rs10850378 (TBX3-AS1): Blood Pressure Variant

Key takeaways

• rs10850378 is located in TBX3-AS1 (TBX3 antisense RNA 1), a long non-coding RNA gene on chromosome 12 that runs in the opposite direction to the protein-coding TBX3 gene
• This variant was identified as a novel blood pressure locus in a pleiotropy analysis of over 1 million participants
• Evidence is preliminary - no specific odds ratios or effect sizes for this variant appear in the available study data
• In testis tissue only, the alternative allele reduces TBX3-AS1 gene activity (effect slope -0.12 in GTEx v11 data)

What the research says A genome-wide bidirectional Mendelian Randomization and horizontal pleiotropy analysis - examining summary statistics from the UK Biobank, the International Consortium for Blood Pressure (up to 757,601 European-ancestry participants), and the Million Veteran Program (318,891 predominantly male multiethnic participants) - identified rs10850378 as a novel blood pressure-associated variant. The locus sits within TBX3-AS1, a long non-coding RNA gene (one that produces RNA but no protein) transcribed in the opposite direction to the neighboring TBX3 gene, which encodes a transcription factor; horizontal pleiotropic variants are those that influence two correlated traits through distinct biological pathways rather than one causing the other, and this variant is classed as pleiotropic for both systolic and diastolic blood pressure. In testis tissue, the alternative allele is associated with reduced TBX3-AS1 expression (slope -0.12, p=9.4e-7) GTEx Portal.

Reported associations

• Systolic blood pressure: identified as a horizontally pleiotropic variant in a meta-analysis of over 1 million participants; specific effect sizes for this variant are not reported in the available study text
• Diastolic blood pressure: identified in the same analysis as having a separate association with diastolic blood pressure, distinct from any effect on systolic pressure
• TBX3-AS1 gene expression (testis): the alternative allele reduces expression of the gene in testis tissue, with slope -0.12 (p=9.4e-7, FDR<0.05) GTEx Portal

Evidence quality The blood pressure association for rs10850378 comes from a single large-scale pleiotropy analysis examining summary statistics from the UK Biobank and International Consortium for Blood Pressure (up to 757,601 European-ancestry participants) followed by replication in the Million Veteran Program (318,891 predominantly male multiethnic participants). The study identified 118 novel BP pleiotropic variants that achieved replication across cohorts, and an additional 219 signals found in meta-analysis but not independently replicated; the specific replication tier of this variant is not stated in the provided text, and no p-values or odds ratios specific to rs10850378 are reported in the available excerpts. The eQTL (expression quantitative trait locus - a genetic variant associated with changes in nearby gene expression levels) signal in testis is modest but statistically significant (slope -0.12, p=9.4e-7, n=953 donors in GTEx v11) GTEx Portal. Overall, this is a discovery-stage finding requiring further independent confirmation.

Tissue-specific expression effects

• TBX3-AS1: the alternative allele is associated with reduced expression specifically in testis tissue; no other tissues reached significance in GTEx v11 data (953 donors); the functional significance of this tissue-specific regulatory effect is not established GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.