Sex differences in anxiety and depression in children with attention deficit hyperactivity disorder: Investigating genetic liability and comorbidity

Joanna Martin; Sharifah Shameem Agha; Olga Eyre; Lucy Riglin; Kate Langley; Leon Hubbard; Evie Stergiakouli; Michael O'Donovan; Anita Thapar; Ole A. Andreassen; Aurina Arnatkeviciute; Tobias Banaschewski; Mark Bellgrove; Anders Borglum; Jan Buitelaar; Christie Burton; Alice Charach; Elizabeth Corfield; Bru Cormand; Jennifer Crosbie; Ditte Demontis; Steve V. Faraone; Barbara Franke; Ian Gizer; Eugenio H. Grevet; Jan Haavik; Hakon Hakonarson; Catharina Hartman; Alexandra Havdahl; Ziarih Hawi; Johannes Hebebrand; Anke Hinney; Ridha Joober; Richard Karlsson Linnér; Marieke Klein; Jonna Kuntsi; Henrik Larsson; Klaus P. Lesch; Patrick W.L. Leung; Calwing Liao; Sandra Loo; Sarah Medland; Alexandra Philipsen; Josep A. Ramos-Quiroga; Ted Reichborn-Kjennerud; Andreas Reif; Marta Ribases; Giovanni Salum; Russell Schachar; Sarojini M. Sengupta; Psychiatric Genomics Consortium ADHD Working Group

doi:10.1002/ajmg.b.32842

Sex differences in anxiety and depression in children with attention deficit hyperactivity disorder: Investigating genetic liability and comorbidity

Joanna Martin^*, Sharifah Shameem Agha, Olga Eyre, Lucy Riglin, Kate Langley, Leon Hubbard, Evie Stergiakouli, Michael O'Donovan, Anita Thapar, Ole A. Andreassen, Aurina Arnatkeviciute, Tobias Banaschewski, Mark Bellgrove, Anders Borglum, Jan Buitelaar, Christie Burton, Alice Charach, Elizabeth Corfield, Bru Cormand, Jennifer CrosbieDitte Demontis, Steve V. Faraone, Barbara Franke, Ian Gizer, Eugenio H. Grevet, Jan Haavik, Hakon Hakonarson, Catharina Hartman, Alexandra Havdahl, Ziarih Hawi, Johannes Hebebrand, Anke Hinney, Ridha Joober, Richard Karlsson Linnér, Marieke Klein, Jonna Kuntsi, Henrik Larsson, Klaus P. Lesch, Patrick W.L. Leung, Calwing Liao, Sandra Loo, Sarah Medland, Alexandra Philipsen, Josep A. Ramos-Quiroga, Ted Reichborn-Kjennerud, Andreas Reif, Marta Ribases, Giovanni Salum, Russell Schachar, Sarojini M. Sengupta, Psychiatric Genomics Consortium ADHD Working Group

^*Corresponding author for this work

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

Abstract

It is unknown why attention deficit hyperactivity disorder (ADHD) is more common in males, whereas anxiety and depression show a female population excess. We tested the hypothesis that anxiety and depression risk alleles manifest as ADHD in males. We also tested whether anxiety and depression in children with ADHD show a different etiology to typical anxiety and depression and whether this differs by sex. The primary clinical ADHD sample consisted of 885 (14% female) children. Psychiatric symptoms were assessed using standardized interviews. Polygenic risk scores (PRS) were derived using large genetic studies. Replication samples included independent clinical ADHD samples (N = 3,794; 25.7% female) and broadly defined population ADHD samples (N = 995; 33.4% female). We did not identify sex differences in anxiety or depression PRS in children with ADHD. In the primary sample, anxiety PRS were associated with social and generalized anxiety in males, with evidence of a sex-by-PRS interaction for social anxiety. These results did not replicate in the broadly defined ADHD sample. Depression PRS were not associated with comorbid depression symptoms. The results suggest that anxiety and depression genetic risks are not more likely to lead to ADHD in males. Also, the evidence for shared etiology between anxiety symptoms in those with ADHD and typical anxiety was weak and needs replication.

