Late-onset Alzheimer disease risk variants mark brain regulatory loci

abstract: ...Objective: To investigate the top late-onset Alzheimer disease (LOAD) risk loci detected or confirmed by the International Genomics of Alzheimer's Project for association with brain gene expression levels to identify variants that influence Alzheimer disease (AD) risk through gene expression regulation. Methods: Expression levels from the cerebellum (CER) and temporal cortex (TCX) were obtained using Illumina whole-genome cDNA-mediated annealing, selection, extension, and ligation assay (WG-DASL) for 400 autopsied patients (200 with AD and 200 with non-AD pathologies). We tested 12 significant LOAD genome-wide association study (GWAS) index single nucleotide polymorphisms (SNPs) for cis association with levels of 34 genes within 100 kb. We also evaluated brain levels of 14 LOAD GWAS candidate genes for association with 1,899 cis -SNPs. Significant associations were validated in a subset of TCX samples using next-generation RNA sequencing (RNAseq). Results: We identified strong associations of brain CR1 , HLA-DRB1 , and PILRB levels with LOAD GWAS index SNPs. We also detected other strong cis- SNPs for LOAD candidate genes MEF2C , ZCWPW1 , and SLC24A4 . MEF2C and SLC24A4 , but not ZCWPW1 cis -SNPs, also associate with LOAD risk, independent of the index SNPs. The TCX expression associations could be validated with RNAseq for CR1 , HLA-DRB1 , ZCWPW1 , and SLC24A4. Conclusions: Our results suggest that some LOAD GWAS variants mark brain regulatory loci, nominate genes under regulation by LOAD risk variants, and annotate these variants for their brain regulatory effects.

... LOAD GWAS index SNPs. We also detected other strong cis- SNPs for LOAD candidate genes MEF2C , ZCWPW1 , and SLC24A4 . MEF2C and SLC24A4 , but not ZCWPW1 cis -SNPs, also associate with LOAD risk, independent of the index SNPs. The TCX expression associations could be validated with RNAseq for CR1 , HLA-DRB1 , ZCWPW1 , and SLC24A4. Conclusions: Our results suggest that some LOAD GWAS variants mark brain regulatory loci, nominate genes under regulation by LOAD risk variants, and annotate these

... , ZCWPW1 , and SLC24A4 ). Expression levels were compared between patients with AD and patients without AD in multivariable linear regression analyses adjusting for age at death, sex, RIN, RIN 2 adjusted (RIN-RINmean) 2 , PCR plates as technical variables, and expression levels for 5 transcripts that are specific for 5 cell types in the CNS to account for neuronal loss, gliosis, and/or vascular tissue in the assessed brain regions. The following probes were used as covariates: ENO2 for neurons

... LOAD risk association and functional evidence of regulatory potential. The most significant cis -eSNPs for each gene are summarized in table e-3, with detailed findings depicted in tables e-4 to e-24. MEF2C , ZCWPW1 , and SLC24A4 had cis -eSNPs that achieved study-wide significance in at least 1 tissue region. These variants were different than the LOAD GWAS index SNPs ( table 2 , table e-3). Table 2 Significant brain transcript level associations for the candidate genes at the LOAD GWAS loci

... (C) SLC24A4 cerebellum expression levels cis- SNP associations. See figure 2 legend for description of other features. CER = cerebellum; SNP = single nucleotide polymorphism; TCX = temporal cortex. SLC24A4 cis -eSNPs achieved study-wide significant association with CER gene levels, many of which also had nominally significant TCX level associations (tables e-11 and e-12). The top SLC24A4 cis -eSNP rs7150592 is significantly associated with increased SLC24A4 CER levels and suggestively associated with higher TCX levels and increased LOAD risk. 5 TCX RNAseq validation also reveals suggestive association with higher levels. This variant is not in LD with the LOAD index SNP at this locus, rs10498633 ( r 2 = 0.001; D = 0.053; figure 3C ). None of the strong SLC24A4 cis -eSNPs have good Regulome scores. ZCWPW1 cis -eSNP associations were strongest in TCX, with RNAseq validation and nominally significant CER associations (table e-13). Fine mapping of ZCWPW1 variants revealed many strong cis

... this study 20 that also existed in our data set (tables e-4 to e-13). We were able to make comparisons for all except SLC24A4 cis -eSNPs, as none existed in the LOAD/HD/HC study. Cis -eSNPs for CR1 , HLA-DRB1 , ZCWPW1 , and PILRB were highly significant in both data sets (table e-26). The common MEF2C cis-eSNP rs770463 had nominal significance in our study and was highly significant in the LOAD/HD/HC study. 20 Differential gene expression. TCX CR1 levels were nominally significantly higher in patients with AD compared to patients without AD (table e-27). While this finding would not remain significant after Bonferroni corrections for the 6 genes evaluated, this trend is consistent with expectations based on the highlighted cis -eSNP results ( table 1 ), i.e., rs3818361 minor allele is associated with both increased AD risk (higher frequency in patients with AD) and greater TCX CR1 levels. TCX SLC24A4 levels are significantly higher in patients with AD, again consistent with the direction of

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Gene: SLC24A4 - solute carrier family 24 (sodium/potassium/calcium exchanger), member 4 - (NCBI)

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