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

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Anxiety/*genetics ; Depression/*genetics ; Neurodevelopmental Disorders/*genetics; Adolescent ; Adult ; Age of Onset ; Aged ; Attention Deficit Disorder with Hyperactivity ; Child ; Cohort Studies ; DNA Copy Number Variations ; Depressive Disorder, Major/genetics ; Female ; Genetic Predisposition to Disease ; Humans ; Male ; Medical History Taking ; Middle Aged ; Schizophrenia/genetics ; Sex Factors ; Young Adult

Competing Interests: MOD, JTRW and IJ have received a collaborative research grant from Takeda Pharmaceuticals. Takeda played no part in the conception, design, implementation, or interpretation of this study. CML is on the Scientific Advisory Board of Myriad Neuroscience. All other authors report no conflicts of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
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.

JAMA Psychiatry. 2019 Aug 1;76(8):818-825. (PMID: 30994872)
Neurochem Int. 2007 Oct;51(5):246-53. (PMID: 17664028)
BJPsych Open. 2020 Jun 18;6(4):e65. (PMID: 32552921)
JAMA Psychiatry. 2013 Oct;70(10):1100-6. (PMID: 23986338)
Am J Hum Genet. 2007 Sep;81(3):559-75. (PMID: 17701901)
Biol Psychiatry Cogn Neurosci Neuroimaging. 2018 Jul;3(7):635-643. (PMID: 30047479)
Mol Psychiatry. 2020 Dec;25(12):3292-3303. (PMID: 31748690)
J Child Psychol Psychiatry. 2018 Aug;59(8):908-916. (PMID: 29451303)
Lancet. 2018 Nov 24;392(10161):2299-2312. (PMID: 30396512)
Psychol Med. 2008 May;38(5):641-9. (PMID: 18272011)
PLoS Genet. 2011 Nov;7(11):e1002334. (PMID: 22102821)
Br J Psychiatry. 2019 Nov;215(5):647-653. (PMID: 30806336)
JAMA Psychiatry. 2019 Mar 1;76(3):306-313. (PMID: 30326013)
Nat Genet. 2019 Mar;51(3):431-444. (PMID: 30804558)
Am J Psychiatry. 2000 Oct;157(10):1552-62. (PMID: 11007705)
Cell. 2019 Dec 12;179(7):1469-1482.e11. (PMID: 31835028)
Lancet. 2012 Dec 15;380(9859):2163-96. (PMID: 23245607)
Lancet Psychiatry. 2017 Apr;4(4):339-346. (PMID: 27979720)
J Affect Disord. 2014 Mar;156:156-63. (PMID: 24388685)
JAMA Psychiatry. 2020 Feb 1;77(2):155-164. (PMID: 31746968)
Arch Gen Psychiatry. 1998 May;55(5):468-72. (PMID: 9596050)
Am J Med Genet B Neuropsychiatr Genet. 2019 Sep;180(6):341-350. (PMID: 30307693)
Am J Psychiatry. 2006 Jan;163(1):109-14. (PMID: 16390897)
J Am Acad Child Adolesc Psychiatry. 2010 Aug;49(8):820-9. (PMID: 20643315)
Nat Genet. 2018 May;50(5):668-681. (PMID: 29700475)
Nat Genet. 2019 Jan;51(1):63-75. (PMID: 30478444)
Nat Rev Dis Primers. 2017 May 04;3:17024. (PMID: 28470168)
Depress Res Treat. 2015;2015:476238. (PMID: 26649194)
Acta Psychiatr Scand. 1983 Jun;67(6):361-70. (PMID: 6880820)
Nat Genet. 2020 Apr;52(4):437-447. (PMID: 32231276)
Mol Psychiatry. 2020 Aug;25(8):1631-1639. (PMID: 31959848)
J Affect Disord. 2011 Dec;135(1-3):89-94. (PMID: 21782247)
Neuron. 2015 Sep 23;87(6):1215-1233. (PMID: 26402605)
Genome Res. 2007 Nov;17(11):1665-74. (PMID: 17921354)
Am J Psychiatry. 2001 Oct;158(10):1568-78. (PMID: 11578982)
Biol Psychiatry. 2017 Feb 15;81(4):325-335. (PMID: 27519822)
Am J Epidemiol. 2017 Nov 1;186(9):1026-1034. (PMID: 28641372)
Am J Psychiatry. 2006 Jan;163(1):28-40. (PMID: 16390886)
Nat Genet. 2019 May;51(5):793-803. (PMID: 31043756)
Genet Epidemiol. 2020 Oct;44(7):676-686. (PMID: 32691445)
Biol Psychiatry. 2022 Jan 1;91(1):102-117. (PMID: 34099189)
Am J Psychiatry. 2012 Feb;169(2):195-204. (PMID: 22420048)
Biol Psychiatry. 2021 Jun 15;89(12):1127-1137. (PMID: 33648717)

G1000632 United Kingdom MRC_ Medical Research Council; U01 MH109514 United States MH NIMH NIH HHS; United Kingdom WT_ Wellcome Trust; MR/L010305/1 United Kingdom MRC_ Medical Research Council; U01 MH109528 United States MH NIMH NIH HHS

Date Created: 20210902 Date Completed: 20211112 Latest Revision: 20250530

20250530

PMC8412369

10.1371/journal.pone.0248254

34473692