Original language	English
Pages (from-to)	412-422
Number of pages	11
Journal	American Journal of Medical Genetics Part B-neuropsychiatric Genetics
Volume	186
Issue number	7
DOIs	https://doi.org/10.1002/ajmg.b.32842
Publication status	Published - 1 Oct 2021

Keywords

ADHD
ALSPAC
anxiety disorders
depression
polygenic risk scores
sex differences

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10.1002/ajmg.b.32842Licence: CC BY

Cite this

Martin, J., Agha, S. S., Eyre, O., Riglin, L., Langley, K., Hubbard, L., Stergiakouli, E., O'Donovan, M., Thapar, A., Andreassen, O. A., Arnatkeviciute, A., Banaschewski, T., Bellgrove, M., Borglum, A., Buitelaar, J., Burton, C., Charach, A., Corfield, E., Cormand, B., ... Psychiatric Genomics Consortium ADHD Working Group (2021). Sex differences in anxiety and depression in children with attention deficit hyperactivity disorder: Investigating genetic liability and comorbidity. American Journal of Medical Genetics Part B-neuropsychiatric Genetics, 186(7), 412-422. https://doi.org/10.1002/ajmg.b.32842

@article{4bd6df92723449c6b18f8ebb9fbb2248,

title = "Sex differences in anxiety and depression in children with attention deficit hyperactivity disorder: Investigating genetic liability and comorbidity",

abstract = "It is unknown why attention deficit hyperactivity disorder (ADHD) is more common in males, whereas anxiety and depression show a female population excess. We tested the hypothesis that anxiety and depression risk alleles manifest as ADHD in males. We also tested whether anxiety and depression in children with ADHD show a different etiology to typical anxiety and depression and whether this differs by sex. The primary clinical ADHD sample consisted of 885 (14% female) children. Psychiatric symptoms were assessed using standardized interviews. Polygenic risk scores (PRS) were derived using large genetic studies. Replication samples included independent clinical ADHD samples (N = 3,794; 25.7% female) and broadly defined population ADHD samples (N = 995; 33.4% female). We did not identify sex differences in anxiety or depression PRS in children with ADHD. In the primary sample, anxiety PRS were associated with social and generalized anxiety in males, with evidence of a sex-by-PRS interaction for social anxiety. These results did not replicate in the broadly defined ADHD sample. Depression PRS were not associated with comorbid depression symptoms. The results suggest that anxiety and depression genetic risks are not more likely to lead to ADHD in males. Also, the evidence for shared etiology between anxiety symptoms in those with ADHD and typical anxiety was weak and needs replication.",

keywords = "ADHD, ALSPAC, anxiety disorders, depression, polygenic risk scores, sex differences",

author = "Joanna Martin and Agha, {Sharifah Shameem} and Olga Eyre and Lucy Riglin and Kate Langley and Leon Hubbard and Evie Stergiakouli and Michael O'Donovan and Anita Thapar and Andreassen, {Ole A.} and Aurina Arnatkeviciute and Tobias Banaschewski and Mark Bellgrove and Anders Borglum and Jan Buitelaar and Christie Burton and Alice Charach and Elizabeth Corfield and Bru Cormand and Jennifer Crosbie and Ditte Demontis and Faraone, {Steve V.} and Barbara Franke and Ian Gizer and Grevet, {Eugenio H.} and Jan Haavik and Hakon Hakonarson and Catharina Hartman and Alexandra Havdahl and Ziarih Hawi and Johannes Hebebrand and Anke Hinney and Ridha Joober and Linn{\'e}r, {Richard Karlsson} and Marieke Klein and Jonna Kuntsi and Henrik Larsson and Lesch, {Klaus P.} and Leung, {Patrick W.L.} and Calwing Liao and Sandra Loo and Sarah Medland and Alexandra Philipsen and Ramos-Quiroga, {Josep A.} and Ted Reichborn-Kjennerud and Andreas Reif and Marta Ribases and Giovanni Salum and Russell Schachar and Sengupta, {Sarojini M.} and {Psychiatric Genomics Consortium ADHD Working Group}",

