Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression

Joanna Martin; Kimiya Asjadi; Leon Hubbard; Kimberley Kendall; Antonio F. Pardiñas; Bradley Jermy; Cathryn M. Lewis; Bernhard T. Baune; Dorret I. Boomsma; Steven P. Hamilton; Susanne Lucae; Patrik K. Magnusson; Nicholas G. Martin; Andrew M. McIntosh; Divya Mehta; Ole Mors; Niamh Mullins; Brenda W.J.H. Penninx; Martin Preisig; Marcella Rietschel; Ian Jones; James T.R. Walters; Frances Rice; Anita Thapar; Michael O'Donovan

doi:10.1371/journal.pone.0248254

Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression

Joanna Martin^*, Kimiya Asjadi, Leon Hubbard, Kimberley Kendall, Antonio F. Pardiñas, Bradley Jermy, Cathryn M. Lewis, Bernhard T. Baune, Dorret I. Boomsma, Steven P. Hamilton, Susanne Lucae, Patrik K. Magnusson, Nicholas G. Martin, Andrew M. McIntosh, Divya Mehta, Ole Mors, Niamh Mullins, Brenda W.J.H. Penninx, Martin Preisig, Marcella RietschelIan Jones, James T.R. Walters, Frances Rice, Anita Thapar, Michael O'Donovan

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Anxiety and depression are common mental health disorders and have a higher prevalence in females. They are modestly heritable, share genetic liability with other psychiatric disorders, and are highly heterogeneous. There is evidence that genetic liability to neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) is associated with anxiety and depression, particularly in females. We investigated sex differences in family history for neurodevelopmental and psychiatric disorders and neurodevelopmental genetic risk burden (indexed by ADHD polygenic risk scores (PRS) and rare copy number variants; CNVs) in individuals with anxiety and depression, also taking into account age at onset. We used two complementary datasets: 1) participants with a self-reported diagnosis of anxiety or depression (N = 4,178, 65.5% female; mean age = 41.5 years; N = 1,315 with genetic data) from the National Centre for Mental Health (NCMH) cohort and 2) a clinical sample of 13,273 (67.6% female; mean age = 45.2 years) patients with major depressive disorder (MDD) from the Psychiatric Genomics Consortium (PGC). We tested for sex differences in family history of psychiatric problems and presence of rare CNVs (neurodevelopmental and >500kb loci) in NCMH only and for sex differences in ADHD PRS in both datasets. In the NCMH cohort, females were more likely to report family history of neurodevelopmental and psychiatric disorders, but there were no robust sex differences in ADHD PRS or presence of rare CNVs. There was weak evidence of higher ADHD PRS in females compared to males in the PGC MDD sample, particularly in those with an early onset of MDD. These results do not provide strong evidence of sex differences in neurodevelopmental genetic risk burden in adults with anxiety and depression. This indicates that sex may not be a major index of neurodevelopmental genetic heterogeneity, that is captured by ADHD PRS and rare CNV burden, in adults with anxiety and depression.

Original language	English
Article number	e0248254
Pages (from-to)	1-14
Number of pages	14
Journal	PLoS ONE
Volume	16
Issue number	9
DOIs	https://doi.org/10.1371/journal.pone.0248254
Publication status	Published - 2 Sept 2021

Bibliographical note

Funding Information:
Funding:JMwassupportedbyaSêrCymruII COFUNDFellowshipfromtheWelshGovernment (grantno.663830-CU189)andaNARSADYoung InvestigatorGrantfromtheBrain&Behavior ResearchFoundation(grantno.27879).LH,AFP, andJTRWweresupportedbyanMRCMental HealthDataPathfindergrant(MC-PC-17212).CML andBJarepart-fundedbytheNationalInstitutefor HealthResearch(NIHR)BiomedicalResearch CentreatSouthLondonandMaudsleyNHS FoundationTrustandKing’sCollegeLondon.KK wasfundedbyaWellcomeTrustResearch TrainingFellowship.TheNationalCentreforMental Health(NCMH)isfundedbyWelshGovernment throughHealthandCareResearchWales(grant number:514032).ThePGChasreceivedcore fundingfromtheUSNationalInstituteofMental Health(5U01MH109528-03).MOD,CMLandthe PGCaresupportedfromtheNationalInstituteof MentalHealthoftheNationalInstitutesofHealth underAwardNumberU01MH109514.Thecontent issolelytheresponsibilityoftheauthorsanddoes notnecessarilyrepresenttheofficialviewsofthe NationalInstitutesofHealth.

