Attention-deficit/hyperactivity disorder and major depressive disorder: evidence from multiple genetically informed designs
Attention-deficit/hyperactivity disorder and major depressive disorder: evidence from multiple genetically informed designs
Background: attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) are two highly prevalent disorders that frequently co-occur. Prior evidence from genetic and cohort studies supports an association between ADHD and MDD. However, the direction and mechanisms underlying their association remain unclear. As onset of ADHD occurs in early life, it has been hypothesized that ADHD may cause MDD.
Methods: we examined the association of ADHD with MDD using 3 different genetically informed methods to disentangle causality from confounding: 1) a nationwide longitudinal register-based full sibling comparison (N = 1,018,489) adjusting for shared familial confounding; 2) a prospective co-twin control study comprising 16,477 twins (5084 monozygotic and 11,393 dizygotic); and 3) a two-sample Mendelian randomization analysis using the largest available ADHD (N = 225,534) and MDD (N = 500,199) genome-wide association study summary statistics, adjusting for correlated and uncorrelated horizontal pleiotropy.
Results: sibling and twin comparisons indicated that individuals with ADHD have an increased risk for subsequent development of MDD (hazard ratio = 4.12 [95% CI 3.62–4.69]) after adjusting for shared genetic and familial factors and that ADHD scores endorsed by parents are positively associated with subsequent MDD scores at ages 15 and 18 years (b = 0.07 [95% CI 0.05–0.08] and b = 0.09 [95% CI 0.08–0.11], respectively). Mendelian randomization analyses showed that genetic liability for ADHD is causally related to MDD (odds ratio = 1.15 [95% CI 1.08–1.23]).
Conclusions: our study provides consistent results across 3 different genetically informative approaches, strengthening the hypothesis that ADHD is causally related to MDD.
ADHD, Attention-deficit/hyperactivity disorder, Depression, Mendelian randomization, Twin studies
444-452
Garcia-Argibay, Miguel
e5a6941e-4dcc-401a-9de4-09557c8856ef
Brikell, Isabell
8ce0666a-d578-4128-9385-20358b875b7c
Thapar, Anita
224b4dc1-a6ee-455a-95f9-b9a716606aa6
Lichtenstein, Paul
1e1573e3-7442-4d1f-969f-17dc9b7edaa4
Lundström, Sebastian
c0e400cd-a80a-4cc9-a303-21b49ddd8069
Demontis, Ditte
b47a58df-28ee-401a-897b-6685566a86bf
Larsson, Henrik
4132f7c6-5d52-43a1-be38-d343e67107cf
5 February 2024
Garcia-Argibay, Miguel
e5a6941e-4dcc-401a-9de4-09557c8856ef
Brikell, Isabell
8ce0666a-d578-4128-9385-20358b875b7c
Thapar, Anita
224b4dc1-a6ee-455a-95f9-b9a716606aa6
Lichtenstein, Paul
1e1573e3-7442-4d1f-969f-17dc9b7edaa4
Lundström, Sebastian
c0e400cd-a80a-4cc9-a303-21b49ddd8069
Demontis, Ditte
b47a58df-28ee-401a-897b-6685566a86bf
Larsson, Henrik
4132f7c6-5d52-43a1-be38-d343e67107cf
Garcia-Argibay, Miguel, Brikell, Isabell, Thapar, Anita, Lichtenstein, Paul, Lundström, Sebastian, Demontis, Ditte and Larsson, Henrik
(2024)
Attention-deficit/hyperactivity disorder and major depressive disorder: evidence from multiple genetically informed designs.
Biological Psychiatry, 95 (5), .
(doi:10.1016/j.biopsych.2023.07.017).
Abstract
Background: attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) are two highly prevalent disorders that frequently co-occur. Prior evidence from genetic and cohort studies supports an association between ADHD and MDD. However, the direction and mechanisms underlying their association remain unclear. As onset of ADHD occurs in early life, it has been hypothesized that ADHD may cause MDD.
Methods: we examined the association of ADHD with MDD using 3 different genetically informed methods to disentangle causality from confounding: 1) a nationwide longitudinal register-based full sibling comparison (N = 1,018,489) adjusting for shared familial confounding; 2) a prospective co-twin control study comprising 16,477 twins (5084 monozygotic and 11,393 dizygotic); and 3) a two-sample Mendelian randomization analysis using the largest available ADHD (N = 225,534) and MDD (N = 500,199) genome-wide association study summary statistics, adjusting for correlated and uncorrelated horizontal pleiotropy.
Results: sibling and twin comparisons indicated that individuals with ADHD have an increased risk for subsequent development of MDD (hazard ratio = 4.12 [95% CI 3.62–4.69]) after adjusting for shared genetic and familial factors and that ADHD scores endorsed by parents are positively associated with subsequent MDD scores at ages 15 and 18 years (b = 0.07 [95% CI 0.05–0.08] and b = 0.09 [95% CI 0.08–0.11], respectively). Mendelian randomization analyses showed that genetic liability for ADHD is causally related to MDD (odds ratio = 1.15 [95% CI 1.08–1.23]).
Conclusions: our study provides consistent results across 3 different genetically informative approaches, strengthening the hypothesis that ADHD is causally related to MDD.
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Accepted/In Press date: 30 July 2023
e-pub ahead of print date: 9 August 2023
Published date: 5 February 2024
Keywords:
ADHD, Attention-deficit/hyperactivity disorder, Depression, Mendelian randomization, Twin studies
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Local EPrints ID: 488965
URI: http://eprints.soton.ac.uk/id/eprint/488965
ISSN: 0006-3223
PURE UUID: c3a8c4eb-24c6-4e9d-9539-753b5095c851
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Date deposited: 10 Apr 2024 16:33
Last modified: 13 Apr 2024 02:11
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Contributors
Author:
Miguel Garcia-Argibay
Author:
Isabell Brikell
Author:
Anita Thapar
Author:
Paul Lichtenstein
Author:
Sebastian Lundström
Author:
Ditte Demontis
Author:
Henrik Larsson
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