Meta-Analysis of Genome-Wide Association Studies for Neuroticism in 449,484 Individuals Identifies Novel Genetic Loci and Pathways 23Andme Research Team
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VU Research Portal Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways 23Andme Research Team published in Nature Genetics 2018 DOI (link to publisher) 10.1038/s41588-018-0151-7 document version Publisher's PDF, also known as Version of record document license Article 25fa Dutch Copyright Act Link to publication in VU Research Portal citation for published version (APA) 23Andme Research Team (2018). Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways. 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Oct. 2021 LETTERS https://doi.org/10.1038/s41588-018-0151-7 Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways Mats Nagel1,2,11, Philip R. Jansen1,3,11, Sven Stringer 1, Kyoko Watanabe1, Christiaan A. de Leeuw1, Julien Bryois4, Jeanne E. Savage 1, Anke R. Hammerschlag 1, Nathan G. Skene5, Ana B. Munoz-Manchado5, 23andMe Research Team6, Tonya White3, Henning Tiemeier 3,7, Sten Linnarsson 5, Jens Hjerling-Leffler 5,8, Tinca J. C. Polderman1, Patrick F. Sullivan 4,9,10, Sophie van der Sluis1,2,12 and Danielle Posthuma 1,2,12* Neuroticism is an important risk factor for psychiatric traits, strategy because Skol et al.17 showed that this is almost always including depression1, anxiety2,3, and schizophrenia4–6. At more powerful, even though less correction for multiple testing is the time of analysis, previous genome-wide association required in the replication stage. studies7–12 (GWAS) reported 16 genomic loci associated to The quantile–quantile plot of the genome-wide meta-analysis neuroticism10–12. Here we conducted a large GWAS meta- on 449,484 subjects and 14,978,477 SNPs showed inflation (link- 18 2 analysis (n = 449,484) of neuroticism and identified 136 age disequilibrium score regression (LDSC) : λGC = 1.65, mean χ independent genome-wide significant loci (124 new at the statistic = 1.91; Fig. 1a and Supplementary Table 1), yet the LDSC time of analysis), which implicate 599 genes. Functional fol- intercept (1.02; standard error (s.e.) = 0.01) and ratio (2.1%) both low-up analyses showed enrichment in several brain regions indicated that the inflation was largely due to true polygenicity 19 and involvement of specific cell types, including dopami- and the large sample size . The λGC value of 1.65 is consistent with nergic neuroblasts (P = 3.49 × 10−8), medium spiny neurons values observed in recent large-sample GWAS (n > 100,000) for (P = 4.23 × 10−8), and serotonergic neurons (P = 1.37 × 10−7). diverse and polygenic traits (Supplementary Note). The LDSC SNP- 2 Gene set analyses implicated three specific pathways: neu- based heritability (hSNP) of neuroticism was 0.100 (s.e. = 0.003). rogenesis (P = 4.43 × 10−9), behavioral response to cocaine The GWAS meta-analysis identified 9,745 genome-wide signifi- processes (P = 1.84 × 10−7), and axon part (P = 5.26 × 10−8). cant SNPs (P < 5 × 10–8), of which 157 and 2,414 were located in We show that neuroticism’s genetic signal partly originates known associated inversion regions on chromosomes 8 and 1710–12, in two genetically distinguishable subclusters13 (‘depressed respectively (Fig. 1b and Supplementary Fig. 3; see Supplementary affect’ and ‘worry’), suggesting distinct causal mechanisms Table 2 for cohort-specific information). We used FUMA20, a tool to for subtypes of individuals. Mendelian randomization analy- functionally map and annotate results from GWAS (Methods), and sis showed unidirectional and bidirectional effects between extracted 170 independent lead SNPs (158 new; see the Methods for neuroticism and multiple psychiatric traits. These results definition of lead SNPs) that mapped to 136 independent genomic enhance neurobiological understanding of neuroticism and loci (124 new at the time of analysis) (Methods, Supplementary provide specific leads for functional follow-up experiments. Tables 3–8, and Supplementary Note). Of all the lead SNPs, 4 were The meta-analysis of neuroticism comprised data from the in exonic regions, 88 were in intronic regions, and 52 were in inter- UK Biobank study (UKB, full release14; n = 372,903; Methods genic regions. Of the 17,794 SNPs in high linkage disequilibrium and Supplementary Figs. 1 and 2), 