Impact of Copy Number Variants and Polygenic Risk Scores on Psychopathology in the UK Biobank.
Anxiety
Copy number variants
Depression
Mood
Polygenic risk scores
Psychopathology
Journal
Biological psychiatry
ISSN: 1873-2402
Titre abrégé: Biol Psychiatry
Pays: United States
ID NLM: 0213264
Informations de publication
Date de publication:
01 10 2023
01 10 2023
Historique:
received:
06
07
2022
revised:
31
01
2023
accepted:
31
01
2023
pmc-release:
01
10
2024
medline:
8
9
2023
pubmed:
11
2
2023
entrez:
10
2
2023
Statut:
ppublish
Résumé
Our understanding of the impact of copy number variants (CNVs) on psychopathology and their joint influence with polygenic risk scores (PRSs) remains limited. The UK Biobank recruited 502,534 individuals ages 37 to 73 years living in the United Kingdom between 2006 and 2010. After quality control, genotype data from 459,855 individuals were available for CNV calling. A total of 61 commonly studied recurrent neuropsychiatric CNVs were selected for analyses and examined individually and in aggregate (any CNV, deletion, or duplication). CNV risk scores were used to quantify intolerance of CNVs to haploinsufficiency. Major depressive disorder and generalized anxiety disorder PRSs were generated for White British individuals (N = 408,870). Mood/anxiety factor scores were generated using item-level questionnaire data (N = 501,289). CNV carriers showed higher mood/anxiety scores than noncarriers, with the largest effects seen for intolerant deletions. A total of 11 individual deletions and 8 duplications were associated with higher mood/anxiety. Carriers of the 9p24.3 (DMRT1) duplication showed lower mood/anxiety. Associations remained significant for most CNVs when excluding individuals with psychiatric diagnoses. Nominally significant CNV × PRS interactions provided preliminary evidence that associations between select individual CNVs, but not CNVs in aggregate, and mood/anxiety may be modulated by PRSs. CNVs associated with risk for psychiatric disorders showed small to large effects on dimensional mood/anxiety scores in a general population cohort, even when excluding individuals with psychiatric diagnoses. CNV × PRS interactions showed that associations between select CNVs and mood/anxiety may be modulated by PRSs.
Sections du résumé
BACKGROUND
Our understanding of the impact of copy number variants (CNVs) on psychopathology and their joint influence with polygenic risk scores (PRSs) remains limited.
METHODS
The UK Biobank recruited 502,534 individuals ages 37 to 73 years living in the United Kingdom between 2006 and 2010. After quality control, genotype data from 459,855 individuals were available for CNV calling. A total of 61 commonly studied recurrent neuropsychiatric CNVs were selected for analyses and examined individually and in aggregate (any CNV, deletion, or duplication). CNV risk scores were used to quantify intolerance of CNVs to haploinsufficiency. Major depressive disorder and generalized anxiety disorder PRSs were generated for White British individuals (N = 408,870). Mood/anxiety factor scores were generated using item-level questionnaire data (N = 501,289).
RESULTS
CNV carriers showed higher mood/anxiety scores than noncarriers, with the largest effects seen for intolerant deletions. A total of 11 individual deletions and 8 duplications were associated with higher mood/anxiety. Carriers of the 9p24.3 (DMRT1) duplication showed lower mood/anxiety. Associations remained significant for most CNVs when excluding individuals with psychiatric diagnoses. Nominally significant CNV × PRS interactions provided preliminary evidence that associations between select individual CNVs, but not CNVs in aggregate, and mood/anxiety may be modulated by PRSs.
CONCLUSIONS
CNVs associated with risk for psychiatric disorders showed small to large effects on dimensional mood/anxiety scores in a general population cohort, even when excluding individuals with psychiatric diagnoses. CNV × PRS interactions showed that associations between select CNVs and mood/anxiety may be modulated by PRSs.
