rs117956829 (FOLH1B): Major Depression Risk Locus
Key takeaways
- This variant near FOLH1B and H3P34 was identified as one of 53 novel risk loci for major depression in a study combining over 88,000 cases from multiple ancestry groups
- The ALT allele reduces expression of a nearby gene in the brain, including the cerebellar hemisphere and caudate basal ganglia, regions associated with coordination and reward processing
- Cross-disorder genetic research has found extensive genetic overlap among psychiatric conditions, with many risk loci affecting multiple disorders
- The multi-ancestry design of the discovery study improves the chance that findings apply broadly across different population groups
- Per-allele effect sizes for this specific variant have not been reported in the available evidence, and the association should be considered preliminary
Key takeaways
- This variant near FOLH1B and H3P34 was identified as one of 53 novel risk loci for major depression in a study combining over 88,000 cases from multiple ancestry groups
- The ALT allele reduces expression of a nearby gene in the brain, including the cerebellar hemisphere and caudate basal ganglia, regions associated with coordination and reward processing
- Cross-disorder genetic research has found extensive genetic overlap among psychiatric conditions, with many risk loci affecting multiple disorders
- The multi-ancestry design of the discovery study improves the chance that findings apply broadly across different population groups
- Per-allele effect sizes for this specific variant have not been reported in the available evidence, and the association should be considered preliminary
What the research says A multi-ancestry genome-wide association study (GWAS, a genome-wide scan for statistical links between genetic variants and a trait) meta-analyzed data from 21 cohorts totaling 88,316 major depression (MD) cases and 902,757 controls, drawing from African (36% of effective sample size), East Asian (26%), South Asian (6%), and Hispanic/Latin American (32%) ancestry groups, and identified 53 novel genome-wide significant loci alongside 205 novel genes through a transcriptome-wide association analysis PMID 38036741. A cross-disorder analysis of eight psychiatric conditions, including MD, schizophrenia, bipolar disorder, autism spectrum disorder, ADHD, OCD, anorexia nervosa, and Tourette syndrome, in 232,964 cases and 494,162 controls identified 109 pleiotropic loci (variants statistically associated with two or more disorders), concentrated in genes with heightened brain expression beginning prenatally and continuing throughout the lifespan PMID 31835028.
Reported associations
- Major depression: rs117956829 was identified among 53 novel genome-wide significant loci in a multi-ancestry GWAS (88,316 cases, 902,757 controls); per-allele effect sizes for this locus were not provided in the available study text PMID 38036741
- Cross-disorder psychiatric risk: Loci of the class identified by the cross-disorder analysis tend to reside in brain-expressed genes active from prenatal life and carry statistical associations across multiple psychiatric conditions (23 of the 109 pleiotropic loci showed effects on four or more disorders, and 11 showed antagonistic effects across disorders); whether this specific locus was among the 109 confirmed cross-disorder associations is not stated in the available text PMID 31835028
Evidence quality The primary association evidence comes from a large GWAS of 88,316 MD cases and 902,757 controls that used ancestral diversity to improve fine-mapping resolution, the process of narrowing down which specific variant within a chromosomal region is most likely causal PMID 38036741. The cross-disorder study (232,964 cases, 494,162 controls) provides supporting context for the broader class of brain-expressed psychiatric loci but does not report individual-locus results for this SNP PMID 31835028. Per-allele effect sizes for rs117956829 are not available in the provided study excerpts. Notably, the multi-ancestry GWAS found that fewer European-ancestry loci transferred to other ancestry groups than expected, which is a relevant caution when interpreting this locus across diverse populations PMID 38036741. No independent replication study specifically for this SNP is described in the available materials; the evidence is consistent with early-stage GWAS discovery and should be regarded as preliminary.
Tissue-specific expression effects
- ENSG00000280367 (at this locus): The ALT allele is associated with reduced expression of this gene across multiple tissues, including the brain cerebellar hemisphere, brain caudate basal ganglia, esophagus gastroesophageal junction, testis, heart atrial appendage, and thyroid GTEx Portal
- ENSG00000280385 (at this locus): The ALT allele is associated with increased expression of this gene in colon sigmoid and thyroid GTEx Portal
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
What is rs117956829 and which genes is it near?
rs117956829 is a single-nucleotide polymorphism located near two genes: FOLH1B (folate hydrolase 1B) and H3P34 (a histone pseudogene). It has been studied as a candidate risk locus for major depression in large genetic studies.
Is rs117956829 linked to depression?
A large multi-ancestry GWAS identified this locus among 53 novel genome-wide significant associations with major depression, using data from 88,316 people with depression and 902,757 controls drawn from multiple ancestry groups. Like most GWAS findings, the individual effect size is expected to be small, and independent replication data for this specific SNP are not yet available.
Does rs117956829 affect brain gene expression?
GTEx data show that the ALT allele at this position is associated with reduced expression of a nearby gene in the brain cerebellar hemisphere and caudate basal ganglia, as well as in the thyroid, heart, and other tissues. The clinical significance of these expression changes is not yet established.
What is FOLH1B and what does it do?
FOLH1B (folate hydrolase 1B) is a gene related to FOLH1, which encodes an enzyme involved in folate metabolism. Its specific functional role in major depression biology is still under investigation.
Could this variant affect more than one psychiatric condition?
Cross-disorder genetic studies have found that many psychiatric risk loci are pleiotropic, meaning they affect more than one condition. Whether rs117956829 has confirmed effects beyond major depression is not explicitly stated in the available evidence, though the class of brain-expressed loci it belongs to frequently shows cross-disorder effects.