O1‐03‐05: High‐Resolution Imputation in Genome‐Wide Association Studies of Late‐Onset Alzheimer's Disease Identifies Novel Rare Variant Associations

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The largest genome-wide association study (GWAS) to date for late-onset Alzheimer Disease (LOAD), published by the International Genomics of Alzheimer’s Project (IGAP) in 2013, identified 19 susceptibility LOAD loci in addition to APOE, however the majority of loci identified were common (minor allele frequency (MAF)>0.05). The newly-released Haplotype Reference Consortium (HRC) reference panel of 64,976 haplotypes with 39,235,157 SNPs allows imputation down to an unprecedented MAF=0.00008, allowing for accurate imputation and analysis of very-low-frequency variants. ADGC imputed 33 case-control, family, and prospective datasets to the HRC panel to identify novel rare variant associations. HRC panel imputation was performed using Minimac3 on the University of Michigan Imputation Server on 14,743 cases and 15,871 controls. Logistic regression on individual variants with MAF>0.01 was performed using imputed genotype probabilities in PLINKv1.9 (xtgee/R was used for family data) and meta-analyzed in METAL, while variants with MAF≤0.01 were analyzed using score-based tests and meta-analyzed in the SeqMeta/R package; both analyses were adjusted for age-at-onset(cases)/age-at-last-exam(controls), sex, and population substructure. Within- and across-dataset measures of genomic inflation of measures were estimated for variants of MAF>0.01. We analyzed an average of 39,216,773 genotyped or imputed SNVs per dataset. Preliminary analyses identified 5 loci with P<5×10 in known GWAS candidate loci (APOE, BIN1, the MS4A region, PICALM, and CR1), consistent with previously observed associations in these data (PMID: 21460841). An additional 13 loci demonstrated multiple single variant associations with P<10, including variants at two IGAP GWAS loci (PMID: 24162737), rs13155750 in MEF2C (OR(95% CI): 1.13(1.08,1.20); P=5.09×10) and rs755951 in PTK2B (OR(95% CI): 1.11(1.06,1.16); P=5.61×10). Novel associations observed include signals at LILRA5 (19:54821819; OR(95% CI): 1.14(1.08,1.20); P=4.84×10), known to be involved in innate immunity; and at SMOX (rs1884732; OR(95% CI): 1.11(1.06,1.17); P=5.17×10), which is involved in the catabolism of polyamines, levels of which are altered in AD brains. Score test analyses and replication analyses are underway and these results will be presented. Several novel candidate loci for LOAD have been identified using high-quality imputation of rare and low-frequency variants in the ADGC, demonstrating the utility of rare variant imputation using dense haplotype reference panels in identifying novel disease loci.

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