Genetic and Environmental Risk for Chronic Pain and the Contribution of Risk Variants for Major Depressive Disorder: A Family-Based Mixed-Model Analysis

Andrew M McIntosh, Lynsey S Hall, Yanni Zeng, Mark J Adams, Jude Gibson, Eleanor Wigmore, Saskia P Hagenaars, Gail Davies, Ana Maria Fernandez-Pujals, Archie I Campbell, Toni-Kim Clarke, Caroline Hayward, Chris S Haley, David J Porteous, Ian J Deary, Daniel J Smith, Barbara I Nicholl, David A Hinds, Amy V Jones, Serena ScollenWeihua Meng, Blair H Smith, Lynne J Hocking

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Abstract

BACKGROUND: 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.

METHODS AND FINDINGS: 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.

CONCLUSIONS: 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.

Original languageEnglish
Article numbere1002090
JournalPLoS Medicine
Volume13
Issue number8
DOIs
Publication statusPublished - 16 Aug 2016

Fingerprint

Major Depressive Disorder
Chronic Pain
Family Health
Scotland
Spouses
Genome-Wide Association Study
Population
General Practitioners
Psychiatry
Siblings

Keywords

  • Adult
  • Aged
  • Chronic Pain
  • Depressive Disorder, Major
  • Family
  • Female
  • Genome-Wide Association Study
  • Humans
  • Male
  • Middle Aged
  • Multifactorial Inheritance
  • Pedigree
  • Risk Factors
  • Social Environment
  • Surveys and Questionnaires
  • United Kingdom
  • Journal Article

Cite this

Genetic and Environmental Risk for Chronic Pain and the Contribution of Risk Variants for Major Depressive Disorder : A Family-Based Mixed-Model Analysis. / McIntosh, Andrew M; Hall, Lynsey S; Zeng, Yanni; Adams, Mark J; Gibson, Jude; Wigmore, Eleanor; Hagenaars, Saskia P; Davies, Gail; Fernandez-Pujals, Ana Maria; Campbell, Archie I; Clarke, Toni-Kim; Hayward, Caroline; Haley, Chris S; Porteous, David J; Deary, Ian J; Smith, Daniel J; Nicholl, Barbara I; Hinds, David A; Jones, Amy V; Scollen, Serena; Meng, Weihua; Smith, Blair H; Hocking, Lynne J.

In: PLoS Medicine, Vol. 13, No. 8, e1002090, 16.08.2016.

Research output: Contribution to journalArticle

McIntosh, AM, Hall, LS, Zeng, Y, Adams, MJ, Gibson, J, Wigmore, E, Hagenaars, SP, Davies, G, Fernandez-Pujals, AM, Campbell, AI, Clarke, T-K, Hayward, C, Haley, CS, Porteous, DJ, Deary, IJ, Smith, DJ, Nicholl, BI, Hinds, DA, Jones, AV, Scollen, S, Meng, W, Smith, BH & Hocking, LJ 2016, 'Genetic and Environmental Risk for Chronic Pain and the Contribution of Risk Variants for Major Depressive Disorder: A Family-Based Mixed-Model Analysis', PLoS Medicine, vol. 13, no. 8, e1002090. https://doi.org/10.1371/journal.pmed.1002090
McIntosh, Andrew M ; Hall, Lynsey S ; Zeng, Yanni ; Adams, Mark J ; Gibson, Jude ; Wigmore, Eleanor ; Hagenaars, Saskia P ; Davies, Gail ; Fernandez-Pujals, Ana Maria ; Campbell, Archie I ; Clarke, Toni-Kim ; Hayward, Caroline ; Haley, Chris S ; Porteous, David J ; Deary, Ian J ; Smith, Daniel J ; Nicholl, Barbara I ; Hinds, David A ; Jones, Amy V ; Scollen, Serena ; Meng, Weihua ; Smith, Blair H ; Hocking, Lynne J. / Genetic and Environmental Risk for Chronic Pain and the Contribution of Risk Variants for Major Depressive Disorder : A Family-Based Mixed-Model Analysis. In: PLoS Medicine. 2016 ; Vol. 13, No. 8.
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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 = "BACKGROUND: 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.METHODS AND FINDINGS: 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.CONCLUSIONS: 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.",
keywords = "Adult, Aged, Chronic Pain, Depressive Disorder, Major, Family, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Multifactorial Inheritance, Pedigree, Risk Factors, Social Environment, Surveys and Questionnaires, United Kingdom, Journal Article",
author = "McIntosh, {Andrew M} and Hall, {Lynsey S} and Yanni Zeng and Adams, {Mark J} and Jude Gibson and Eleanor Wigmore and Hagenaars, {Saskia P} and Gail Davies and Fernandez-Pujals, {Ana Maria} and Campbell, {Archie I} and Toni-Kim Clarke and Caroline Hayward and Haley, {Chris S} and Porteous, {David J} and Deary, {Ian J} and Smith, {Daniel J} and Nicholl, {Barbara I} and Hinds, {David A} and Jones, {Amy V} and Serena Scollen and Weihua Meng and Smith, {Blair H} and Hocking, {Lynne J}",
note = "Funding: This study was funded by Wellcome Trust (www.wellcome.ac.uk) Strategic Grant 104036/Z/14/Z. Generation Scotland (www.gen.acot) is funded by the Chief Scientist Office [CZD/16/6] and the Scottish Funding Council [HR03006]. UK Biobank (www.ukbiobank.ac.uk) is funded by the Wellcome Trust, Medical Research Council, The Scottish Government and other funders. These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The analysis of pain data collected by 23andMe in collaboration with Pfizer and was funded by Pfizer. Employees of Pfizer and 23andMe are represented in the authorship. Data Availability: Data from Generation Scotland are available on application to an independent access committee. The committee can be contacted through the following email (info@generationscotland.org) or web addresses (www.generationscotland.org). Data from UK Biobank are available on application to the UK Biobank Access Committee. The Access Committee may be contacted by email (access@ukbiobank.ac.uk) or through the UK Biobank web page (http://www.ukbiobank.ac.uk). Data from Pfizer-23andMe are available on application to Pfizer. Please apply by email at the following address: HGCBDataAccess@pfizer.com.",
year = "2016",
month = "8",
day = "16",
doi = "10.1371/journal.pmed.1002090",
language = "English",
volume = "13",
journal = "PLoS Medicine",
issn = "1549-1277",
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number = "8",

