Alzheimer disease risk variant rs11218343 determines functional expression of SORL1 in microglia

IntroductionRs11218343 is a non-coding variant of genome-wide significance for sporadic Alzheimers disease (AD) with one of the most protective effects known. It localizes to SORL1, encoding the AD risk factor SORLA. Still, the functional significance of rs11218343 for AD related processes remains unclear. MethodsWe used iPSC lines from donors, or genome-engineered to carry major and minor rs11218343 alleles, to study the impact of rs11218343 genotype on brain cell activities. ResultsWe show that rs11218343 uniquely controls functional expression of SORLA in microglia, with incrased receptor expression in the minor protective allele correlating with reduced pro-inflammatory responses. This anti-inflammatory effect is seen in donor iPSC lines but not in SNP-engineered isogenic lines, documenting rs11218343 to be diagnostic but not functional. DiscussionOur findings corroborate genetically defined expression levels of SORL1 in microglia as a determinant of protection from pro-inflammatory stimulation, a function encoded by a haplotype linked to rs11218343. RESEARCH IN CONTEXTO_ST_ABSSystematic reviewC_ST_ABSReviewing the literature on single nucleotide polymorphisms (SNP) showing genome-wide association with the risk of sporadic AD, we learned that prior studies identified rs11218343 as a major predictor of protection from the disease. We also learned that this SNP localizes to SORL1, encoding the AD risk factor SORLA. However, no data were available whether this SNP controls functional expression of SORLA or other AD-related proteins in brain cell types. InterpretationOur study documents that rs11218343 controls the expression of SORL1 in iPSC-derived human microglia, an effect not seen for other microglial genes. Increased expression of SORLA in the minor allele correlates with decreased inflammatory responses in this cell type. These findings suggest that the ability of SORLA to contain pro-inflammatory actions of microglia contributes to its protective effect in AD. Future directionsOur studies document rs11218343 to be diagnostic but not functional in SORL1 expression control. These findings should be corroborated in a replication cohort of donor cell lines. Also, further analyses need to identify the sequence variation in disequilibrium with rs11218343, that controls SORL1 gene transcription. Such information will be essential to mechanistically resolve the mode of action of the most protective genotype in sporadic AD known to date. HIGHLIGHTSO_LIrs11218343 predicts expressions of AD risk gene SORL1 C_LIO_LIexpression control by the linked haplotype is specific to human microglia C_LIO_LIincreased SORL1 levels with minor allele ameliorates pro-inflammatory responses C_LI