rs1129367 (CAPN1-AS1): Aging and Body Shape Variant

Key takeaways

• rs1129367 sits in the CAPN1-AS1 locus and has been studied in large-scale UK Biobank genomic analyses of aging phenotypes and allometric body shape.
• The ALT allele consistently increases POLA2 gene expression across testis, pancreas, and at least six distinct brain regions.
• A longitudinal study found baseline physical function has much higher heritability (31.38%) than the rate of physical decline (3.15%), suggesting different genetic factors drive aging baselines versus rates of change.
• A body-shape GWAS in over 400,000 UK Biobank participants used height- and BMI-adjusted indices, revealing novel loci not detected by traditional measures adjusted for BMI alone.

What the research says A longitudinal genomic study of UK Biobank participants examined both baseline cognitive and physical function and the rate of age-related decline, finding markedly different heritability levels - for example, 31.38% for baseline physical function versus 3.15% for the rate of physical decline; cognitive decline was largely driven by Alzheimer's disease liability (standardized Mendelian Randomization effect gamma = 0.17) while physical decline was most impacted by telomere length (gamma = -0.05) and bone mineral density (gamma = -0.05). A separate genome-wide association study (GWAS, a method scanning hundreds of thousands of genetic variants simultaneously across the genome) of allometric body-shape indices - measures of body shape mathematically corrected for both height and BMI - was conducted in 219,872 women and 186,825 men of white British ancestry from the UK Biobank, identifying novel loci not previously detected by traditional body-shape measures that adjust for BMI alone.

Reported associations

• Cognitive and physical aging phenotypes: rs1129367 has been examined in a longitudinal genomic study of age-related changes in cognitive and physical function in the UK Biobank, where baseline function and accelerated decline showed distinct heritability levels and associated genetic loci.
• Body shape indices: This variant has been examined in a GWAS of allometric body-shape indices including A Body Shape Index (ABSI, a measure of abdominal shape independent of height and BMI), Hip Index (HI), and Waist-to-Hip Index in a UK Biobank sample of over 400,000 individuals; genetic associations were assessed separately for women and men given documented sex differences in body-shape genetics.
• POLA2 expression: The ALT allele of rs1129367 is associated with increased expression of POLA2 across multiple tissues, with the strongest effects in testis and pancreas, and significant increases across six brain regions - caudate basal ganglia, anterior cingulate cortex (BA24), cortex, frontal cortex (BA9), nucleus accumbens basal ganglia, and pituitary gland. GTEx Portal

Evidence quality The longitudinal aging study used simulation-validated models of change applied to UK Biobank prospective data, though the authors explicitly flag selective attrition as a limitation - participants with multiple follow-up waves represent a healthier-than-average subset, which may bias genetic effect estimates. The body-shape GWAS used Bayesian linear mixed-models (BOLT-LMM) in a combined sample of over 406,000 individuals, providing substantial statistical power for discovery; the authors note that adjusting for both height and BMI revealed novel loci not found with BMI-only adjustment, with one to two thirds of loci for allometric indices classified as novel. The GTEx eQTL data for POLA2 is based on 953 donors and reaches high significance in testis (p=1.1e-16) and pancreas (p=1.2e-9), with multiple brain regions also reaching significance under FDR<0.05 (p values from 2.1e-6 to 2.0e-8). GTEx Portal No specific p-value or effect size for rs1129367 in either GWAS was available in the provided study excerpts, so the magnitude of this variant's contribution to aging and body-shape traits should be interpreted cautiously.

Tissue-specific expression effects

• POLA2: The ALT allele of rs1129367 is associated with increased POLA2 expression across a broad set of tissues - including testis (strongest signal) and pancreas - and consistently across six brain regions: cortex, caudate basal ganglia, anterior cingulate cortex, frontal cortex, nucleus accumbens basal ganglia, and pituitary gland. The direction of effect is positive in all eight reported tissue-gene pairs, indicating a uniform upregulatory pattern. GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.