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

INTRODUCTION: Rs11218343 is a non-coding variant of genome-wide significance for sporadic Alzheimer’s 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. METHODS: We 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. RESULTS: We 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. DISCUSSION: Our 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.