rs11225170 (YAP1): Alzheimer's Resilience eQTL

Key takeaways

• rs11225170 sits near the YAP1 gene and is linked to increased YAP1 activity in tibial nerve and esophageal muscle tissue
• The alternate allele also reduces activity of a neighboring uncharacterized gene (ENSG00000277459) across skeletal muscle, skin, artery, and thyroid tissue
• This variant was studied in the context of why roughly 30% of elderly people remain cognitively healthy despite carrying Alzheimer's disease neuropathology in their brains
• Cognitive resilience to Alzheimer's neuropathology is 20-25% heritable overall and 15-44% heritable within each sex, pointing to meaningful sex-specific genetic contributions
• Direct association evidence for this specific variant and any disease trait is not established in the available data; tissue-level expression data is the primary available signal

What the research says A sex-stratified genome-wide association study (GWAS) - a scan of millions of genetic variants for statistical links to a trait - examined cognitive resilience, defined as remaining cognitively unimpaired despite carrying Alzheimer's disease neuropathology (amyloid plaques and neurofibrillary tangles in the brain) at autopsy, a pattern seen in roughly 30% of elderly adults. Using harmonized cognitive and amyloid biomarker data across multiple cohorts, the study ran sex-stratified analyses in n=2,093 males and n=2,931 females and a sex-interaction analysis in n=5,024 combined participants, finding cognitive resilience to be 20-25% heritable overall and 15-44% heritable within each sex among cognitively normal individuals. Separately, tissue-level expression data from GTEx v11 (953 donors, false discovery rate below 5%) identifies rs11225170 as a statistically significant expression quantitative trait locus (eQTL) - meaning the variant is linked to measurable differences in nearby gene activity in specific tissue types GTEx Portal.

Reported associations

• YAP1 expression in tibial nerve tissue: The alternate allele is associated with increased YAP1 (Yes-associated protein 1) expression (slope +0.14, p=1.4x10^-11, n=953 donors) GTEx Portal
• YAP1 expression in esophagus muscularis: The alternate allele is associated with increased expression (slope +0.08, p=1.3x10^-5) GTEx Portal
• ENSG00000277459 expression in skeletal muscle: The alternate allele is associated with reduced expression (slope -0.21, p=1.1x10^-10) GTEx Portal
• ENSG00000277459 expression in sun-exposed lower leg skin: The alternate allele is associated with reduced expression (slope -0.17, p=1.2x10^-6) GTEx Portal
• ENSG00000277459 expression in tibial artery: The alternate allele is associated with reduced expression (slope -0.14, p=6.7x10^-5) GTEx Portal
• ENSG00000277459 expression in thyroid: The alternate allele is associated with reduced expression (slope -0.12, p=1.1x10^-4) GTEx Portal
• ENSG00000288833 expression in unexposed suprapubic skin: The alternate allele is associated with increased expression (slope +0.14, p=4.9x10^-5) GTEx Portal
• BIRC3 expression in subcutaneous adipose tissue: The alternate allele is associated with increased expression (slope +0.12, p=9.9x10^-5) GTEx Portal
• Cognitive resilience to Alzheimer's disease neuropathology: This locus falls within a sex-stratified GWAS of cognitive resilience (n=5,024 participants); the study's reported genome-wide significant female-specific finding was at a separate locus (rs827389, chromosome 10, near GATA3), and no genome-wide significant association at rs11225170 is reported in the available data

Evidence quality The eQTL evidence from GTEx v11 (953 donors, false discovery rate below 5%) is the strongest available signal for rs11225170. The YAP1 eQTL in tibial nerve reaches p=1.4x10^-11, a highly stringent threshold supporting confidence in that expression-level finding GTEx Portal. The ENSG00000277459 signal shows directional consistency across four independent tissues (skeletal muscle, sun-exposed skin, tibial artery, thyroid), adding internal coherence to the eQTL evidence. The GWAS of cognitive resilience used a large multi-cohort design (n=5,024, harmonized cognitive and amyloid data) and found the trait substantially heritable; however, the study's reported genome-wide significant locus is rs827389, not rs11225170. Association evidence for this specific variant at any disease-level trait should be considered preliminary until independent replication is reported.

Tissue-specific expression effects

• YAP1: The alternate allele is associated with increased expression in tibial nerve tissue and esophageal muscle tissue GTEx Portal
• ENSG00000277459: The alternate allele is associated with reduced expression in skeletal muscle, sun-exposed lower leg skin, tibial artery, and thyroid tissue GTEx Portal
• ENSG00000288833: The alternate allele is associated with increased expression in unexposed suprapubic skin GTEx Portal
• BIRC3: The alternate allele is associated with increased expression in subcutaneous adipose tissue GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.