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| PMID |
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| TITLE |
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| Genome-wide analysis of over 106?000 individuals identifies 9 neuroticism-associated loci. |
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| ABSTRACT |
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| Neuroticism is a personality trait of fundamental importance for psychological well-being and public health. It is strongly associated with major depressive disorder (MDD) and several other psychiatric conditions. Although neuroticism is heritable, attempts to identify the alleles involved in previous studies have been limited by relatively small sample sizes. Here we report a combined meta-analysis of genome-wide association study (GWAS) of neuroticism that includes 91 370 participants from the UK Biobank cohort, 6659 participants from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and 8687 participants from a QIMR (Queensland Institute of Medical Research) Berghofer Medical Research Institute (QIMR) cohort. All participants were assessed using the same neuroticism instrument, the Eysenck Personality Questionnaire-Revised (EPQ-R-S) Short Form's Neuroticism scale. We found a single-nucleotide polymorphism-based heritability estimate for neuroticism of ∼15% (s.e.=0.7%). Meta-analysis identified nine novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (P=1.5 × 10(-15)) spanning 4 Mb and containing at least 36 genes. Other associated loci included interesting candidate genes on chromosome 1 (GRIK3 (glutamate receptor ionotropic kainate 3)), chromosome 4 (KLHL2 (Kelch-like protein 2)), chromosome 17 (CRHR1 (corticotropin-releasing hormone receptor 1) and MAPT (microtubule-associated protein Tau)) and on chromosome 18 (CELF4 (CUGBP elav-like family member 4)). We found no evidence for genetic differences in the common allelic architecture of neuroticism by sex. By comparing our findings with those of the Psychiatric Genetics Consortia, we identified a strong genetic correlation between neuroticism and MDD and a less strong but significant genetic correlation with schizophrenia, although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured ∼1% of the variance in neuroticism in the GS:SFHS and QIMR samples, although most of the genome-wide significant alleles identified within a UK Biobank-only GWAS of neuroticism were not independently replicated within these cohorts. The identification of nine novel neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| received |
2015/11/20 |
| revised |
2016/02/19 |
| accepted |
2016/03/02 |
| aheadofprint |
2016/04/12 |
| entrez |
2016/04/13 06:00 |
| pubmed |
2016/04/14 06:00 |
| medline |
2016/04/14 06:00 |
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| AUTHORS |
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| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Smith DJ |
|
Smith |
D J |
DJ |
|
Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK. |
| Escott-Price V |
|
Escott-Price |
V |
V |
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MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK. |
| Davies G |
|
Davies |
G |
G |
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Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK. |
| Bailey ME |
|
Bailey |
M E S |
ME |
|
School of Life Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. |
| Colodro-Conde L |
|
Colodro-Conde |
L |
L |
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QIMR Berghofer Medical Research Institute, Herston, QLD, Australia. |
| Ward J |
|
Ward |
J |
J |
|
Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK. |
| Vedernikov A |
|
Vedernikov |
A |
A |
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MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK. |
| Marioni R |
|
Marioni |
R |
R |
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Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. |
| Cullen B |
|
Cullen |
B |
B |
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Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK. |
| Lyall D |
|
Lyall |
D |
D |