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TY - JOUR

T1 - Genetic and Environmental Risk for Chronic Pain and the Contribution of Risk Variants for Major Depressive Disorder

T2 - A Family-Based Mixed-Model Analysis

AU - McIntosh, Andrew M

AU - Hall, Lynsey S

AU - Zeng, Yanni

AU - Adams, Mark J

AU - Gibson, Jude

AU - Wigmore, Eleanor

AU - Hagenaars, Saskia P

AU - Davies, Gail

AU - Fernandez-Pujals, Ana Maria

AU - Campbell, Archie I

AU - Clarke, Toni-Kim

AU - Hayward, Caroline

AU - Haley, Chris S

AU - Porteous, David J

AU - Deary, Ian J

AU - Smith, Daniel J

AU - Nicholl, Barbara I

AU - Hinds, David A

AU - Jones, Amy V

AU - Scollen, Serena

AU - Meng, Weihua

AU - Smith, Blair H

AU - Hocking, Lynne J

N1 - Funding: This study was funded by Wellcome Trust (www.wellcome.ac.uk) Strategic Grant 104036/Z/14/Z. Generation Scotland (www.gen.acot) is funded by the Chief Scientist Office [CZD/16/6] and the Scottish Funding Council [HR03006]. UK Biobank (www.ukbiobank.ac.uk) is funded by the Wellcome Trust, Medical Research Council, The Scottish Government and other funders. These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The analysis of pain data collected by 23andMe in collaboration with Pfizer and was funded by Pfizer. Employees of Pfizer and 23andMe are represented in the authorship. Data Availability: Data from Generation Scotland are available on application to an independent access committee. The committee can be contacted through the following email (info@generationscotland.org) or web addresses (www.generationscotland.org). Data from UK Biobank are available on application to the UK Biobank Access Committee. The Access Committee may be contacted by email (access@ukbiobank.ac.uk) or through the UK Biobank web page (http://www.ukbiobank.ac.uk). Data from Pfizer-23andMe are available on application to Pfizer. Please apply by email at the following address: HGCBDataAccess@pfizer.com.

PY - 2016/8/16

Y1 - 2016/8/16

N2 - BACKGROUND: 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.METHODS AND FINDINGS: 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.CONCLUSIONS: 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.

AB - BACKGROUND: 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.METHODS AND FINDINGS: 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.CONCLUSIONS: 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.

KW - Adult

KW - Aged

KW - Chronic Pain

KW - Depressive Disorder, Major

KW - Family

KW - Female

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Middle Aged

KW - Multifactorial Inheritance

KW - Pedigree

KW - Risk Factors

KW - Social Environment

KW - Surveys and Questionnaires

KW - United Kingdom

KW - Journal Article

U2 - 10.1371/journal.pmed.1002090

DO - 10.1371/journal.pmed.1002090

M3 - Article

C2 - 27529168

VL - 13

JO - PLoS Medicine

JF - PLoS Medicine

SN - 1549-1277

IS - 8

M1 - e1002090

ER -