23andMe, Inc.15 (n = 59,206), (LD) with one of the independent significant SNPs (see the Methods and the Genetics of Personality Consortium (GPC19; n = 17,375; for definition), most were intronic (9,147; 51.4%) or intergenic Methods) (n = 449,484 in total). In all of the samples, neuroti- (5,460; 30.7%), and 3.8% were annotated as potentially having a cism was measured through (digital) questionnaires (Methods and functional impact, with 0.9% (155 SNPs) being exonic (Fig. 1c Supplementary Note). To achieve optimal power, SNP associations and Supplementary Table 9; see Supplementary Tables 10 and 11 were subjected to meta-analysis using METAL16, with weighting by for an overview of the chromatin state and regulatory functions of sample size (Methods). We chose to perform meta-analysis on the these SNPs). Of these 155 SNPs, 70 were exonic nonsynonymous available samples rather than use a two-stage discovery–replication (ExNS) (Table 1 and Supplementary Table 12). The ExNS SNP with 1Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. 2Department of Clinical Genetics, Section of Complex Trait Genetics, Amsterdam Neuroscience, VU University Medical Center, Amsterdam, the Netherlands. 3Department of Child and Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, the Netherlands. 4Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 5Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. 6A list of members and affiliations appears at the end of the paper. 7Department of Social and Behavioral Science, Harvard T.H. Chan School of Public Health, Boston, MA, USA. 8UCL Institute of Neurology, Queen Square, London, UK. 9Department of Genetics, University of North Carolina, Chapel Hill, NC, USA. 10Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA. 11These authors contributed equally: Mats Nagel, Philip R. Jansen. 12These authors jointly supervised this work: Sophie van der Sluis, Danielle Posthuma. *e-mail: [email protected] 920 NatURE GENETICS | VOL 50 | JULY 2018 | 920–927 | www.nature.com/naturegenetics © 2018 Nature America Inc., part of Springer Nature. All rights reserved. NATURE GENETICS LETTERS a b 30 30 ) 25 25 P ( 10 20 20 ) P ( 15 10 15 10 –log 10 Observed –log 5 5 0 0 012 46 2345678 9101112131416182022 Expected –log10 (P ) Chromosome c Functional annotation SNPs Chromatin state RegulomeDB category 0.01% 1.08% 0.37% 0.28% 4.01% 1.20% 0.02% 3.49%0.14% 0.71% 0.80% Annotation: State: 0.87% 1.02% 5.63% 0.26% 1.41% Regulome DB: 0.92% Downstream 0.03% 5.64% 0.02% 0.06% 0.99% 1 12 1.69% 1a 3a Exonic 0.05% 2 13 11.4% 1b 3b 12.8% Intergenic 4.69% 16.4% 3 14 1c 4 30.7% Intronic 4 15 1.17% 20.6% 18.7% 1d 5 ncRNA intronic 3.78% 5 30.7% 1e 6 ncRNA exonic 0.12% 6 1f 7 Upstream 39.4% 7 27.0% 2a None 3 UTR 51.4% ′ 8 2b 5 UTR ′ 9 2c d ) 15 10 Significance level P > 0.05 P < 0.05 / proportion of SNPs 2 5 P < 0.0023 (0.05/22) h Enrichment 0 (proportion of TSS: 1.8 UTR: 0.5 UTR: 1.1 CTCF: 2.4 DGF: 13.8DHS: 16.8 5′ 3′ Coding: 1.5 TFBS: 13.2 Intron: 38.7 Promoter: 3.1 H3K9ac: 12.6 Conserved: 2.6 Fetal DHS: 8.5 Transcribed: 34.5 Repressed: 46.1 Weak enhancer: 2.1 Promoter flanking: 0.8 H3K4me3 peaks: 13.3 Super-enhancer: 16.8 H3K27acH3K4me1 (Hnisz): 39.1peaks: 42.7 Enhancer (Hoffman): 6.3 Annotation (ordered by proportion of SNPs) Fig. 1 | SNP-based associations with neuroticism in the GWAS meta-analysis. a, Quantile–quantile plot of the SNP-based associations with neuroticism (n = 449,484 individuals). SNP P values were computed in METAL using a two-sided, sample-size-weighted z-score method. b, Manhattan plot showing the –log10-transformed P value of each SNP on the y axis and base-pair positions along the chromosomes on the x axis (n = 449,484 individuals). SNP P values were computed in METAL using a two-sided, sample-size-weighted z-score method. The upper dashed line indicates genome-wide significance (P < 5 × 10−8), and the lower dashed line shows the threshold for suggestive associations (P < 1 × 10−5). c, Pie charts showing the distribution of functional consequences of SNPs in LD with genome-wide significant lead SNPs in the meta-analysis, the minimum chromatin state across 127 tissue and cell types, and the distribution of RegulomeDB score (a categorical score between 1a and 7, indicating biological evidence of a SNP being a regulatory element, with a low score denoting a higher likelihood of a SNP being regulatory).