Publisher Copyright:
© 2021 Martin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

Funding

Funding:JMwassupportedbyaSêrCymruII COFUNDFellowshipfromtheWelshGovernment (grantno.663830-CU189)andaNARSADYoung InvestigatorGrantfromtheBrain&Behavior ResearchFoundation(grantno.27879).LH,AFP, andJTRWweresupportedbyanMRCMental HealthDataPathfindergrant(MC-PC-17212).CML andBJarepart-fundedbytheNationalInstitutefor HealthResearch(NIHR)BiomedicalResearch CentreatSouthLondonandMaudsleyNHS FoundationTrustandKing’sCollegeLondon.KK wasfundedbyaWellcomeTrustResearch TrainingFellowship.TheNationalCentreforMental Health(NCMH)isfundedbyWelshGovernment throughHealthandCareResearchWales(grant number:514032).ThePGChasreceivedcore fundingfromtheUSNationalInstituteofMental Health(5U01MH109528-03).MOD,CMLandthe PGCaresupportedfromtheNationalInstituteof MentalHealthoftheNationalInstitutesofHealth underAwardNumberU01MH109514.Thecontent issolelytheresponsibilityoftheauthorsanddoes notnecessarilyrepresenttheofficialviewsofthe NationalInstitutesofHealth.

Funders	Funder number
National Institute of Mental Health	U01MH109514
National Institute for Health Research	5U01MH109528-03

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Martin, J., Asjadi, K., Hubbard, L., Kendall, K., Pardiñas, A. F., Jermy, B., Lewis, C. M., Baune, B. T., Boomsma, D. I., Hamilton, S. P., Lucae, S., Magnusson, P. K., Martin, N. G., McIntosh, A. M., Mehta, D., Mors, O., Mullins, N., Penninx, B. W. J. H., Preisig, M., ... O'Donovan, M. (2021). Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression. PLoS ONE, 16(9), 1-14. Article e0248254. https://doi.org/10.1371/journal.pone.0248254

@article{2700bd30159043df8477f1f03ac00189,

title = "Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression",

abstract = "Anxiety and depression are common mental health disorders and have a higher prevalence in females. They are modestly heritable, share genetic liability with other psychiatric disorders, and are highly heterogeneous. There is evidence that genetic liability to neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) is associated with anxiety and depression, particularly in females. We investigated sex differences in family history for neurodevelopmental and psychiatric disorders and neurodevelopmental genetic risk burden (indexed by ADHD polygenic risk scores (PRS) and rare copy number variants; CNVs) in individuals with anxiety and depression, also taking into account age at onset. We used two complementary datasets: 1) participants with a self-reported diagnosis of anxiety or depression (N = 4,178, 65.5% female; mean age = 41.5 years; N = 1,315 with genetic data) from the National Centre for Mental Health (NCMH) cohort and 2) a clinical sample of 13,273 (67.6% female; mean age = 45.2 years) patients with major depressive disorder (MDD) from the Psychiatric Genomics Consortium (PGC). We tested for sex differences in family history of psychiatric problems and presence of rare CNVs (neurodevelopmental and >500kb loci) in NCMH only and for sex differences in ADHD PRS in both datasets. In the NCMH cohort, females were more likely to report family history of neurodevelopmental and psychiatric disorders, but there were no robust sex differences in ADHD PRS or presence of rare CNVs. There was weak evidence of higher ADHD PRS in females compared to males in the PGC MDD sample, particularly in those with an early onset of MDD. These results do not provide strong evidence of sex differences in neurodevelopmental genetic risk burden in adults with anxiety and depression. This indicates that sex may not be a major index of neurodevelopmental genetic heterogeneity, that is captured by ADHD PRS and rare CNV burden, in adults with anxiety and depression.",

