Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways

Nagel, Mats; Jansen, Philip R.; Stringer, Sven; Watanabe, Kyoko; Leeuw, Christiaan de; Bryois, Julien; Savage, Jeanne E.; Hammerschlag, Anke R.; Skene, Nathan G.; Muñoz-Manchado, Ana B.; White, Tonya; Tiemeier, Henning; Linnarsson, Sten; Hjerling-Leffler, Jens; Polderman, Tinca J. C.; Sullivan, Patrick F.; Sluis, Sophie van der; Posthuma, Daniëlle

doi:10.1038/s41588-018-0151-7

Cited by 718 publications

(714 citation statements)

References 51 publications

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“…In comparison, only four of the 19 PGC BD loci 8 reached genome-wide significance in MOOD. MOOD loci overlapped considerably 9 with previous studies of depression and depressive symptoms (51/73) (20, 23, 48-10 52), bipolar disorder (3/73) (53)(54)(55)(56), neuroticism (32/73) (23,(57)(58)(59), and 11 schizophrenia (15/73) (32,60), although participants overlap between MOOD and 12 many of these studies. Locus 52 (chromosome 12) passed genome-wide 13 significance in a previous meta-analysis of broad depression and bipolar disorder, 14 although the two other loci from this study did not replicate (51).…”

supporting

confidence: 68%

“…Cell-types more associated with 10 bipolar disorder (pyramidal neurons and striatal interneurons) were also enriched in 11 analyses of schizophrenia (38). Cell-types more associated in major depressive 12 disorder (neuroblasts, adult dopaminergic neurons, embryonic GABAergic neurons) 13 had weaker enrichments in schizophrenia, but were enriched in analyses of 14 neuroticism (57). The higher rank of the enrichment of serotonergic neurons with 15 major depressive disorder compared to bipolar disorder is striking given the use of 16 drugs targeting the serotonergic system in the treatment of depression (63).…”

Section: Snp-based Heritability and Genetic Correlationsmentioning

confidence: 99%

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The genetics of the mood disorder spectrum: genome-wide association analyses of over 185,000 cases and 439,000 controls

Coleman

Breen

2018

Preprint

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Mood disorders affect 10-20% of the population, ranging from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Multiple approaches have shown considerable sharing of genetic risk factors between unipolar and bipolar mood disorders. We use data from the largest genome-wide association studies of major depression (MD) and bipolar disorder (BD) to investigate the molecular basis of the shared genetic liability to mood disorders. We meta-analysed we implicate pathways and neuronal subtypes which highlight similarities but also potential differences between MD and BD. Our results reflected MD more than BD, perhaps due to the larger sample size for MD, but also perhaps because depression is their predominant common feature. Overall, these results provide evidence for a genetic mood disorders spectrum.

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supporting

confidence: 68%

Section: Snp-based Heritability and Genetic Correlationsmentioning

confidence: 99%

The genetics of the mood disorder spectrum: genome-wide association analyses of over 185,000 cases and 439,000 controls

Coleman

Breen

2018

Preprint

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“…Indeed genetic variants within core clock genes, including ARTNL have been linked to psychiatric disorders and AD (Charrier, Olliac, Roubertoux, & Tordjman, 2017;Chen, Peng, Huang, Hu, & Zhang, 2015;Gonzalez et al, 2015;Kim et al, 2015). Interestingly the lead SNP in this region, rs34588274, has previously been linked to neuroticism, well-being spectrum (life satisfaction, positive affect, neuroticism, and depressive symptoms, collectively referred to as the well-being spectrum), positive affect and BMI (GWAS catalog, https://www.ebi.ac.uk/gwas/ (Baselmans et al, 2019;Nagel et al, 2018)), indicating that our construct indeed seems to capture aspects related to sociability. This is also supported by the significant positive genetic correlations of our GWAS to loneliness (Gao et al, 2017) and social anxiety (Stein et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Genetic underpinnings of sociability in the UK Biobank

