rs114409151 (KLHL18): aging and PTH1R brain expression

Key takeaways

• The alternate allele of rs114409151 substantially increases PTH1R (parathyroid hormone 1 receptor) expression in at least six brain regions, including frontal cortex, cerebellum, and hypothalamus
• PTH1R is primarily known for calcium and bone regulation, making its strong upregulation in the brain a notable finding
• rs114409151, located near KLHL18 (Kelch-like family member 18), was identified in a 2025 longitudinal genome-wide study of aging in the UK Biobank
• The alternate allele also increases PTH1R expression in visceral adipose tissue and boosts expression of a nearby gene (ENSG00000308167) in subcutaneous fat
• Evidence is early-stage: one study without independent replication, and variant-level effect sizes for rs114409151 are not reported in the available materials

What the research says A 2025 genome-wide association study (GWAS) published in Nature Communications analyzed longitudinal aging phenotypes in UK Biobank participants, performing genome-wide scans on measures of baseline cognitive and physical function and their rates of change over time. The study found markedly different heritability levels for physical function baseline (31.38%) versus physical decline (3.15%), and identified physical decline as most strongly influenced at the population level by bone mineral density and telomere length (Mendelian Randomization standardized effects: gamma = -0.05 for each). The alternate allele of rs114409151 is separately associated with substantially increased PTH1R expression across six brain regions and visceral adipose tissue, based on GTEx v11 eQTL data from 953 donors GTEx Portal.

Reported associations

• Age-related physical and cognitive decline: This locus was identified in a longitudinal GWAS examining genetic contributors to changes in physical and cognitive aging phenotypes across the UK Biobank cohort
• Increased PTH1R expression in the brain: The alternate allele is associated with increased expression of PTH1R in the cerebellar hemisphere, cerebellum, frontal cortex (BA9), hypothalamus, cortex, and anterior cingulate cortex (BA24), with the largest effects in the cerebellar hemisphere and cerebellum GTEx Portal
• Increased PTH1R expression in visceral adipose tissue: The alternate allele is associated with increased PTH1R expression in the omentum (visceral adipose depot) GTEx Portal
• Increased ENSG00000308167 expression in subcutaneous adipose: The alternate allele is associated with increased expression of the gene ENSG00000308167 in subcutaneous adipose tissue GTEx Portal

Evidence quality The primary GWAS source is a 2025 paper by Schoeler, Pingault, and Kutalik published in Nature Communications, based on UK Biobank longitudinal data. A methodological strength is the use of simulation-validated models of change to select appropriate statistical approaches for two-wave longitudinal data; the authors also explicitly caution that selective attrition - the tendency for healthier participants to remain in a study over time - may limit the generalizability of findings. No PMID was available for this study in the provided materials, and no independent replication cohort findings are described in the available study excerpt. The GTEx eQTL evidence draws on a well-powered reference dataset (GTEx v11, 953 donors, FDR < 0.05), providing robust statistical support for tissue-specific gene-expression regulation at this locus; however, eQTL effects reflect gene-expression levels rather than clinical outcomes, and the relationship between the aging GWAS association and the PTH1R eQTL signal is not resolved in the provided materials.

Tissue-specific expression effects

• PTH1R: Increased expression in six brain regions (cerebellar hemisphere, cerebellum, frontal cortex BA9, hypothalamus, cortex, and anterior cingulate cortex BA24) and in visceral omentum adipose tissue; effects are largest in the cerebellar hemisphere and cerebellum GTEx Portal
• ENSG00000308167: Increased expression in subcutaneous adipose tissue GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.