RT Journal Article SR Electronic T1 Genome-wide analysis of over 106,000 individuals identifies 9 neuroticism-associated loci JF bioRxiv FD Cold Spring Harbor Laboratory SP 032417 DO 10.1101/032417 A1 Daniel J. Smith A1 Valentina Escott-Price A1 Gail Davies A1 Mark E.S. Bailey A1 Lucía Colodro-Conde A1 Joey Ward A1 Alexey Vedernikov A1 Riccardo Marioni A1 Breda Cullen A1 Donald Lyall A1 Saskia P. Hagenaars A1 David C.M. Liewald A1 Michelle Luciano A1 Catharine R. Gale A1 Stuart J. Ritchie A1 Caroline Hayward A1 Barbara Nicholl A1 Brendan Bulik-Sullivan A1 Mark Adams A1 Baptiste Couvy-Duchesne A1 Nicholas Graham A1 Daniel Mackay A1 Jonathan Evans A1 Blair H. Smith A1 David J. Porteous A1 Sarah Medland A1 Nick G. Martin A1 Peter Holmans A1 Andrew M. McIntosh A1 Jill P. Pell A1 Ian J. Deary A1 Michael O’Donovan YR 2016 UL http://biorxiv.org/content/early/2016/01/23/032417.abstract AB Neuroticism is a personality trait of fundamental importance for psychological wellbeing 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 and heterogeneity in the measurement of neuroticism. Here we report a genome-wide association study of neuroticism in 91,370 participants of the UK Biobank cohort and a combined meta-analysis which includes a further 6,659 participants from the Generation Scotland Scottish Family Health Study (GS:SFHS) and 8,687 participants from a QIMR 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 SNP-based heritability estimate for neuroticism of approximately 15% (SE = 0.7%). Meta-analysis identified 9 novel loci associated with neuroticism. The strongest evidence for association was at a locus on chromosome 8 (p = 1.5x10-15) 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 (0.64) and a less strong but significant genetic correlation with schizophrenia (0.22), although not with bipolar disorder. Polygenic risk scores derived from the primary UK Biobank sample captured about 1% of the variance in neuroticism in independent samples. Overall, our findings confirm a polygenic basis for neuroticism and substantial shared genetic architecture between neuroticism and MDD. The identification of 9 new neuroticism-associated loci will drive forward future work on the neurobiology of neuroticism and related phenotypes.