rs1012053 (DGKH): Bipolar Disorder Risk Variant
Key takeaways
- rs1012053 sits in DGKH, a gene whose protein operates in the same signaling pathway that lithium is thought to target
- It was the single strongest genetic signal for bipolar disorder in a scan of 550,000+ variants, with an odds ratio of 1.59
- The same study found 88 separate variants across 80 genes all linked to bipolar disorder, suggesting the condition has a many-gene architecture
- The ALT allele is associated with slightly higher DGKH expression in thyroid tissue and lower AKAP11 expression in esophageal muscle tissue
Key takeaways
- rs1012053 sits within the first intron of diacylglycerol kinase eta (DGKH), a gene encoding a protein central to lithium-sensitive cell signaling
- It was the single strongest association signal for bipolar disorder in a GWAS screening over 550,000 SNPs, with an odds ratio of 1.59
- Bipolar disorder appears polygenic: 88 SNPs across 80 genes all showed evidence of replication in the same study
- The ALT allele is associated with slightly increased DGKH expression in thyroid tissue and reduced AKAP11 expression in esophageal muscle tissue
What the research says A genome-wide association study (GWAS - a simultaneous scan of hundreds of thousands of common DNA variants across the genome) conducted in two independent European case-control samples identified rs1012053, located in the first intron (a non-coding segment within the gene sequence) of diacylglycerol kinase eta (DGKH), as the strongest signal for bipolar disorder risk, with an odds ratio of 1.59 and a genome-wide-significant p-value of 1.5 × 10^-8 (experiment-wide P < 0.01) PMID 18285837. The locus encodes a protein playing a key role in the phosphatidyl inositol (PI) signaling pathway - a cellular communication network known to be sensitive to lithium, a medication commonly used to treat bipolar disorder PMID 18285837. Across the same study, 88 SNPs (single-nucleotide polymorphisms - single-letter DNA differences) representing 80 different genes met replication criteria, indicating a polygenic architecture in which many variants each contribute only modest risk PMID 18285837.
Reported associations
- Bipolar disorder: Strongest GWAS signal among over 550,000 tested SNPs in two independent European case-control samples; odds ratio = 1.59, p = 1.5 × 10^-8, experiment-wide P < 0.01 PMID 18285837
Evidence quality The 2008 GWAS employed pooled DNA for the initial discovery phase - an approach the authors explicitly acknowledge reduces statistical power compared to individual-sample genotyping - before confirming top signals by individual genotyping in two independent European samples PMID 18285837. The rs1012053 signal reached genome-wide significance (p = 1.5 × 10^-8, experiment-wide P < 0.01) with an odds ratio of 1.59; however, effect sizes across the full study were described as modest, with no single variant of large effect detected PMID 18285837. Both discovery and replication samples were restricted to European ancestry, limiting generalizability to other populations. No conflicting findings are present in the provided evidence set; the evidence derives from a single publication with internal replication, and independent external replication is not represented in this evidence base.
Tissue-specific expression effects
- DGKH: The ALT allele is associated with increased expression in thyroid tissue GTEx Portal
- AKAP11: The ALT allele is associated with reduced expression in esophagus muscularis (the muscular wall of the esophagus) GTEx Portal
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
What does the DGKH gene do?
DGKH (diacylglycerol kinase eta) encodes an enzyme involved in the phosphatidyl inositol signaling pathway, a cellular communication network that is sensitive to lithium - a medication widely used to treat bipolar disorder.
Is rs1012053 linked to bipolar disorder?
Yes. A genome-wide study identified it as the strongest genetic signal for bipolar disorder among more than 550,000 tested variants, with an odds ratio of 1.59. Effect size is considered modest, and many other genes also contribute.
What does an odds ratio of 1.59 mean for rs1012053?
In the studied population, people carrying the associated allele had approximately 59% higher odds of bipolar disorder compared to those without it. For common genetic variants, this is considered a modest effect.
Does rs1012053 affect gene expression?
GTEx data show the ALT allele is associated with slightly increased DGKH expression in thyroid tissue and slightly reduced expression of the nearby AKAP11 gene in esophageal muscle tissue. These are expression-level observations, not direct measures of disease risk.
Why is the DGKH pathway relevant to bipolar disorder?
DGKH operates in the phosphatidyl inositol signaling pathway, which is believed to be among the targets of lithium, one of the most established treatments for bipolar disorder. A genetic risk variant in this gene adds biological support to that proposed mechanism.