author = "Joanna Martin and Kimiya Asjadi and Leon Hubbard and Kimberley Kendall and Pardi{\~n}as, {Antonio F.} and Bradley Jermy and Lewis, {Cathryn M.} and Baune, {Bernhard T.} and Boomsma, {Dorret I.} and Hamilton, {Steven P.} and Susanne Lucae and Magnusson, {Patrik K.} and Martin, {Nicholas G.} and McIntosh, {Andrew M.} and Divya Mehta and Ole Mors and Niamh Mullins and Penninx, {Brenda W.J.H.} and Martin Preisig and Marcella Rietschel and Ian Jones and Walters, {James T.R.} and Frances Rice and Anita Thapar and Michael O'Donovan",

note = "Funding Information: Funding:JMwassupportedbyaS{\^e}rCymruII COFUNDFellowshipfromtheWelshGovernment (grantno.663830-CU189)andaNARSADYoung InvestigatorGrantfromtheBrain&Behavior ResearchFoundation(grantno.27879).LH,AFP, andJTRWweresupportedbyanMRCMental HealthDataPathfindergrant(MC-PC-17212).CML andBJarepart-fundedbytheNationalInstitutefor HealthResearch(NIHR)BiomedicalResearch CentreatSouthLondonandMaudsleyNHS FoundationTrustandKing{\textquoteright}sCollegeLondon.KK wasfundedbyaWellcomeTrustResearch TrainingFellowship.TheNationalCentreforMental Health(NCMH)isfundedbyWelshGovernment throughHealthandCareResearchWales(grant number:514032).ThePGChasreceivedcore fundingfromtheUSNationalInstituteofMental Health(5U01MH109528-03).MOD,CMLandthe PGCaresupportedfromtheNationalInstituteof MentalHealthoftheNationalInstitutesofHealth underAwardNumberU01MH109514.Thecontent issolelytheresponsibilityoftheauthorsanddoes notnecessarilyrepresenttheofficialviewsofthe NationalInstitutesofHealth. Publisher Copyright: {\textcopyright} 2021 Martin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

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doi = "10.1371/journal.pone.0248254",

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Martin, J, Asjadi, K, Hubbard, L, Kendall, K, Pardiñas, AF, Jermy, B, Lewis, CM, Baune, BT, Boomsma, DI, Hamilton, SP, Lucae, S, Magnusson, PK, Martin, NG, McIntosh, AM, Mehta, D, Mors, O, Mullins, N, Penninx, BWJH, Preisig, M, Rietschel, M, Jones, I, Walters, JTR, Rice, F, Thapar, A & O'Donovan, M 2021, 'Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression', PLoS ONE, vol. 16, no. 9, e0248254, pp. 1-14. https://doi.org/10.1371/journal.pone.0248254

TY - JOUR

T1 - Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression

AU - Martin, Joanna

AU - Asjadi, Kimiya

AU - Hubbard, Leon

AU - Kendall, Kimberley

AU - Pardiñas, Antonio F.

AU - Jermy, Bradley

AU - Lewis, Cathryn M.

AU - Baune, Bernhard T.

AU - Boomsma, Dorret I.

AU - Hamilton, Steven P.

AU - Lucae, Susanne

AU - Magnusson, Patrik K.

AU - Martin, Nicholas G.

AU - McIntosh, Andrew M.

AU - Mehta, Divya

AU - Mors, Ole

AU - Mullins, Niamh

AU - Penninx, Brenda W.J.H.

AU - Preisig, Martin

AU - Rietschel, Marcella

AU - Jones, Ian

AU - Walters, James T.R.

AU - Rice, Frances

AU - Thapar, Anita

AU - O'Donovan, Michael

N1 - Funding Information: Funding:JMwassupportedbyaSêrCymruII COFUNDFellowshipfromtheWelshGovernment (grantno.663830-CU189)andaNARSADYoung InvestigatorGrantfromtheBrain&Behavior ResearchFoundation(grantno.27879).LH,AFP, andJTRWweresupportedbyanMRCMental HealthDataPathfindergrant(MC-PC-17212).CML andBJarepart-fundedbytheNationalInstitutefor HealthResearch(NIHR)BiomedicalResearch CentreatSouthLondonandMaudsleyNHS FoundationTrustandKing’sCollegeLondon.KK wasfundedbyaWellcomeTrustResearch TrainingFellowship.TheNationalCentreforMental Health(NCMH)isfundedbyWelshGovernment throughHealthandCareResearchWales(grant number:514032).ThePGChasreceivedcore fundingfromtheUSNationalInstituteofMental Health(5U01MH109528-03).MOD,CMLandthe PGCaresupportedfromtheNationalInstituteof MentalHealthoftheNationalInstitutesofHealth underAwardNumberU01MH109514.Thecontent issolelytheresponsibilityoftheauthorsanddoes notnecessarilyrepresenttheofficialviewsofthe NationalInstitutesofHealth. Publisher Copyright: © 2021 Martin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/9/2

