TY - JOUR
T1 - Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways
AU - 23andMe Research Team
AU - Nagel, Mats
AU - Jansen, Philip R
AU - Stringer, Sven
AU - Watanabe, Kyoko
AU - de Leeuw, Christiaan A
AU - Bryois, Julien
AU - Savage, Jeanne E
AU - Hammerschlag, Anke R
AU - Skene, Nathan G
AU - Muñoz-Manchado, Ana B
AU - White, Tonya
AU - Tiemeier, Henning
AU - Linnarsson, Sten
AU - Hjerling-Leffler, Jens
AU - Polderman, Tinca J C
AU - Sullivan, Patrick F
AU - van der Sluis, Sophie
AU - Posthuma, Danielle
AU - Agee, Michelle
AU - Alipanahi, Babak
AU - Auton, Adam
AU - Bell, Robert K.
AU - Bryc, Katarzyna
AU - Elson, Sarah L.
AU - Fontanillas, Pierre
AU - Furlotte, Nicholas A.
AU - Hinds, David A.
AU - Hromatka, Bethann S.
AU - Huber, Karen E.
AU - Kleinman, Aaron
AU - Litterman, Nadia K.
AU - McIntyre, Matthew H.
AU - Mountain, Joanna L.
AU - Noblin, Elizabeth S.
AU - Northover, Carrie A.M.
AU - Pitts, Steven J.
AU - Sathirapongsasuti, J. Fah
AU - Sazonova, Olga V.
AU - Shelton, Janie F.
AU - Shringarpure, Suyash
AU - Tian, Chao
AU - Tung, Joyce Y.
AU - Vacic, Vladimir
AU - Wilson, Catherine H.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - Neuroticism is an important risk factor for psychiatric traits, including depression1, anxiety2,3, and schizophrenia4-6. At the time of analysis, previous genome-wide association studies7-12 (GWAS) reported 16 genomic loci associated to neuroticism10-12. Here we conducted a large GWAS meta-analysis (n = 449,484) of neuroticism and identified 136 independent genome-wide significant loci (124 new at the time of analysis), which implicate 599 genes. Functional follow-up analyses showed enrichment in several brain regions and involvement of specific cell types, including dopaminergic neuroblasts (P = 3.49 × 10-8), medium spiny neurons (P = 4.23 × 10-8), and serotonergic neurons (P = 1.37 × 10-7). Gene set analyses implicated three specific pathways: neurogenesis (P = 4.43 × 10-9), behavioral response to cocaine processes (P = 1.84 × 10-7), and axon part (P = 5.26 × 10-8). We show that neuroticism's genetic signal partly originates in two genetically distinguishable subclusters13 ('depressed affect' and 'worry'), suggesting distinct causal mechanisms for subtypes of individuals. Mendelian randomization analysis showed unidirectional and bidirectional effects between neuroticism and multiple psychiatric traits. These results enhance neurobiological understanding of neuroticism and provide specific leads for functional follow-up experiments.
AB - Neuroticism is an important risk factor for psychiatric traits, including depression1, anxiety2,3, and schizophrenia4-6. At the time of analysis, previous genome-wide association studies7-12 (GWAS) reported 16 genomic loci associated to neuroticism10-12. Here we conducted a large GWAS meta-analysis (n = 449,484) of neuroticism and identified 136 independent genome-wide significant loci (124 new at the time of analysis), which implicate 599 genes. Functional follow-up analyses showed enrichment in several brain regions and involvement of specific cell types, including dopaminergic neuroblasts (P = 3.49 × 10-8), medium spiny neurons (P = 4.23 × 10-8), and serotonergic neurons (P = 1.37 × 10-7). Gene set analyses implicated three specific pathways: neurogenesis (P = 4.43 × 10-9), behavioral response to cocaine processes (P = 1.84 × 10-7), and axon part (P = 5.26 × 10-8). We show that neuroticism's genetic signal partly originates in two genetically distinguishable subclusters13 ('depressed affect' and 'worry'), suggesting distinct causal mechanisms for subtypes of individuals. Mendelian randomization analysis showed unidirectional and bidirectional effects between neuroticism and multiple psychiatric traits. These results enhance neurobiological understanding of neuroticism and provide specific leads for functional follow-up experiments.
KW - Adult
KW - Aged
KW - Anxiety Disorders/genetics
KW - Axons/physiology
KW - Depression/genetics
KW - Female
KW - Genetic Loci
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study/methods
KW - Humans
KW - Male
KW - Middle Aged
KW - Neurogenesis/genetics
KW - Neurons/physiology
KW - Neuroticism/physiology
KW - Polymorphism, Single Nucleotide
KW - Risk Factors
KW - Schizophrenia/genetics
UR - https://www.scopus.com/pages/publications/85049049628
U2 - 10.1038/s41588-018-0151-7
DO - 10.1038/s41588-018-0151-7
M3 - Article
C2 - 29942085
SN - 1061-4036
VL - 50
SP - 920
EP - 927
JO - Nature genetics
JF - Nature genetics
IS - 7
ER -