note = "Funding Information: This research was funded in whole, or in part, by the Wellcome Trust [079711]. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. The work was supported by funding from the Medical Research Council Center (grant no. MR/L010305/1), Health and Care Research Wales (grant no. 514032), Action Medical Research and Baily Thomas. We also acknowledge the support of the Supercomputing Wales project, which is part-funded by the European Regional Development Fund (ERDF) via Welsh Government. JM was supported by a S{\^e}r Cymru II COFUND Fellowship from the Welsh Government (grant no. 663830 - CU189) and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (grant no. 27879). LR and AT were supported by the Wellcome Trust (204895/Z/16/Z). ES works in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1). Funding Information: This research was funded in whole, or in part, by the Wellcome Trust [079711]. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. The work was supported by funding from the Medical Research Council Center (grant no. MR/L010305/1), Health and Care Research Wales (grant no. 514032), Action Medical Research and Baily Thomas. We also acknowledge the support of the Supercomputing Wales project, which is part-funded by the European Regional Development Fund (ERDF) via Welsh Government. JM was supported by a S{\^e}r Cymru II COFUND Fellowship from the Welsh Government (grant no. 663830 - CU189) and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (grant no. 27879). LR and AT were supported by the Wellcome Trust (204895/Z/16/Z). ES works in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1). ALSPAC: We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and Joanna Martin will serve as guarantor for the contents of this article. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). With thanks to Dr Benjamin Neale for useful discussions related to the project. We would also like to acknowledge all other members of the Psychiatric Genomics Consortium ADHD Working Group not already listed: Jessica Agnew-Blais, Tony Altar, Richard Anney, Paul Arnold, Philip Asherson, Allison Ashley-Koch, Yorgos Athanasiadis, Ciebele Bandeira, Claiton Bau, Monica Bayes, Joseph Biederman, Isabell Brikell, Maria Jesus Arranz Calderun, Miguel Casas, Felecia Cerrato, Christine Cornforth, Alejandro Corsico, Soren Dalsgaard, Jurgen Deckert, Franziska Degenhardt, Alysa Doyle, Richard Ebstein, Josephine Elia, Juanita Gamble, Joel Gelernter, Michael Gill, Eugenio Horacio Grevet, Rachel Guerra, A.R. Hammerschlag, Amaia Hervas, Peter Holmans, Stefan Johansson, Lindsey Kent, Hyo-Won Kim, Gun Peggy Stromstad Knudsen, Paul Lichtenstein, Veera Manikandan, Meg Mariano, Nick Martin, Glaucia Chiyoko Akutagava Martins, Manuel Mattheisen, Jim McGough, Ana Miranda, Niels Peter Ole Mors, Preben Bo Mortensen, Nina Roth Mota, Fernando Mulas, Steve Nelson, Robert Oades, Pedro Pan, Julia Pinsonneault, Tinca Polderman, Danielle Posthuma, Herber Roeyers, Luis Rohde, Anna Rommel, Aribert Rothenberger, Paula Rovira, Cristina Sanchez, Andre Scherag, Susann Scherag, Joseph Sergeant, Pak Sham, Susan Smalley, Anna Starnawska, H.C. Steinhausen, Hans-Christoph Steinhausen, Patrick Sullivan, Alexandre Todorov, Raymond Walters, Yufeng Wang, Anne Wheeler, Nigel Williams, Li Yang, Tetyana Zayats, and Yanil Zhang. Funding Information: : We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and Joanna Martin will serve as guarantor for the contents of this article. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). ALSPAC Funding Information: Brain Behavior Research Foundation, Grant/Award Number: 27879; Health and Care Research Wales, Grant/Award Number: 514032; Medical Research Council, Grant/Award Number: MR/L010305/1; Wellcome Trust, Grant/Award Numbers: 079711, 204895/Z/16/Z; Welsh Government, Grant/Award Number: 663830-CU189; University of Bristol and the UK Medical Research Council, Grant/Award Number: MC_UU_00011/1 Funding information Publisher Copyright: {\textcopyright} 2021 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.",

