rs1184523 (ARPP21): Neuroticism and Mood Trait Genetics
Key takeaways
- This variant near ARPP21 is one of 255 genome-wide significant signals for neuroticism sub-traits found in over 366,000 UK Biobank participants across two independent samples.
- Neuroticism's 12 questionnaire items are genetically heterogeneous, with pairwise genetic correlations ranging from 0.38 to 0.91, meaning different items tap partly different biology.
- 138 of the 255 loci are item-specific and would have been severely diluted or missed by analyzing the composite neuroticism sum-score alone.
- Two genetically distinct sub-clusters of neuroticism were identified: 'depressed affect' and 'worry,' suggesting partly separate underlying biology for each.
- GTEx data links this variant to reduced ARPP21 expression in arterial tissues and liver, pointing to possible tissue-level mechanisms.
Key takeaways
- This variant, located near ARPP21 (cAMP-regulated phosphoprotein 21) and RPL36AP17, was identified in a large genome-wide study of neuroticism sub-traits.
- Neuroticism is genetically heterogeneous: genetic correlations among its 12 questionnaire items range from 0.38 to 0.91, meaning different items capture partly different biology.
- A meta-analysis of two UK Biobank samples found 255 genome-wide significant loci; 138 were specific to individual neuroticism items and would have been severely diluted or undetectable using the overall composite sum-score.
- Two genetically distinct sub-clusters of neuroticism emerged: "depressed affect" and "worry," suggesting these dimensions have partly separate genetic causes.
- GTEx data links this variant to reduced ARPP21 gene expression in arterial tissues and liver, pointing to possible tissue-level biological mechanisms.
What the research says A genome-wide association study (GWAS, a large scan of the genome for trait-linked variants) of 12 individual neuroticism items from the UK Biobank, meta-analyzed across two independent samples (sample 1 n = 106,218-109,017 per item; sample 2 n = 260,083-266,896 per item), identified 255 genome-wide significant independent genomic regions PMID 30287866. Pairwise genetic correlations (rg, a measure of shared genetic architecture) among the 12 items ranged from 0.38 to 0.91 (mean rg = 0.63), confirming that these items do not share a single unified genetic blueprint PMID 30287866. Hierarchical clustering of the genetic signals identified two internally coherent groups of items, labeled "depressed affect" and "worry," each with a distinct pattern of genetic correlations with 33 external traits PMID 30287866.
Reported associations
- Neuroticism (item-level GWAS): One of 255 genome-wide significant loci identified in a meta-analysis of UK Biobank participants (per-item n up to approximately 266,896 in the larger sample); 138 of these loci were item-specific, meaning they were not detectable in analyses of the overall composite neuroticism score PMID 30287866.
Evidence quality The neuroticism GWAS was conducted in two independent UK Biobank samples and meta-analyzed: sample 1 contributed 106,218-109,017 participants per item and sample 2 contributed 260,083-266,896, with results from the second sample used to replicate key findings from the first PMID 30287866. The SNP-based heritability (h2SNP, the proportion of trait variance attributable to common genetic variants) of neuroticism is modest at 0.09-0.15, consistent with a highly polygenic trait in which any single variant explains only a very small fraction of variance PMID 30287866. No specific p-value or effect size for rs1184523 individually is reported in the available study text, and no conflicting findings are described in the provided sources. Independent external replication of this specific signal outside the UK Biobank is not reported, so this finding should be considered preliminary.
Tissue-specific expression effects
- ARPP21: The alternate allele is associated with reduced expression of this gene in liver, tibial artery, coronary artery, aorta, and sun-exposed lower leg skin; the largest reductions are observed in tibial artery and liver GTEx Portal.
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
What is the ARPP21 gene?
ARPP21 stands for cAMP-regulated phosphoprotein 21. Variants near it have been associated with neuroticism-related traits in large genome-wide studies, and expression data show it is active in tissues including arteries and liver.
Is rs1184523 linked to depression or anxiety?
This variant was identified in a GWAS of 12 neuroticism questionnaire items, which include questions related to both depressed mood and worry. The study found that these sub-clusters have partly distinct genetic architectures, but whether this specific variant maps more closely to depressed affect or worry is not detailed in the available study text.
How was rs1184523 discovered?
It was identified through a genome-wide association study of 12 individual neuroticism questionnaire items in the UK Biobank, meta-analyzed across two independent samples totaling over 366,000 participants per item.
What body tissues does this variant affect at the gene-expression level?
GTEx expression data show that the alternate allele at rs1184523 is associated with reduced ARPP21 gene activity in liver, tibial artery, coronary artery, aorta, and sun-exposed lower leg skin. Whether these tissue-level effects are related to the neuroticism association is not established by the available studies.
How reliable is the evidence for rs1184523?
The finding comes from a large meta-analysis of UK Biobank data with within-study replication across two independent samples. Independent replication in external cohorts is not described in the provided sources, so this variant should be considered a preliminary finding.