Item-level analyses reveal genetic heterogeneity in neuroticism.
- Authors
- Nagel, Mats; Watanabe, Kyoko; Stringer, Sven; Posthuma, Danielle; van der Sluis, Sophie
- Year
- 2018
- Journal
- Nature communications
- PMID
- 29500382
- DOI
- 10.1038/s41467-018-03242-8
- PMCID
- PMC5834468
Genome-wide association studies (GWAS) of psychological traits are generally conducted on (dichotomized) sums of items or symptoms (e.g., case-control status), and not on the individual items or symptoms themselves. We conduct large-scale GWAS on 12 neuroticism items and observe notable and replicable variation in genetic signal between items. Within samples, genetic correlations among the items range between 0.38 and 0.91 (mean rβ=β.63), indicating genetic heterogeneity in the full item set. Meta-analyzing the two samples, we identify 255 genome-wide significant independent genomic regions, of which 138 are item-specific. Genetic analyses and genetic correlations with 33 external traits support genetic differences between the items. Hierarchical clustering analysis identifies two genetically homogeneous item clusters denoted depressed affect and worry. We conclude that the items used to measure neuroticism are genetically heterogeneous, and that biological understanding can be gained by studying them in genetically more homogeneous clusters.
Genetic correlations between the 12 neuroticism items. Genetic correlations between the 12 neuroticism items within both samples (sample 1 is presented in the upper triangle and sample 2 in the bottom triangle). The genetic correlations of the same items measured in both samples are presented on the diagonal. All reported genetic correlations, computed with bivariate LD score regression, are significantly different from zero after Bonferroni correction (P < 2.22 Γ 10β4). For the genetic correlations between the same items (diagonal) all 95% confidence intervals included 1, emphasizing concordance in genetic signal across samples. For all other, cross-phenotype genetic correlations, none of the 95% confidence intervals included 1, indicating that all genetic correlations deviated from unity (Supplementary Data 2). See Supplementary Table 1 for a description of the item labels
Circle plot of statistically associated gene-sets of the 7,297 gene-sets tested (MsigDB gene-sets and gene-expression profiles). This circle plot presents all gene-sets that were significantly associated (Bonferroni corrected P-value threshold: 0.05/7,297 = 6.85 Γ 10β6) to at least one of the individual neuroticism items or to the sum-score. Each tract connects a gene-set to the phenotype with which it is associated. Tracts colored in red indicate gene-sets that were associated to individual items, but not to the sum-score. In contrast, tracts colored in yellow indicate gene-sets that were associated to the neuroticism sum-score, but not to any of the individual items. Blue tracts refer to gene-sets that were found to be associated to the sum-score and at least one of the individual items. See Supplementary Data 47 for a description of the gene-sets included in this figure. See Supplementary Table 1 for a description of the item labels
Genetic correlations of 12 neuroticism items, the sum-score and the two item clusters with 33 external traits. Genetic correlations of neuroticism items (see Supplementary Table 1 for a description of the item labels), sum-score, and the item clusters depressed affect (CLUSTER: DEPRAFF) and worry (CLUSTER: WORRY; x axis) with 33 other traits (y axis; Supplementary Data 49) computed with cross-trait LD score regression. P values and 95% confidence intervals for the rgβs are provided in Supplementary Data 50. Exact values of the genetic correlations are shown in the cells. *P < 0.01; **Bonferroni corrected P-value threshold: P < 1.01 Γ 10β4 (0.05/(15 Γ 33))
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