rs115430035 (SRGAP2): Aging and Cognitive Decline

Key takeaways

• rs115430035 is in the SRGAP2 gene, flagged in a large UK Biobank genome-wide study of aging.
• The genetics of baseline physical fitness and the genetics of how fast fitness declines are largely separate - with very different heritability levels (31% vs. 3%).
• Cognitive decline in this study was mostly tied to Alzheimer's disease genetic risk.
• Physical decline was tied to genetic factors linked to bone mineral density and telomere length.
• Evidence for this specific variant is preliminary and comes from a single study without described replication.

What the research says A genome-wide association study (GWAS) using longitudinally curated aging phenotypes from the UK Biobank examined whether genetic factors underlying baseline cognitive and physical function differ from those driving accelerated decline over time. The study found marked heritability differences between baseline and decline: baseline physical function showed 31.38% heritability versus only 3.15% for the rate of physical decline, indicating these are genetically distinct outcomes. Using Mendelian Randomization (a statistical method that tests whether a genetic proxy for one trait causally influences another), the study estimated that genetic liability for Alzheimer's disease had a standardized effect of 0.17 on cognitive decline, while shorter telomere length and lower bone mineral density each had a standardized effect of -0.05 on physical decline.

Reported associations

• Age-related cognitive and physical decline: rs115430035 in SRGAP2 was identified through a genome-wide scan of longitudinal aging phenotypes in the UK Biobank; the specific effect size and significance threshold for this variant are not available in the provided study excerpt.
• Physical function decline: The broader study identified loci such as DUSP6 as specific to physical decline over time rather than baseline physical function, illustrating that distinct genetic variants govern different aspects of physical aging.
• Cognitive decline: Alzheimer's disease genetic liability showed a standardized Mendelian Randomization effect of 0.17 on cognitive decline, identifying it as a primary genetic driver of cognitive aging in this sample.
• Physical decline via bone mineral density: Genetic proxies for lower bone mineral density were associated with faster physical decline, with a standardized effect of -0.05.
• Physical decline via telomere length: Genetic proxies for shorter telomere length were associated with faster physical decline, also with a standardized effect of -0.05.

Evidence quality The source study used the UK Biobank, a large prospective cohort, to conduct genome-wide scans on longitudinal aging phenotypes. The authors note several important limitations. First, selective participation and attrition in the UK Biobank mean the analytic sample skews healthier than the general population, which may bias genetic estimates. Second, most participants contributed data at only two time points, constraining the precision of change estimates. Third, heritability of accelerated physical decline (3.15%) is substantially lower than that of baseline physical function (31.38%), meaning longitudinal genetic signals are harder to detect and more susceptible to noise. A PMID for this study is not included in the provided metadata, and no independent replication of the rs115430035 association in SRGAP2 is described in the available literature. All findings specific to this variant should be treated as preliminary.

Lifestyle considerations No lifestyle considerations on file for this variant.