rs10078721 (LINC02058): Anxiety and Essential Tremor

Key takeaways

• This variant at the LINC02058 and POLD2P1 locus has been linked to anxiety disorders in a GWAS spanning more than 1.2 million participants across five world regions
• The same locus has also been associated with essential tremor (ET), a common movement disorder characterized by involuntary shaking, in a study of 483,054 individuals
• Common genetic variants at ET-associated loci collectively explain approximately 18% of ET heritability
• The ET study found significant genetic overlap between ET and both Parkinson disease and depression
• GTEx data links the ALT allele at this variant to reduced NR2F1 gene expression in esophageal tissue and increased CCT7P2 expression in tibial nerve tissue

What the research says A cross-ancestry GWAS involving more than 1.2 million participants, including 97,383 anxiety cases, identified this locus among 51 genome-wide significant anxiety-associated regions, 39 of which were novel, with anxiety heritability enriched in the limbic system, cerebral cortex, cerebellum, metencephalon, entorhinal cortex, and brain stem PMID 39030279. A separate GWAS meta-analysis of 7,177 individuals with ET and 475,877 controls found genome-wide significant association at this locus, with common variants collectively explaining approximately 18% of ET heritability and functional enrichment in the cerebellar hemisphere, cerebellum, and axonogenesis pathways PMID 35226062. That ET study also reported a significant genetic correlation between ET and Parkinson disease (r = 0.28, p = 2.38 x 10^-8) and between ET and depression (r = 0.12, p = 9.78 x 10^-4), suggesting shared genetic architecture across these neurological conditions PMID 35226062.

Reported associations

• Anxiety disorders: Identified among 51 genome-wide significant loci (39 novel) in a multi-ancestry GWAS of more than 1.2 million participants including 97,383 anxiety cases spanning five continental groups PMID 39030279
• Essential tremor: Associated with ET risk in a GWAS meta-analysis of 483,054 individuals (7,177 ET cases), with common ET variants collectively explaining approximately 18% of ET heritability PMID 35226062

Evidence quality The anxiety association rests on one of the largest anxiety genetics studies to date, with more than 1.2 million participants across five continental ancestry groups and 97,383 anxiety cases; polygenic risk scores (genome-wide scores that aggregate many small genetic effects) derived from European-ancestry participants transferred significantly to African, admixed American, and East Asian groups, supporting cross-ancestry relevance PMID 39030279. The ET association comes from a GWAS meta-analysis of 483,054 individuals from European cohorts, representing the first genome-wide significant loci identified for ET, with functional analyses pointing to enrichment in the cerebellar hemisphere, cerebellum, and axonogenesis (the biological process of nerve fiber growth) pathways PMID 35226062. The two studies independently implicate this locus in distinct neurological phenotypes, which supports the region's biological relevance, though neither study reports an individual effect size for rs10078721 specifically and the ET cohort is predominantly of European descent, limiting cross-ancestry generalizability for the ET association. The studies do not conflict with each other as they investigate different conditions.

Tissue-specific expression effects

• NR2F1-AS1: The ALT allele is associated with reduced expression of this antisense RNA gene (a non-protein-coding gene transcribed from the opposite DNA strand, located near NR2F1) in esophageal muscularis tissue GTEx Portal
• NR2F1: The ALT allele is associated with reduced expression of the NR2F1 gene in both esophageal muscularis and esophageal gastroesophageal junction tissue GTEx Portal
• CCT7P2: The ALT allele is associated with increased expression of this pseudogene (a DNA sequence resembling a functional gene but not producing a working protein) in tibial nerve tissue GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.