year = "2021",

month = oct,

day = "1",

doi = "10.1002/ajmg.b.32842",

language = "English",

volume = "186",

pages = "412--422",

journal = "American Journal of Medical Genetics Part B-neuropsychiatric Genetics",

issn = "1552-4841",

publisher = "Wiley",

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}

Martin, J, Agha, SS, Eyre, O, Riglin, L, Langley, K, Hubbard, L, Stergiakouli, E, O'Donovan, M, Thapar, A, Andreassen, OA, Arnatkeviciute, A, Banaschewski, T, Bellgrove, M, Borglum, A, Buitelaar, J, Burton, C, Charach, A, Corfield, E, Cormand, B, Crosbie, J, Demontis, D, Faraone, SV, Franke, B, Gizer, I, Grevet, EH, Haavik, J, Hakonarson, H, Hartman, C, Havdahl, A, Hawi, Z, Hebebrand, J, Hinney, A, Joober, R, Linnér, RK, Klein, M, Kuntsi, J, Larsson, H, Lesch, KP, Leung, PWL, Liao, C, Loo, S, Medland, S, Philipsen, A, Ramos-Quiroga, JA, Reichborn-Kjennerud, T, Reif, A, Ribases, M, Salum, G, Schachar, R, Sengupta, SM & Psychiatric Genomics Consortium ADHD Working Group 2021, 'Sex differences in anxiety and depression in children with attention deficit hyperactivity disorder: Investigating genetic liability and comorbidity', American Journal of Medical Genetics Part B-neuropsychiatric Genetics, vol. 186, no. 7, pp. 412-422. https://doi.org/10.1002/ajmg.b.32842

Sex differences in anxiety and depression in children with attention deficit hyperactivity disorder: Investigating genetic liability and comorbidity. / Martin, Joanna; Agha, Sharifah Shameem; Eyre, Olga et al.
In: American Journal of Medical Genetics Part B-neuropsychiatric Genetics, Vol. 186, No. 7, 01.10.2021, p. 412-422.

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

TY - JOUR

T1 - Sex differences in anxiety and depression in children with attention deficit hyperactivity disorder

T2 - Investigating genetic liability and comorbidity

AU - Martin, Joanna

AU - Agha, Sharifah Shameem

AU - Eyre, Olga

AU - Riglin, Lucy

AU - Langley, Kate

AU - Hubbard, Leon

AU - Stergiakouli, Evie

AU - O'Donovan, Michael

AU - Thapar, Anita

AU - Andreassen, Ole A.

AU - Arnatkeviciute, Aurina

AU - Banaschewski, Tobias

AU - Bellgrove, Mark

AU - Borglum, Anders

AU - Buitelaar, Jan

AU - Burton, Christie

AU - Charach, Alice

AU - Corfield, Elizabeth

AU - Cormand, Bru

AU - Crosbie, Jennifer

AU - Demontis, Ditte

AU - Faraone, Steve V.

AU - Franke, Barbara

AU - Gizer, Ian

AU - Grevet, Eugenio H.

AU - Haavik, Jan

AU - Hakonarson, Hakon

AU - Hartman, Catharina

AU - Havdahl, Alexandra

AU - Hawi, Ziarih

AU - Hebebrand, Johannes

AU - Hinney, Anke

AU - Joober, Ridha

AU - Linnér, Richard Karlsson

AU - Klein, Marieke

AU - Kuntsi, Jonna

AU - Larsson, Henrik

AU - Lesch, Klaus P.

