Confronting complexity in late‐onset Alzheimer disease: application of two‐stage analysis approach addressing heterogeneity and epistasis

Abstract

Common diseases with a genetic basis are likely to have a very complex etiology, in which the mapping between genotype and phenotype is far from straightforward. A new comprehensive statistical and computational strategy for identifying the missing link between genotype and phenotype has been proposed, which emphasizes the need to address heterogeneity in the first stage of any analysis and gene-gene interactions in the second stage. We applied this two-stage analysis strategy to late-onset Alzheimer disease (LOAD) data, which included functional and positional candidate genes and markers in a region of interest on chromosome 10. Bayesian Classification found statistically significant clusterings for independent family-based and case-control datasets, which used the same five markers in LRRTM3 as the most influential in determining cluster assignment. In subsequent analyses to detect main effects and gene-gene interactions, markers in three genes-PLAU, ACE and CDC2-were found to be associated with late-onset Alzheimer disease in particular subsets of the data based on their LRRTM3 multilocus genotype. All of these genes are viable candidates for LOAD based on their known biological function, even though PLAU, CDC2 and LRRTM3 were initially identified as positional candidates. Further studies are needed to replicate these statistical findings and to elucidate possible biological interaction mechanisms between LRRTM3 and these genes.

Aβ degradation or cerebral perfusion? Divergent effects of multifunctional enzymes

“…A common Alu (indel) insertion(I)/deletion(D) polymorphism (rs 1799752) in intron 16 of the ACE gene was reported to be associated with sporadic AD, the greatest risk being associated with homozygosity of the I allele (Kehoe et al, 1999 ). This was confirmed in several meta-analyses (Narain et al, 2000 ; Kehoe et al, 2003 ; Elkins et al, 2004 ; Lehmann et al, 2005 ) and was supported to some extent by some of the earlier whole-genome association studies (Li et al, 2008 ; Thornton-Wells et al, 2008 ) although a number of more recent and larger studies have failed to find any association. In the original studies, homozygosity of the D and I alleles was associated with the highest and lowest ACE protein level in the periphery, respectively, (Rigat et al, 1990 ) although this association only partly explains the total variance of ACE in the periphery (Terao et al, 2013 ).…”

LRRTM3 Interacts with APP and BACE1 and Has Variants Associating with Late-Onset Alzheimer’s Disease (LOAD)

“…In a two-stage analysis assessing for heterogeneity and gene-gene interactions in 22 candidate genes, LRRTM3 SNPs were identified to be the most influential in determining clusters for AD risk [15]. Furthermore in this study, LRRTM3 SNP multilocus genotypes (MLGs) were shown to have statistical interactions with PLAU , previously implicated in AD risk and Aβ levels [16], as well as CDC2 and ACE in conferring AD risk.…”

“…Indeed, two other studies utilized the MLG approach with LRRTM3 SNPs and showed association with AD risk. One study identified 5 LRRTM3 SNPs, the MLGs of which formed three clusters, wherein variants of PLAU , CDC2 and ACE showed significant AD risk association [15]. Another study identified two and three locus genotypes with SNPs in LRRTM3 , ACE and A2M that associate with AD risk [17].…”

Neural Cell Adhesion Molecules Belonging to the Family of Leucine-Rich Repeat Proteins

“…A large region of chromosome 10, including the region encoding LRRTM3, has received attention in relation to the development of late-onset AD. Investigations of SNPs potentially related to late-onset AD, as well as other statistical and genetic studies, have observed SNPs in LRRTM3 as well as CCTNNA3 (the α-Catenin-encoding gene in which LRRTM3 is nested in an intron) and identifi ed LRRTM3 as a potential late-onset AD candidate gene (Reitz et al 2012 ;Liang et al 2007 ;Thornton-Wells et al 2008 ;Edwards et al 2009 ).…”