rs11218343 (SORL1): Alzheimer's Disease Risk Variant

Key takeaways

• The rare C allele at rs11218343 in SORL1 is linked to roughly 16% lower Alzheimer's disease odds, confirmed in studies of over 111,000 cases
• This association reached P = 1.4 x 10^-21 in the largest Alzheimer's GWAS meta-analysis and has been replicated in datasets totaling over a million people
• Two independent signals act at the SORL1 locus in opposite directions: rs11218343 lowers risk while a nearby variant raises it
• GTEx data links this variant to higher SORL1 expression in nerve tissue, consistent with the gene's role in protein sorting
• Most evidence is from European-ancestry populations; early data from Argentina and Chile suggest the effect is broadly shared

What the research says rs11218343 sits within the SORL1 (sortilin-related receptor 1) locus on chromosome 11. In the largest Alzheimer's disease GWAS meta-analysis at the time of publication, totaling 111,326 clinically diagnosed or proxy cases and 677,663 controls, the C allele was associated with reduced Alzheimer's disease risk at an odds ratio of 0.84 (95% CI 0.81-0.87, P = 1.4 x 10^-21) PMID 35379992. The locus appeared among 38 genome-wide significant signals confirmed in a separate meta-analysis spanning 1,126,563 individuals, which also highlighted microglia and protein catabolism as relevant to late-onset Alzheimer's disease PMID 34385711. A trans-ethnic study including participants from Argentina and Chile, meta-analyzed with European data, found that functional annotations at identified AD loci implicated endosomal and lysosomal function, consistent with SORL1's established biological role PMID 38356174.

Reported associations

• Alzheimer's disease (protective association): The C allele at rs11218343 carries an odds ratio of 0.84 (95% CI 0.81-0.87, P = 1.4 x 10^-21) for Alzheimer's disease; the C allele is the minor allele with a population frequency of approximately 3.9% PMID 35379992
• Alzheimer's disease (second independent SORL1 signal): A distinct nearby variant, rs74685827, at the same locus carries an odds ratio of 1.19 (95% CI 1.13-1.25, P = 2.8 x 10^-11, MAF ~1.9%) for increased Alzheimer's disease risk, demonstrating two independent signals at this locus acting in opposite directions PMID 35379992
• Alzheimer's disease (replication in 1.1 million individuals): The SORL1 locus was among 38 independently replicated genome-wide significant AD loci in a meta-analysis spanning 1,126,563 individuals across 13 cohorts PMID 34385711
• Alzheimer's disease (UK Biobank proxy phenotype): The SORL1 locus was replicated in a GWAS using parental history of Alzheimer's dementia as a proxy phenotype in 314,278 UK Biobank participants, meta-analysed with published case-control data totaling 74,046 additional individuals PMID 30926938
• Alzheimer's disease clinical endophenotypes: In the GR@ACE genome-wide study of dementia, the SORL1 locus was replicated among known AD signals; vascular processes were identified as a causal mechanism specifically in probable Alzheimer's cases, with the locus classified by its relationship to diagnostic certainty and vascular burden PMID 32506639
• All-cause dementia and vascular dementia: A meta-analysis of 800,597 individuals including 46,902 all-cause dementia cases and 8,702 vascular dementia cases replicated known Alzheimer's disease loci, including the SORL1 region, as risk factors for both conditions

Evidence quality The association between rs11218343 and Alzheimer's disease is among the most robustly supported common-variant signals in the field. The primary signal (P = 1.4 x 10^-21, OR = 0.84) derives from a two-stage meta-analysis of 111,326 cases and 677,663 controls PMID 35379992. Independent replication is documented in a 1,126,563-individual meta-analysis PMID 34385711, a UK Biobank proxy-phenotype study of 314,278 participants meta-analysed with case-control data PMID 30926938, and the GR@ACE consortium PMID 32506639. No conflicting findings were identified across the provided studies for the direction of effect. The vast majority of evidence comes from European-ancestry populations. An initial GWAS in 539 Argentinian and Chilean cases and 854 controls found that an Alzheimer's genetic risk score built from European GWAS signals performed comparably, but its predictive value declined as participants' Native American ancestry proportion increased PMID 38356174. As with all common-variant GWAS findings, the per-allele effect size (OR 0.84) is modest in absolute terms.

Tissue-specific expression effects

• SORL1: This variant is associated with increased SORL1 expression in tibial nerve tissue (positive slope of +0.22, FDR < 0.05, GTEx v11, 953 donors), suggesting one allele may influence risk in part by altering expression of the named gene in peripheral nerve GTEx Portal
• TECTA: This variant is also associated with increased TECTA expression in brain nucleus accumbens basal ganglia (positive slope of +0.47, FDR < 0.05, GTEx v11); TECTA encodes alpha tectorial membrane protein, and the functional relevance of this eQTL (expression quantitative trait locus - a variant that influences how much of a gene is expressed) to Alzheimer's disease biology is not established in the studies provided GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.