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Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK. |
| Hagenaars SP |
|
Hagenaars |
S P |
SP |
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Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK. |
| Liewald DC |
|
Liewald |
D C M |
DC |
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Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK. |
| Luciano M |
|
Luciano |
M |
M |
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Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK. |
| Gale CR |
|
Gale |
C R |
CR |
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MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital, Southampton, UK. |
| Ritchie SJ |
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Ritchie |
S J |
SJ |
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Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, UK. |
| Hayward C |
|
Hayward |
C |
C |
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Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. |
| Nicholl B |
|
Nicholl |
B |
B |
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Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK. |
| Bulik-Sullivan B |
|
Bulik-Sullivan |
B |
B |
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Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. |
| Adams M |
|
Adams |
M |
M |
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Division of Psychiatry, University of Edinburgh, Edinburgh, UK. |
| Couvy-Duchesne B |
|
Couvy-Duchesne |
B |
B |
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QIMR Berghofer Medical Research Institute, Herston, QLD, Australia. |
| Graham N |
|
Graham |
N |
N |
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Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK. |
| Mackay D |
|
Mackay |
D |
D |
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Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK. |
| Evans J |
|
Evans |
J |
J |
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Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK. |
| Smith BH |
|
Smith |
B H |
BH |
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Division of Population Health Sciences, University of Dundee, Dundee, UK. |
| Porteous DJ |
|
Porteous |
D J |
DJ |
|
Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. |
| Medland SE |
|
Medland |
S E |
SE |
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QIMR Berghofer Medical Research Institute, Herston, QLD, Australia. |
| Martin NG |
|
Martin |
N G |
NG |
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QIMR Berghofer Medical Research Institute, Herston, QLD, Australia. |
| Holmans P |
|
Holmans |
P |
P |
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MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK. |
| McIntosh AM |
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McIntosh |
A M |
AM |
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Division of Psychiatry, University of Edinburgh, Edinburgh, UK. |
| Pell JP |
|
Pell |
J P |
JP |
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Institute of Health and Wellbeing, University of Glasgow, Glasgow, UK. |
| Deary IJ |
|
Deary |
I J |
IJ |
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Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK. |
| O'Donovan MC |
|
O'Donovan |
M C |
MC |
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MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK. |
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| INVESTIGATORS |
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| JOURNAL |
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| VOLUME: 21 |
| ISSUE: 6 |
| TITLE: Molecular psychiatry |
| ISOABBREVIATION: Mol. Psychiatry |
| YEAR: 2016 |
| MONTH: Jun |
| DAY: |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1476-5578 |
| ISSNTYPE: Electronic |
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| MEDLINE JOURNAL |
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| MEDLINETA: Mol Psychiatry |
| COUNTRY: England |
| ISSNLINKING: 1359-4184 |
| NLMUNIQUEID: 9607835 |
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| PUBLICATION TYPE |
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| PUBLICATIONTYPE TEXT |