AU - Leung, Patrick W.L.

AU - Liao, Calwing

AU - Loo, Sandra

AU - Medland, Sarah

AU - Philipsen, Alexandra

AU - Ramos-Quiroga, Josep A.

AU - Reichborn-Kjennerud, Ted

AU - Reif, Andreas

AU - Ribases, Marta

AU - Salum, Giovanni

AU - Schachar, Russell

AU - Sengupta, Sarojini M.

AU - Psychiatric Genomics Consortium ADHD Working Group

N1 - Funding Information: This research was funded in whole, or in part, by the Wellcome Trust [079711]. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. The work was supported by funding from the Medical Research Council Center (grant no. MR/L010305/1), Health and Care Research Wales (grant no. 514032), Action Medical Research and Baily Thomas. We also acknowledge the support of the Supercomputing Wales project, which is part-funded by the European Regional Development Fund (ERDF) via Welsh Government. JM was supported by a Sêr Cymru II COFUND Fellowship from the Welsh Government (grant no. 663830 - CU189) and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (grant no. 27879). LR and AT were supported by the Wellcome Trust (204895/Z/16/Z). ES works in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1). Funding Information: This research was funded in whole, or in part, by the Wellcome Trust [079711]. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. The work was supported by funding from the Medical Research Council Center (grant no. MR/L010305/1), Health and Care Research Wales (grant no. 514032), Action Medical Research and Baily Thomas. We also acknowledge the support of the Supercomputing Wales project, which is part-funded by the European Regional Development Fund (ERDF) via Welsh Government. JM was supported by a Sêr Cymru II COFUND Fellowship from the Welsh Government (grant no. 663830 - CU189) and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation (grant no. 27879). LR and AT were supported by the Wellcome Trust (204895/Z/16/Z). ES works in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1). ALSPAC: We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and Joanna Martin will serve as guarantor for the contents of this article. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). With thanks to Dr Benjamin Neale for useful discussions related to the project. We would also like to acknowledge all other members of the Psychiatric Genomics Consortium ADHD Working Group not already listed: Jessica Agnew-Blais, Tony Altar, Richard Anney, Paul Arnold, Philip Asherson, Allison Ashley-Koch, Yorgos Athanasiadis, Ciebele Bandeira, Claiton Bau, Monica Bayes, Joseph Biederman, Isabell Brikell, Maria Jesus Arranz Calderun, Miguel Casas, Felecia Cerrato, Christine Cornforth, Alejandro Corsico, Soren Dalsgaard, Jurgen Deckert, Franziska Degenhardt, Alysa Doyle, Richard Ebstein, Josephine Elia, Juanita Gamble, Joel Gelernter, Michael Gill, Eugenio Horacio Grevet, Rachel Guerra, A.R. Hammerschlag, Amaia Hervas, Peter Holmans, Stefan Johansson, Lindsey Kent, Hyo-Won Kim, Gun Peggy Stromstad Knudsen, Paul Lichtenstein, Veera Manikandan, Meg Mariano, Nick Martin, Glaucia Chiyoko Akutagava Martins, Manuel Mattheisen, Jim McGough, Ana Miranda, Niels Peter Ole Mors, Preben Bo Mortensen, Nina Roth Mota, Fernando Mulas, Steve Nelson, Robert Oades, Pedro Pan, Julia Pinsonneault, Tinca Polderman, Danielle Posthuma, Herber Roeyers, Luis Rohde, Anna Rommel, Aribert Rothenberger, Paula Rovira, Cristina Sanchez, Andre Scherag, Susann Scherag, Joseph Sergeant, Pak Sham, Susan Smalley, Anna Starnawska, H.C. Steinhausen, Hans-Christoph Steinhausen, Patrick Sullivan, Alexandre Todorov, Raymond Walters, Yufeng Wang, Anne Wheeler, Nigel Williams, Li Yang, Tetyana Zayats, and Yanil Zhang. Funding Information: : We are extremely grateful to all the families who took part in the ALSPAC study, the midwives for their help in recruiting them, and the whole ALSPAC team, which includes interviewers, computer and laboratory technicians, clerical workers, research scientists, volunteers, managers, receptionists and nurses. GWAS data was generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and Joanna Martin will serve as guarantor for the contents of this article. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). ALSPAC Funding Information: Brain Behavior Research Foundation, Grant/Award Number: 27879; Health and Care Research Wales, Grant/Award Number: 514032; Medical Research Council, Grant/Award Number: MR/L010305/1; Wellcome Trust, Grant/Award Numbers: 079711, 204895/Z/16/Z; Welsh Government, Grant/Award Number: 663830-CU189; University of Bristol and the UK Medical Research Council, Grant/Award Number: MC_UU_00011/1 Funding information Publisher Copyright: © 2021 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.

