rs117108035 (BLMH-TMIGD1): Cognitive Decline Locus

Key takeaways

• rs117108035, in the BLMH-TMIGD1 gene region, was included in a UK Biobank genome-wide study of age-related cognitive and physical aging.
• GTEx data from 953 donors links the alternate allele to reduced expression of BLMH (Bleomycin Hydrolase, an enzyme involved in protein breakdown) in both sun-exposed and non-sun-exposed skin tissue.
• The longitudinal study found baseline physical function is substantially more heritable (about 31%) than the rate of physical decline (about 3%), indicating these two dimensions are governed by largely different genes.
• Cognitive decline in the study was most strongly linked via Mendelian Randomization (a method using genetic variants as natural experiments) to Alzheimer's disease genetic liability (standardized effect 0.17), while physical decline was tied to telomere length and bone mineral density (both at -0.05).
• Evidence specific to this variant is preliminary, as the provided study text does not report an effect size or p-value for this locus directly.

What the research says A longitudinal genome-wide association study (GWAS, a method that scans hundreds of thousands of genetic positions simultaneously) using UK Biobank data examined loci including those in the BLMH-TMIGD1 region as part of research into age-related cognitive and physical decline. The study found that baseline physical function has a heritability of about 31.38%, while the rate of physical decline is only about 3.15% heritable, indicating largely separate genetic architectures for these two dimensions. Cognitive decline was most strongly linked via Mendelian Randomization to Alzheimer's disease genetic liability (standardized effect gamma = 0.17), while physical decline showed weaker connections to telomere length and bone mineral density (gamma = -0.05 each).

Reported associations

• Age-related physical function and decline: This locus was examined in a genome-wide scan of longitudinal physical aging in the UK Biobank, where baseline physical function and the rate of physical decline were found to be genetically distinct, with heritabilities of approximately 31% and 3%, respectively.
• Age-related cognitive function and decline: The same study included genome-wide coverage of cognitive aging, finding that cognitive decline was most strongly linked genome-wide to Alzheimer's disease genetic liability.
• BLMH expression in skin: GTEx v11 data (953 donors) shows the alternate allele at this position is associated with reduced BLMH expression in non-sun-exposed suprapubic skin (p = 1.1e-4) and sun-exposed lower-leg skin (p = 3.8e-5) GTEx Portal.

Evidence quality The UK Biobank longitudinal GWAS represents a large-scale, simulation-validated approach to aging genomics, but the text available here covers only the study introduction, and no p-value or effect size for this locus specifically is reported in the provided material. The study acknowledges that selective participation and attrition in biobank longitudinal samples can affect inference, and calls for careful modeling to avoid biased conclusions. No independent replication of this locus in the context of cognitive or physical decline is described in the provided text, so any association must be considered preliminary. GTEx eQTL evidence for reduced BLMH expression in skin is statistically robust within the GTEx framework (FDR < 0.05, n = 953), but reflects a gene-expression mechanism rather than a clinical outcome.

Tissue-specific expression effects

• BLMH: The alternate allele is associated with reduced expression in non-sun-exposed skin (suprapubic region) and sun-exposed lower-leg skin, based on GTEx v11 data from 953 donors GTEx Portal.

Lifestyle considerations No lifestyle considerations on file for this variant.