| Journal Article |
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| COMMENTS AND CORRECTIONS |
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| REFTYPE |
REFSOURCE |
REFPMID |
NOTE |
| Cites |
Perspect Psychol Sci. 2014 Sep;9(5):481-96 |
26186755 |
|
| Cites |
JAMA Psychiatry. 2015 Jul;72(7):642-50 |
25993607 |
|
| Cites |
Mol Psychiatry. 2015 Sep;20(9):1057-68 |
26169973 |
|
| Cites |
Nat Commun. 2015;6:8111 |
26368830 |
|
| Cites |
Nat Genet. 2015 Nov;47(11):1236-41 |
26414676 |
|
| Cites |
Transl Psychiatry. 2016;6:e791 |
27115122 |
|
| Cites |
Mol Psychiatry. 2016 Jun;21(6):813-22 |
26324098 |
|
| Cites |
Behav Genet. 2000 May;30(3):223-33 |
11105396 |
|
| Cites |
Psychol Med. 2001 Aug;31(6):1129-34 |
11513380 |
|
| Cites |
J Neurochem. 2004 Mar;88(5):1078-90 |
15009664 |
|
| Cites |
Arch Gen Psychiatry. 1993 Nov;50(11):853-62 |
8215811 |
|
| Cites |
Mol Biol Cell. 1999 Jul;10(7):2361-75 |
10397770 |
|
| Cites |
J Neurochem. 2005 Mar;92(5):1191-203 |
15715669 |
|
| Cites |
Behav Genet. 2005 Nov;35(6):707-21 |
16273321 |
|
| Cites |
J Pers Soc Psychol. 2006 Jun;90(6):987-98 |
16784347 |
|
| Cites |
BMC Med Genet. 2006;7:74 |
17014726 |
|
| Cites |
Am J Med Genet B Neuropsychiatr Genet. 2007 Jan 5;144B(1):20-6 |
16958029 |
|
| Cites |
Am J Psychiatry. 2007 Aug;164(8):1181-8 |
17671280 |
|
| Cites |
Twin Res Hum Genet. 2007 Oct;10(5):695-702 |
17903109 |
|
| Cites |
Nat Genet. 2008 Aug;40(8):946-8 |
18660810 |
|
| Cites |
Neuropsychobiology. 2009;59(1):28-33 |
19221446 |
|
| Cites |
Psychosom Med. 2009 May;71(4):385-94 |
19251871 |
|
| Cites |
Am Psychol. 2009 May-Jun;64(4):241-56 |
19449983 |
|
| Cites |
Prog Neuropsychopharmacol Biol Psychiatry. 2009 Aug 1;33(5):875-9 |
19386277 |
|
| Cites |
Biol Psychiatry. 2009 Dec 1;66(11):988-9 |
19900610 |
|
| Cites |
Biol Psychiatry. 2009 Dec 15;66(12):1131-8 |
19748081 |
|
| Cites |
Psychol Med. 2010 May;40(5):801-6 |
19732485 |
|
| Cites |
Nat Genet. 2010 Jul;42(7):565-9 |
20562875 |
|
| Cites |
Cell. 2010 Aug 6;142(3):387-97 |
20655099 |
|
| Cites |
Psychol Bull. 2010 Sep;136(5):768-821 |
20804236 |
|
| Cites |
Arch Gen Psychiatry. 2010 Oct;67(10):1086-93 |
20921124 |
|
| Cites |
Int Rev Psychiatry. 2010;22(5):429-36 |
21047157 |
|
| Cites |
Am J Hum Genet. 2011 Jan 7;88(1):76-82 |
21167468 |
|
| Cites |
Psychosom Med. 2011 Feb-Mar;73(2):114-26 |
21257974 |
|
| Cites |
Mol Cell Neurosci. 2011 Aug;47(4):254-64 |
21549840 |
|
| Cites |
Hippocampus. 2011 Aug;21(8):827-34 |
20607795 |
|
| Cites |
Nat Genet. 2011 Oct;43(10):977-83 |
21926972 |
|
| Cites |
Neuropharmacology. 2012 Jan;62(1):63-77 |
21827775 |
|
| Cites |
Eur Arch Psychiatry Clin Neurosci. 2012 Jun;262(4):305-11 |
22057216 |
|
| Cites |
Transl Psychiatry. 2012;2:e102 |
22832902 |
|
| Cites |
Evolution. 2012 Oct;66(10):3238-51 |
23025612 |
|
| Cites |
Transl Psychiatry. 2012;2:e184 |
23149448 |
|
| Cites |
PLoS Genet. 2012;8(11):e1003067 |
23209433 |
|
| Cites |
Nat Methods. 2013 Jan;10(1):5-6 |
23269371 |
|
| Cites |
Mol Psychiatry. 2013 Apr;18(4):497-511 |
22472876 |
|
| Cites |
BMC Med. 2013;11:126 |
23672542 |
|
| Cites |
Trends Neurosci. 2013 Sep;36(9):522-34 |
23835198 |
|
| Cites |
Philos Trans R Soc Lond B Biol Sci. 2014 Jan 5;369(1633):20130144 |
24298146 |
|
| Cites |
Am J Psychiatry. 2014 Apr;171(4):426-35 |
24525762 |
|
| Cites |
Am J Psychiatry. 2014 Apr;171(4):395-7 |
24687194 |
|
| Cites |
Behav Genet. 2014 Jul;44(4):295-313 |
24828478 |
|
| Cites |
Nature. 2014 Jul 24;511(7510):421-7 |
25056061 |
|
| Cites |
J Child Psychol Psychiatry. 2014 Oct;55(10):1068-87 |
25132410 |
|
| Cites |
Nat Genet. 2015 Mar;47(3):291-5 |
25642630 |
|
| Cites |
Mol Psychiatry. 2015 Feb;20(2):183-92 |
25644384 |
|
| Cites |
PLoS Med. 2015 Mar;12(3):e1001779 |
25826379 |
|
| Cites |
Nature. 2015 Jul 30;523(7562):588-91 |
26176920 |
|
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| GRANTS |
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| GRANTID |
AGENCY |
COUNTRY |
| 104036 |
Wellcome Trust |
United Kingdom |
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| GENERAL NOTE |
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| PMC4879189 |
NLM |
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