PY - 2021/10/1

Y1 - 2021/10/1

N2 - It is unknown why attention deficit hyperactivity disorder (ADHD) is more common in males, whereas anxiety and depression show a female population excess. We tested the hypothesis that anxiety and depression risk alleles manifest as ADHD in males. We also tested whether anxiety and depression in children with ADHD show a different etiology to typical anxiety and depression and whether this differs by sex. The primary clinical ADHD sample consisted of 885 (14% female) children. Psychiatric symptoms were assessed using standardized interviews. Polygenic risk scores (PRS) were derived using large genetic studies. Replication samples included independent clinical ADHD samples (N = 3,794; 25.7% female) and broadly defined population ADHD samples (N = 995; 33.4% female). We did not identify sex differences in anxiety or depression PRS in children with ADHD. In the primary sample, anxiety PRS were associated with social and generalized anxiety in males, with evidence of a sex-by-PRS interaction for social anxiety. These results did not replicate in the broadly defined ADHD sample. Depression PRS were not associated with comorbid depression symptoms. The results suggest that anxiety and depression genetic risks are not more likely to lead to ADHD in males. Also, the evidence for shared etiology between anxiety symptoms in those with ADHD and typical anxiety was weak and needs replication.

AB - It is unknown why attention deficit hyperactivity disorder (ADHD) is more common in males, whereas anxiety and depression show a female population excess. We tested the hypothesis that anxiety and depression risk alleles manifest as ADHD in males. We also tested whether anxiety and depression in children with ADHD show a different etiology to typical anxiety and depression and whether this differs by sex. The primary clinical ADHD sample consisted of 885 (14% female) children. Psychiatric symptoms were assessed using standardized interviews. Polygenic risk scores (PRS) were derived using large genetic studies. Replication samples included independent clinical ADHD samples (N = 3,794; 25.7% female) and broadly defined population ADHD samples (N = 995; 33.4% female). We did not identify sex differences in anxiety or depression PRS in children with ADHD. In the primary sample, anxiety PRS were associated with social and generalized anxiety in males, with evidence of a sex-by-PRS interaction for social anxiety. These results did not replicate in the broadly defined ADHD sample. Depression PRS were not associated with comorbid depression symptoms. The results suggest that anxiety and depression genetic risks are not more likely to lead to ADHD in males. Also, the evidence for shared etiology between anxiety symptoms in those with ADHD and typical anxiety was weak and needs replication.

KW - ADHD

KW - ALSPAC

KW - anxiety disorders

KW - depression

KW - polygenic risk scores

KW - sex differences

U2 - 10.1002/ajmg.b.32842

DO - 10.1002/ajmg.b.32842

M3 - Article

SN - 1552-4841

VL - 186

SP - 412

EP - 422

JO - American Journal of Medical Genetics Part B-neuropsychiatric Genetics

JF - American Journal of Medical Genetics Part B-neuropsychiatric Genetics

IS - 7

ER -