression (ρ = 0.13, 95% CI 0.11 to 0.15, p = 2.72x10-68) and shows a tendency to cluster within families for genetic reasons (genetic correlation = 0.51, 95%CI 0.40 to 0.62, p = 8.24x10-19). Polygenic risk profiles for pain, generated using independent GWAS data, were associated with chronic pain in both GS:SFHS (maximum β = 6.18x10-2, 95% CI 2.84 x10-2 to 9.35 x10-2, p = 4.3x10-4) and UK Biobank (maximum β = 5.68 x 10-2, 95% CI 4.70x10-2 to 6.65x10-2, p < 3x10-4). Genomic risk of MDD is also significantly associated with chronic pain in both GS:SFHS (maximum β = 6.62x10-2, 95% CI 2.82 x10-2 to 9.76 x10-2, p = 4.3x10-4) and UK Biobank (maximum β = 2.56x10-2, 95% CI 1.62x10-2 to 3.63x10-2, p < 3x10-4). Limitations of the current study include the possibility that spouse effects may be due to assortative mating and the relatively small polygenic risk score effect sizes.
  
  
  
  Genetic factors, as well as chronic pain in a partner or spouse, contribute substantially to the risk of chronic pain for an individual. Chronic pain is genetically correlated with MDD, has a polygenic architecture, and is associated with polygenic risk of MDD.
authors.affiliation: Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, United Kingdom.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: McIntosh
authors.affiliation: Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, United Kingdom.
authors.forename: Lynsey S
authors.identifier: 0000-0002-0624-5303
authors.initials: LS
authors.lastname: Hall
authors.affiliation: Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, United Kingdom.
authors.forename: Yanni
authors.initials: Y
authors.lastname: Zeng
authors.affiliation: Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, United Kingdom.
authors.forename: Mark J
authors.identifier: 0000-0002-3599-6018
authors.initials: MJ
authors.lastname: Adams
authors.affiliation: Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, United Kingdom.
authors.forename: Jude
authors.identifier: 0000-0002-3745-8360
authors.initials: J
authors.lastname: Gibson
authors.affiliation: Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, United Kingdom.
authors.forename: Eleanor
authors.identifier: 0000-0003-0864-9990
authors.initials: E
authors.lastname: Wigmore
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.|Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Saskia P
authors.identifier: 0000-0001-9697-8596
authors.initials: SP
authors.lastname: Hagenaars
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.|Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Gail
authors.initials: G
authors.lastname: Davies
authors.affiliation: Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, United Kingdom.
authors.forename: Ana Maria
authors.identifier: 0000-0002-9543-6362
authors.initials: AM
authors.lastname: Fernandez-Pujals
authors.affiliation: Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Archie I
authors.identifier: 0000-0003-0198-5078
authors.initials: AI
authors.lastname: Campbell
authors.affiliation: Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, United Kingdom.
authors.forename: Toni-Kim
authors.initials: TK
authors.lastname: Clarke
authors.affiliation: Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Caroline
authors.initials: C
authors.lastname: Hayward
authors.affiliation: Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: Chris S
authors.initials: CS
authors.lastname: Haley
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.|Institute for Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, United Kingdom.|Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.affiliation: Institute of Health and Wellbeing, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Smith
authors.affiliation: Institute of Health and Wellbeing, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Barbara I
authors.identifier: 0000-0001-5639-0130
authors.initials: BI
authors.lastname: Nicholl
authors.affiliation: 23andMe Inc., Mountain View, California, United States of America.
authors.forename: David A
authors.initials: DA
authors.lastname: Hinds
authors.affiliation: Pfizer WRD, Human Genetics and Computational Biomedicine, Granta Park, Cambridge, United Kingdom.
authors.forename: Amy V
authors.initials: AV
authors.lastname: Jones
authors.affiliation: Pfizer WRD, Human Genetics and Computational Biomedicine, Granta Park, Cambridge, United Kingdom.
authors.forename: Serena
authors.initials: S
authors.lastname: Scollen
authors.affiliation: Division of Population Health Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom.
authors.forename: Weihua
authors.initials: W
authors.lastname: Meng
authors.affiliation: Division of Population Health Sciences, University of Dundee, Ninewells Hospital and Medical School, Dundee, United Kingdom.
authors.forename: Blair H
authors.identifier: 0000-0002-5362-9430
authors.initials: BH
authors.lastname: Smith
authors.affiliation: The Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom.
authors.forename: Lynne J
authors.initials: LJ
authors.lastname: Hocking
mesh_terms: D000328:Adult; D000368:Aged; D059350:Chronic Pain / Q000150:complications / Q000209:etiology* / Q000235:genetics; D003865:Major Depressive Disorder / Q000150:complications / Q000209:etiology* / Q000235:genetics; D005190:Family; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance; D010375:Pedigree; D012307:Risk Factors; D012931:Social Environment; D011795:Surveys and Questionnaires; D006113:United Kingdom