rs10918270 (ATF6): Parkinson's Onset Age Variant

Key takeaways

• rs10918270 sits in the ATF6 gene and was examined in a genome-wide study of what determines when Parkinson's disease begins
• The ALT allele consistently reduces ATF6 expression across six tissue types, from subcutaneous fat to tibial nerve
• The strongest expression-lowering effect is in subcutaneous adipose tissue, reaching p=5.6e-13 across 953 GTEx donors
• The Parkinson's disease onset study combined roughly 2,044 cases but did not reach genome-wide significance
• No lifestyle or drug response data are on file for this variant

What the research says rs10918270 was investigated in a genome-wide association study (GWAS) - a method that scans hundreds of thousands of genetic markers simultaneously - focused on identifying genetic factors that influence age at symptom onset in Parkinson's disease (PD), a question distinct from which genes cause susceptibility to PD. The multi-stage study enrolled 857 familial PD cases in the discovery phase, combined those with 440 idiopathic (non-familial) PD cases in a meta-analysis covering approximately 2 million imputed markers, and added an independent replication cohort of 747 PD cases from the Parkinson Institute Biobank in Milan, Italy; the strongest meta-analysis associations across all tested markers reached p < 1x10-5 but fell below the conventional genome-wide significance threshold of p < 5x10-8. GTEx v11 expression data from 953 donors independently show that the ALT allele at this locus is linked to reduced ATF6 expression across six tissue types, with the most statistically significant effect in subcutaneous adipose tissue (slope -0.13, p=5.6e-13) GTEx Portal.

Reported associations

• Parkinson's disease onset age: rs10918270 was examined in a three-stage GWAS totaling approximately 2,044 PD cases across discovery, meta-analysis, and replication; the study's overall top meta-analysis findings reached p < 1x10-5 but did not achieve genome-wide significance, and specific effect size or p-value data for this variant individually are not reported in the available study text.
• ATF6 expression (eQTL, six tissues): the ALT allele is associated with reduced expression across EBV-transformed lymphocytes, subcutaneous adipose tissue, cultured fibroblasts, thyroid, skeletal muscle, and tibial nerve, with all six effects directionally consistent GTEx Portal.

Evidence quality The Parkinson's disease onset age GWAS used a multi-stage design with discovery (857 familial PD cases), meta-analysis (adding 440 idiopathic cases and approximately 2 million imputed markers), and replication (747 PD cases from Milan). Despite this structure, sample sizes were modest for a complex polygenic trait, and no associations reached genome-wide significance. The specific p-value and effect size for rs10918270 in the PD context are not reported in the available study text, which limits independent assessment of this variant's individual contribution. The GTEx eQTL data, drawn from 953 donors, presents a more statistically anchored picture: all six tissues show reduced ATF6 expression with the ALT allele, with several highly significant p-values (p=5.6e-13 in subcutaneous adipose tissue, p=1.1e-10 in cultured fibroblasts). These eQTL effects reflect gene-expression mechanisms, not clinical outcomes, and should not be interpreted as direct evidence of disease risk.

Tissue-specific expression effects

• ATF6: the ALT allele is associated with reduced expression in EBV-transformed lymphocytes (slope -0.17, p=4.3e-5), subcutaneous adipose tissue (slope -0.13, p=5.6e-13), cultured fibroblasts (slope -0.13, p=1.1e-10), thyroid (slope -0.11, p=6.0e-7), skeletal muscle (slope -0.09, p=2.0e-7), and tibial nerve (slope -0.07, p=2.8e-5); all six tissues show reduced expression with the ALT allele, with the highest statistical confidence in subcutaneous adipose tissue GTEx Portal.

Lifestyle considerations No lifestyle considerations on file for this variant.