Genetic underpinnings of affective temperaments: a pilot GWAS investigation identifies a new genome-wide significant SNP for anxious temperament in ADGRB3 gene

Y Although recently a large-sample GWASs identified significant loci in the background of depression, the heterogeneity of the depressive phenotype and the lack of accurate phenotyping hinders applicability of findings. We carried out a pilot GWAS with in-depth phenotyping of affective temperaments, considered as subclinical manifestations and high-risk states for affective disorders, in a general population sample of European origin. Affective temperaments were measured by TEMPS-A. SNP-level association was assessed by linear regression models, assuming an additive genetic effect, using PLINK1.9. Gender, age, the first ten principal components (PCs) and the other four temperaments were included in the regression models as covariates. SNP-level relevances (p-values) were aggregated to gene level using the PEGASUS method(1). In SNP-based tests, a Bonferroni-corrected significance threshold of p <= 5.0 x 10(-8) and a suggestive significance threshold of p <= 1.0 x 10(-5), whereas in gene-based tests a Bonferroni-corrected significance of 2.0 x 10(-6) and a suggestive significance of p <= 4.0 x 10(-4) was established. To explore known functional effects of the most significant SNPs, FUMA v1.3.5 was used. We identified 1 significant and 21 suggestively significant SNPs in ADGRB3, expressed in the brain, for anxious temperament. Several other brain-relevant SNPs and genes emerged at suggestive significance for the other temperaments. Functional analyses reflecting effect on gene expression and participation in chromatin interactions also pointed to several genes expressed in the brain with potentially relevant phenotypes regulated by our top SNPs. Our findings need to be tested in larger GWA studies and candidate gene analyses in well-phenotyped samples in relation to affective disorders and related phenotypes.

Automated summary

This study conducted a pilot GWAS with in-depth phenotyping of affective temperaments in a European population sample. Significant and suggestively significant SNPs associated with anxious temperament were identified in ADGRB3, expressed in the brain. Functional analyses revealed potential relevant phenotypes regulated by top SNPs expressed in the brain. Further validation in larger GWA studies and candidate gene analyses is needed.