Genetic markers of ADHD-related variations in intracranial volume

Marieke Klein; Raymond K. Walters; Ditte Demontis; Jason L. Stein; Derrek P. Hibar; Hieab H. Adams; Janita Bralten; Nina Roth Mota; Russell Schachar; Edmund Sonuga-Barke; Manuel Mattheisen; Benjamin M. Neale; Paul M. Thompson; Sarah E. Medland; Anders D. Børglum; Stephen V. Faraone; Alejandro Arias-Vasquez; Barbara Franke

doi:10.1176/appi.ajp.2018.18020149

Genetic markers of ADHD-related variations in intracranial volume

Marieke Klein, Raymond K. Walters, Ditte Demontis, Jason L. Stein, Derrek P. Hibar, Hieab H. Adams, Janita Bralten, Nina Roth Mota, Russell Schachar, Edmund Sonuga-Barke, Manuel Mattheisen, Benjamin M. Neale, Paul M. Thompson, Sarah E. Medland, Anders D. Børglum, Stephen V. Faraone, Alejandro Arias-Vasquez, Barbara Franke^*

^*Corresponding author for this work

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

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Abstract

Objective: Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology. Intracranial volume (ICV) and volumes of the nucleus accumbens, amygdala, caudate nucleus, hippocampus, and putamen are smaller in people with ADHD compared with healthy individuals. The authors investigated the overlap between common genetic variation associated with ADHD risk and these brain volume measures to identify underlying biological processes contributing to the disorder.

Methods: The authors combined genome-wide association results from the largest available studies of ADHD (N=55,374) and brain volumes (N=11,221-24,704), using a set of complementary methods to investigate overlap at the level of global common variant genetic architecture and at the single variant level.

Results: Analyses revealed a significant negative genetic correlation between ADHD and ICV (r _g =20.22). Meta-analysis of single variants revealed two significant loci of interest associated with both ADHD risk and ICV; four additional loci were identified for ADHD and volumes of the amygdala, caudate nucleus, and putamen. Exploratory gene-based and gene-set analyses in the ADHD-ICV meta-analytic data showed association with variation in neurite outgrowth-related genes.

Conclusions: This is the first genome-wide study to show significant genetic overlap between brain volume measures and ADHD, both on the global and the single variant level. Variants linked to smaller ICV were associated with increased ADHD risk. These findings can help us develop new hypotheses about biological mechanisms by which brain structure alterations may be involved in ADHD disease etiology.

Original language	English
Pages (from-to)	228-238
Number of pages	11
Journal	American Journal of Psychiatry
Volume	176
Issue number	3
Early online date	1 Mar 2019
DOIs	https://doi.org/10.1176/appi.ajp.2018.18020149
Publication status	Published - 1 Mar 2019

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Genetic markers of ADHD-related variations_BARKE_PublishedonlineMarch2019_GREEN AAMAccepted author manuscript, 808 KB

https://www.biorxiv.org/content/10.1101/184192v1

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Klein, M., Walters, R. K., Demontis, D., Stein, J. L., Hibar, D. P., Adams, H. H., Bralten, J., Mota, N. R., Schachar, R., Sonuga-Barke, E., Mattheisen, M., Neale, B. M., Thompson, P. M., Medland, S. E., Børglum, A. D., Faraone, S. V., Arias-Vasquez, A., & Franke, B. (2019). Genetic markers of ADHD-related variations in intracranial volume. American Journal of Psychiatry, 176(3), 228-238. https://doi.org/10.1176/appi.ajp.2018.18020149

@article{22ed63b2675f4129ba3af3ed2514750b,

title = "Genetic markers of ADHD-related variations in intracranial volume",

abstract = " Objective: Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology. Intracranial volume (ICV) and volumes of the nucleus accumbens, amygdala, caudate nucleus, hippocampus, and putamen are smaller in people with ADHD compared with healthy individuals. The authors investigated the overlap between common genetic variation associated with ADHD risk and these brain volume measures to identify underlying biological processes contributing to the disorder. Methods: The authors combined genome-wide association results from the largest available studies of ADHD (N=55,374) and brain volumes (N=11,221-24,704), using a set of complementary methods to investigate overlap at the level of global common variant genetic architecture and at the single variant level. Results: Analyses revealed a significant negative genetic correlation between ADHD and ICV (r g =20.22). Meta-analysis of single variants revealed two significant loci of interest associated with both ADHD risk and ICV; four additional loci were identified for ADHD and volumes of the amygdala, caudate nucleus, and putamen. Exploratory gene-based and gene-set analyses in the ADHD-ICV meta-analytic data showed association with variation in neurite outgrowth-related genes. Conclusions: This is the first genome-wide study to show significant genetic overlap between brain volume measures and ADHD, both on the global and the single variant level. Variants linked to smaller ICV were associated with increased ADHD risk. These findings can help us develop new hypotheses about biological mechanisms by which brain structure alterations may be involved in ADHD disease etiology. ",

author = "Marieke Klein and Walters, {Raymond K.} and Ditte Demontis and Stein, {Jason L.} and Hibar, {Derrek P.} and Adams, {Hieab H.} and Janita Bralten and Mota, {Nina Roth} and Russell Schachar and Edmund Sonuga-Barke and Manuel Mattheisen and Neale, {Benjamin M.} and Thompson, {Paul M.} and Medland, {Sarah E.} and B{\o}rglum, {Anders D.} and Faraone, {Stephen V.} and Alejandro Arias-Vasquez and Barbara Franke",

year = "2019",

month = mar,

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doi = "10.1176/appi.ajp.2018.18020149",

