Genome-wide analysis of over 106 000 individuals identifies 9 neuroticism-associated loci

Abstract

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.

Genetic risk variants for social anxiety

“…A large meta-analysis of GWAS datasets for extraversion identified no genomewide significant loci, nor did a significant SNP-based heritability estimate emerge [van den Berg et al 2016]. Recent meta-analyses of genomewide association studies (GWAS) have revealed genomewide significant loci for neuroticism [Genetics of Personality et al 2015;Smith et al 2016] and it might be expected that risk loci for these traits might overlap with those for SAD.…”

“…Another personality trait, neuroticism -the recent subject of two large genetic meta-analyses [Genetics of Personality et al 2015;Smith et al 2016] -is thought to underlie many anxiety and depressive disorders, and the evaluation of its genetic relationship to social anxiety would also be informative. We also explored the genetic relationship of social anxiety to an anxiety disorder factor score derived in a large anxiety disorder GWAS meta-analysis [Otowa et al 2016].…”

Polygenic risk for schizophrenia and season of birth within the UK Biobank cohort

“…All analyses in the UKBB were adjusted for the array (the UK Biobank used two different arrays) and the first 8 principal components (PCs), reflecting underlying stratification in the sample due to population and/or genotyping differences. The first 8 PCs, out of 15 available in the Biobank, were selected after visual inspection of each pair of PCs, taking forward only those that resulted in multiple clusters of individuals (see (Smith et al 2016) for detail). AVENGEME provides a set of R functions that allow power for PRS analyses to be calculated (Dudbridge 2013).…”

Adverse metabolic and mental health outcomes associated with shiftwork in a population-based study of 277,168 workers in UK biobank

“…[22] Current mood was assessed using two questions relating to the preceding two weeks: one on depressed mood and another on anhedonia (lacking enthusiasm for life). Participants were also asked whether they had ever consulted a GP in the past for "nerves, anxiety, tension or depression?"…”