Population-based Analysis of Alzheimer’s Disease Risk Alleles Implicates Genetic Interactions

Abstract

Background Reported odds ratios and population attributable fractions (PAF) for late-onset Alzheimer’s disease (LOAD) risk loci (BIN1, ABCA7, CR1, MS4A4E, CD2AP, PICALM, MS4A6A, CD33, and CLU) come from clinically ascertained samples. Little is known about the combined PAF for these LOAD risk alleles and the utility of these combined markers for case-control prediction. Here we evaluate these loci in a large population-based sample to estimate PAF and explore the effects of additive and non-additive interactions on LOAD status prediction performance. Methods 2,419 samples from the Cache County Memory Study were genotyped for APOE and nine LOAD risk loci from AlzGene.org. We used logistic regression and ROC analysis to assess the LOAD status prediction performance of these loci using additive and non-additive models, and compared ORs and PAFs between AlzGene.org and Cache County. Results Odds ratios were comparable between Cache County and AlzGene.org when identical SNPs were genotyped. PAFs from AlzGene.org ranged from 2.25–37%; those from Cache County ranged from 0.05–20%. Including non-APOE alleles significantly improved LOAD status prediction performance (AUC = 0.80) over APOE alone (AUC = 0.78) when not constrained to an additive relationship (p < 0.03). We identified potential allelic interactions (p-values uncorrected): CD33-MS4A4E (Synergy Factor = 5.31; p < 0.003) and CLU-MS4A4E (SF = 3.81; p < 0.016). Conclusions While non-additive interactions between loci significantly improve diagnostic ability, the improvement does not reach the desired sensitivity or specificity for clinical use. Nevertheless, these results suggest that understanding gene-gene interactions may be important in resolving Alzheimer’s disease etiology.

Gene-based aggregate SNP associations between candidate AD genes and cognitive decline

“…Another possibility is that the AD-associated sentinel SNPs which informed our analysis are AD specific and other pathologies such as vascular disease have stronger contributions to the cognitive decline in these cohorts. A recent study found evidence of synergistic interaction effects among ADassociated genes and the development of AD (Ebbert et al 2014). Thus, an association between AD risk genes and cognitive decline may involve more complicated relationships than have been tested here.…”

Interaction between variants in CLU and MS4A4E modulates Alzheimer's disease risk

“…AD is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. Many genetic loci exist that modify AD risk, but collectively, they explain only a fraction of AD’s heritability [2] and are not diagnostically useful [3,4]. Rare variants with large effects and epistatic interactions may account for much of the unexplained AD heritability, but are largely unknown due to limitations in traditional GWAS studies.…”

“…Rare variants with large effects and epistatic interactions may account for much of the unexplained AD heritability, but are largely unknown due to limitations in traditional GWAS studies. While rare variant and epistatic effects on AD are poorly understood, recent studies suggest that gene-gene interactions play a critical role in AD etiology and progression [3,5–7]. …”

“…A previous study [3] reported evidence of two gene-gene interactions that increase AD risk. Specifically, Ebbert et al reported interactions between rs11136000 C/C ( CLU ; minor allele = T, MAF = 0.38) and rs670139 G/G ( MS4A4E ; minor allele = T, MAF = 0.38) genotypes (synergy factor (SF) = 3.81; p = .016), and the rs3865444 C/C ( CD33 ; minor allele = A, MAF = 0.21) and rs670139 G/G ( MS4A4E ) genotypes (SF = 5.31; p = .003).…”

“…We performed an independent meta-analysis of datasets from the Alzheimer’s Disease Genetics Consortium (ADGC) using 3837 cases and 4145 controls, followed by a combined meta-analysis that included the original Cache County results [3] with an additional 326 cases and 2093 controls. We also tested for dosage or dominant effects and an APOEε4 effect.…”