Y1 - 2021/9/2

N2 - Anxiety and depression are common mental health disorders and have a higher prevalence in females. They are modestly heritable, share genetic liability with other psychiatric disorders, and are highly heterogeneous. There is evidence that genetic liability to neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) is associated with anxiety and depression, particularly in females. We investigated sex differences in family history for neurodevelopmental and psychiatric disorders and neurodevelopmental genetic risk burden (indexed by ADHD polygenic risk scores (PRS) and rare copy number variants; CNVs) in individuals with anxiety and depression, also taking into account age at onset. We used two complementary datasets: 1) participants with a self-reported diagnosis of anxiety or depression (N = 4,178, 65.5% female; mean age = 41.5 years; N = 1,315 with genetic data) from the National Centre for Mental Health (NCMH) cohort and 2) a clinical sample of 13,273 (67.6% female; mean age = 45.2 years) patients with major depressive disorder (MDD) from the Psychiatric Genomics Consortium (PGC). We tested for sex differences in family history of psychiatric problems and presence of rare CNVs (neurodevelopmental and >500kb loci) in NCMH only and for sex differences in ADHD PRS in both datasets. In the NCMH cohort, females were more likely to report family history of neurodevelopmental and psychiatric disorders, but there were no robust sex differences in ADHD PRS or presence of rare CNVs. There was weak evidence of higher ADHD PRS in females compared to males in the PGC MDD sample, particularly in those with an early onset of MDD. These results do not provide strong evidence of sex differences in neurodevelopmental genetic risk burden in adults with anxiety and depression. This indicates that sex may not be a major index of neurodevelopmental genetic heterogeneity, that is captured by ADHD PRS and rare CNV burden, in adults with anxiety and depression.

AB - Anxiety and depression are common mental health disorders and have a higher prevalence in females. They are modestly heritable, share genetic liability with other psychiatric disorders, and are highly heterogeneous. There is evidence that genetic liability to neurodevelopmental disorders, such as attention deficit hyperactivity disorder (ADHD) is associated with anxiety and depression, particularly in females. We investigated sex differences in family history for neurodevelopmental and psychiatric disorders and neurodevelopmental genetic risk burden (indexed by ADHD polygenic risk scores (PRS) and rare copy number variants; CNVs) in individuals with anxiety and depression, also taking into account age at onset. We used two complementary datasets: 1) participants with a self-reported diagnosis of anxiety or depression (N = 4,178, 65.5% female; mean age = 41.5 years; N = 1,315 with genetic data) from the National Centre for Mental Health (NCMH) cohort and 2) a clinical sample of 13,273 (67.6% female; mean age = 45.2 years) patients with major depressive disorder (MDD) from the Psychiatric Genomics Consortium (PGC). We tested for sex differences in family history of psychiatric problems and presence of rare CNVs (neurodevelopmental and >500kb loci) in NCMH only and for sex differences in ADHD PRS in both datasets. In the NCMH cohort, females were more likely to report family history of neurodevelopmental and psychiatric disorders, but there were no robust sex differences in ADHD PRS or presence of rare CNVs. There was weak evidence of higher ADHD PRS in females compared to males in the PGC MDD sample, particularly in those with an early onset of MDD. These results do not provide strong evidence of sex differences in neurodevelopmental genetic risk burden in adults with anxiety and depression. This indicates that sex may not be a major index of neurodevelopmental genetic heterogeneity, that is captured by ADHD PRS and rare CNV burden, in adults with anxiety and depression.

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Examining sex differences in neurodevelopmental and psychiatric genetic risk in anxiety and depression

Abstract

Bibliographical note

Funding

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