Neuroticism is an important risk factor for psychiatric traits including depression1, anxiety2,3, and schizophrenia4–6. Previous genome-wide association studies7–12 (GWAS) reported 16 genomic loci10–12. Here we report the largest neuroticism GWAS meta-analysis to date (N=449,484), and identify 136 independent genome-wide significant loci (124 novel), implicating 599 genes. Extensive functional follow-up analyses show enrichment in several brain regions and involvement of specific cell-types, including dopaminergic neuroblasts (P=3×10-8), medium spiny neurons (P=4×10-8) and serotonergic neurons (P=1×10-7). Gene-set analyses implicate three specific pathways: neurogenesis (P=4.4×10-9), behavioural 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, the former being genetically strongly related to depression, rg=0.84), suggesting distinct causal mechanisms for subtypes of individuals. These results vastly enhance our neurobiological understanding of neuroticism, and provide specific leads for functional follow-up experiments.
Insomnia is the second-most prevalent mental disorder, with no sufficient treatment available. Despite a substantial role of genetic factors, only a handful of genes have been implicated and insight into the associated neurobiological pathways remains limited. Here, we use an unprecedented large genetic association sample (N=1,331,010) to allow detection of a substantial number of genetic variants and gain insight into biological functions, cell types and tissues involved in insomnia complaints. We identify 202 genome-wide significant loci implicating 956 genes through positional, eQTL and chromatin interaction mapping. We show involvement of the axonal part of neurons, of specific cortical and subcortical tissues, and of two specific cell-types in insomnia: striatal medium spiny neurons and hypothalamic neurons. These cell-types have been implicated previously in the regulation of reward processing, sleep and arousal in animal studies, but have never been genetically linked to insomnia in humans. We found weak genetic correlations with other sleep-related traits, but strong genetic correlations with psychiatric and metabolic traits. Mendelian randomization identified causal effects of insomnia on specific psychiatric and metabolic traits. Our findings reveal key brain areas and cells implicated in the neurobiology of insomnia and its related disorders, and provide novel targets for treatment.
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