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Klein, M, Walters, RK, Demontis, D, Stein, JL, Hibar, DP, Adams, HH, Bralten, J, Mota, NR, Schachar, R, Sonuga-Barke, E, Mattheisen, M, Neale, BM, Thompson, PM, Medland, SE, Børglum, AD, Faraone, SV, Arias-Vasquez, A & Franke, B 2019, 'Genetic markers of ADHD-related variations in intracranial volume', American Journal of Psychiatry, vol. 176, no. 3, pp. 228-238. https://doi.org/10.1176/appi.ajp.2018.18020149

TY - JOUR

T1 - Genetic markers of ADHD-related variations in intracranial volume

AU - Klein, Marieke

AU - Walters, Raymond K.

AU - Demontis, Ditte

AU - Stein, Jason L.

AU - Hibar, Derrek P.

AU - Adams, Hieab H.

AU - Bralten, Janita

AU - Mota, Nina Roth

AU - Schachar, Russell

AU - Sonuga-Barke, Edmund

AU - Mattheisen, Manuel

AU - Neale, Benjamin M.

AU - Thompson, Paul M.

AU - Medland, Sarah E.

AU - Børglum, Anders D.

AU - Faraone, Stephen V.

AU - Arias-Vasquez, Alejandro

AU - Franke, Barbara

PY - 2019/3/1

Y1 - 2019/3/1

N2 - Objective: Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology. Intracranial volume (ICV) and volumes of the nucleus accumbens, amygdala, caudate nucleus, hippocampus, and putamen are smaller in people with ADHD compared with healthy individuals. The authors investigated the overlap between common genetic variation associated with ADHD risk and these brain volume measures to identify underlying biological processes contributing to the disorder. Methods: The authors combined genome-wide association results from the largest available studies of ADHD (N=55,374) and brain volumes (N=11,221-24,704), using a set of complementary methods to investigate overlap at the level of global common variant genetic architecture and at the single variant level. Results: Analyses revealed a significant negative genetic correlation between ADHD and ICV (r g =20.22). Meta-analysis of single variants revealed two significant loci of interest associated with both ADHD risk and ICV; four additional loci were identified for ADHD and volumes of the amygdala, caudate nucleus, and putamen. Exploratory gene-based and gene-set analyses in the ADHD-ICV meta-analytic data showed association with variation in neurite outgrowth-related genes. Conclusions: This is the first genome-wide study to show significant genetic overlap between brain volume measures and ADHD, both on the global and the single variant level. Variants linked to smaller ICV were associated with increased ADHD risk. These findings can help us develop new hypotheses about biological mechanisms by which brain structure alterations may be involved in ADHD disease etiology.

AB - Objective: Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology. Intracranial volume (ICV) and volumes of the nucleus accumbens, amygdala, caudate nucleus, hippocampus, and putamen are smaller in people with ADHD compared with healthy individuals. The authors investigated the overlap between common genetic variation associated with ADHD risk and these brain volume measures to identify underlying biological processes contributing to the disorder. Methods: The authors combined genome-wide association results from the largest available studies of ADHD (N=55,374) and brain volumes (N=11,221-24,704), using a set of complementary methods to investigate overlap at the level of global common variant genetic architecture and at the single variant level. Results: Analyses revealed a significant negative genetic correlation between ADHD and ICV (r g =20.22). Meta-analysis of single variants revealed two significant loci of interest associated with both ADHD risk and ICV; four additional loci were identified for ADHD and volumes of the amygdala, caudate nucleus, and putamen. Exploratory gene-based and gene-set analyses in the ADHD-ICV meta-analytic data showed association with variation in neurite outgrowth-related genes. Conclusions: This is the first genome-wide study to show significant genetic overlap between brain volume measures and ADHD, both on the global and the single variant level. Variants linked to smaller ICV were associated with increased ADHD risk. These findings can help us develop new hypotheses about biological mechanisms by which brain structure alterations may be involved in ADHD disease etiology.

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SN - 0002-953X

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SP - 228

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JO - American Journal of Psychiatry

JF - American Journal of Psychiatry

IS - 3

ER -

Genetic markers of ADHD-related variations in intracranial volume

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