Identifiants
pubmed: 36764568
pii: S0006-3223(23)00056-2
doi: 10.1016/j.biopsych.2023.01.028
pmc: PMC10409883
mid: NIHMS1874433
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
591-600Subventions
Organisme : NIMH NIH HHS
ID : U01 MH119690
Pays : United States
Informations de copyright
Copyright © 2023 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
Références
Nat Genet. 2019 Mar;51(3):431-444
pubmed: 30804558
Nat Genet. 2016 Oct;48(10):1284-1287
pubmed: 27571263
Trends Genet. 2009 Dec;25(12):536-44
pubmed: 19910074
Am J Psychiatry. 2020 Mar 1;177(3):223-232
pubmed: 31906708
J Med Genet. 2014 Oct;51(10):677-88
pubmed: 25106414
Nat Genet. 2011 Aug 14;43(9):838-46
pubmed: 21841781
Am J Psychiatry. 2019 Jan 1;176(1):29-35
pubmed: 30392412
Pediatrics. 2020 Jan;145(1):
pubmed: 31843864
Cell. 2018 Jun 14;173(7):1705-1715.e16
pubmed: 29906448
Genome Res. 2006 Aug;16(8):949-61
pubmed: 16809666
Nat Med. 2020 Dec;26(12):1912-1918
pubmed: 33169016
Nat Neurosci. 2021 Jul;24(7):954-963
pubmed: 34045744
JAMA Psychiatry. 2022 Jul 1;79(7):699-709
pubmed: 35544191
Trends Genet. 2011 Aug;27(8):323-31
pubmed: 21684621
Nat Genet. 2017 Jan;49(1):27-35
pubmed: 27869829
Nucleic Acids Res. 2007;35(6):2013-25
pubmed: 17341461
Am J Psychiatry. 2021 Jan 1;178(1):87-98
pubmed: 32911998
Am J Med Genet B Neuropsychiatr Genet. 2013 Jul;162B(5):419-430
pubmed: 23728934
JAMA Psychiatry. 2019 Aug 1;76(8):818-825
pubmed: 30994872
Genome Med. 2017 Nov 30;9(1):106
pubmed: 29191242
Biol Psychiatry. 2014 Mar 1;75(5):378-85
pubmed: 23992924
Mol Psychiatry. 2012 Sep;17(9):880-6
pubmed: 22688191
Nature. 2020 May;581(7809):434-443
pubmed: 32461654
Pediatrics. 2006 Jul;118(1):405-20
pubmed: 16818591
JAMA Psychiatry. 2018 May 1;75(5):447-457
pubmed: 29562078
Nature. 2014 Jan 16;505(7483):361-6
pubmed: 24352232
Nat Rev Genet. 2015 Mar;16(3):172-83
pubmed: 25645873
Psychiatry Clin Neurosci. 2020 Jan;74(1):35-39
pubmed: 31461559
J Pers Assess. 2010 Nov;92(6):544-59
pubmed: 20954056
Mol Psychiatry. 2016 Jan;21(1):89-93
pubmed: 25560756
Nat Commun. 2019 Oct 8;10(1):4558
pubmed: 31594949
Mol Psychiatry. 2021 Jun;26(6):2663-2676
pubmed: 33414497
Transl Psychiatry. 2015 Feb 10;5:e506
pubmed: 25668434
Nature. 2010 Jul 15;466(7304):368-72
pubmed: 20531469
Neuron. 2015 Sep 23;87(6):1215-1233
pubmed: 26402605
Genome Res. 2007 Nov;17(11):1665-74
pubmed: 17921354
HGG Adv. 2022 Jan 21;3(2):100091
pubmed: 35199043
Nat Neurosci. 2019 Mar;22(3):343-352
pubmed: 30718901
Harv Rev Psychiatry. 1999 Nov-Dec;7(4):185-207
pubmed: 10579099
Mol Psychiatry. 2016 Aug;21(8):1085-9
pubmed: 26390827
Mol Psychiatry. 2021 Aug;26(8):4496-4510
pubmed: 32015465
Nat Genet. 2019 May;51(5):793-803
pubmed: 31043756
Nat Commun. 2019 Apr 16;10(1):1776
pubmed: 30992449
Mol Psychiatry. 2013 Oct;18(10):1090-5
pubmed: 23044707
Nucleic Acids Res. 2019 Jan 8;47(D1):D766-D773
pubmed: 30357393
Lancet. 2002 Feb 2;359(9304):426-30
pubmed: 11844533
Am J Psychiatry. 2022 Mar;179(3):189-203
pubmed: 35236119
Science. 2010 Oct 29;330(6004):641-6
pubmed: 21030649
Nat Genet. 2014 Oct;46(10):1063-71
pubmed: 25217958
Science. 2007 Apr 20;316(5823):445-9
pubmed: 17363630
Bipolar Disord. 2013 Dec;15(8):893-8
pubmed: 24127788
Biol Psychiatry. 2019 Jul 15;86(2):110-119
pubmed: 30686506
J Autism Dev Disord. 2021 Jan;51(1):276-285
pubmed: 32462456
Biol Psychiatry. 2014 Oct 1;76(7):536-41
pubmed: 24529801