Bralten

Klemann

Mota

et al. 2019

Preprint

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Difficulties with sociability include a tendency to avoid social contacts and activities, and to prefer being alone rather than being with others. While sociability is a continuously distributed trait in the population, decreased sociability represent a common early manifestation of multiple neuropsychiatric disorders such as Schizophrenia (SCZ), Bipolar Disorder (BP), Major Depressive Disorder (MDD), Autism Spectrum Disorders (ASDs), and Alzheimer's disease (AD). We aimed to investigate the genetic underpinnings of sociability as a continuous trait in the general population. In this respect, we performed a genome-wide association study (GWAS) using a sociability score based on 4 social functioning-related self-report questions in the UK Biobank sample (n=342,461) to test the effect of individual genetic variants. This was followed by LD score analyses to investigate the genetic correlation with psychiatric disorders (SCZ, BP, MDD, ASDs) and a neurological disorder (AD) as well as related phenotypes (Loneliness and Social Anxiety). The phenotypic data indeed showed that the sociability score was decreased in individuals with ASD, (probable) MDD, BP and SCZ, but not in individuals with AD. Our GWAS showed 604 genome-wide significant SNPs, coming from 18 independent loci (SNP-based h2=0.06). Genetic correlation analyses showed significant correlations with SCZ (rg=0.15, p=9.8e-23), MDD (rg=0.68, and ASDs (rg=0.27,, but no correlation with BP (rg=0.01, p=0.45) or AD (rg=0.04, p=0.55). Our sociability trait was also genetically correlated with Loneliness (rg=0.45, p=2.4e-8) and Social Anxiety (rg=0.48, p=0.002). Our study shows that there is a significant genetic component to variation in population levels of sociability, which is relevant to some psychiatric disorders (SCZ, MDD, ASDs), but not to BP and AD.

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“…The region on chromosome 1 was previously linked to cerebrospinal fluid biomarker level, 54 migraine, 55 illegal substance dependence, 56 and neuroticism. 57 This region encompasses gene RABGAP1L, with many other genes nearby ( Figure S4A). RABGAP1L is broadly expressed in brain regions and showed association with cerebrospinal fluid biomarker levels 54 and migraine.…”

Section: Discussionmentioning

confidence: 99%

Genome‐wide association studies of alcohol dependence, DSM‐IV criterion count and individual criteria

Lai

Wetherill

Bertelsen

et al. 2019

Genes Brain and Behavior

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Genome‐wide association studies (GWAS) of alcohol dependence (AD) have reliably identified variation within alcohol metabolizing genes (eg, ADH1B) but have inconsistently located other signals, which may be partially attributable to symptom heterogeneity underlying the disorder. We conducted GWAS of DSM‐IV AD (primary analysis), DSM‐IV AD criterion count (secondary analysis), and individual dependence criteria (tertiary analysis) among 7418 (1121 families) European American (EA) individuals from the Collaborative Study on the Genetics of Alcoholism (COGA). Trans‐ancestral meta‐analyses combined these results with data from 3175 (585 families) African‐American (AA) individuals from COGA. In the EA GWAS, three loci were genome‐wide significant: rs1229984 in ADH1B for AD criterion count (P = 4.16E−11) and Desire to cut drinking (P = 1.21E−11); rs188227250 (chromosome 8, Drinking more than intended, P = 6.72E−09); rs1912461 (chromosome 15, Time spent drinking, P = 1.77E−08). In the trans‐ancestral meta‐analysis, rs1229984 was associated with multiple phenotypes and two additional loci were genome‐wide significant: rs61826952 (chromosome 1, DSM‐IV AD, P = 8.42E−11); rs7597960 (chromosome 2, Time spent drinking, P = 1.22E−08). Associations with rs1229984 and rs18822750 were replicated in independent datasets. Polygenic risk scores derived from the EA GWAS of AD predicted AD in two EA datasets (P < .01; 0.61%‐1.82% of variance). Identified novel variants (ie, rs1912461, rs61826952) were associated with differential central evoked theta power (loss − gain; P = .0037) and reward‐related ventral striatum reactivity (P = .008), respectively. This study suggests that studying individual criteria may unveil new insights into the genetic etiology of AD liability.

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Meta-analysis of genome-wide association studies for neuroticism in 449,484 individuals identifies novel genetic loci and pathways

Cited by 718 publications

References 51 publications

The genetics of the mood disorder spectrum: genome-wide association analyses of over 185,000 cases and 439,000 controls

The genetics of the mood disorder spectrum: genome-wide association analyses of over 185,000 cases and 439,000 controls

Genetic underpinnings of sociability in the UK Biobank

Genome‐wide association studies of alcohol dependence, DSM‐IV criterion count and individual criteria

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