A genome-wide association meta-analysis of plasma Aβ peptides concentrations in the elderly

Abstract

Amyloid beta (Aβ) peptides are the major components of senile plaques, one of the main pathological hallmarks of Alzheimer disease (AD). However, Aβ peptides’ functions are not fully understood and seem to be highly pleiotropic. We hypothesized that plasma Aβ peptides concentrations could be a suitable endophenotype for a genome-wide association study (GWAS) designed to (i) identify novel genetic factors involved in amyloid precursor protein metabolism and (ii) highlight relevant Aβ-related physiological and pathophysiological processes. Hence, we performed a genome-wide association meta-analysis of four studies totaling 3 528 healthy individuals of European descent and for whom plasma Aβ1–40 and Aβ1–42 peptides levels had been quantified. Although we did not observe any genome-wide significant locus, we identified 18 suggestive loci (P<1 × 10−5). Enrichment-pathway analyses revealed canonical pathways mainly involved in neuronal functions, for example, axonal guidance signaling. We also assessed the biological impact of the gene most strongly associated with plasma Aβ1–42 levels (cortexin 3, CTXN3) on APP metabolism in vitro and found that the gene protein was able to modulate Aβ1–42 secretion. In conclusion, our study results suggest that plasma Aβ peptides levels are valid endophenotypes in GWASs and can be used to characterize the metabolism and functions of APP and its metabolites.

Copy number variation associates with mortality in long‐lived individuals: a genome‐wide assessment

“…These seven nominally significant CNVs are surrounded by numerous genes (see Table S3), of which two, TRPM3 and STARD13 , have previously been implicated in the regulation of human lifespan (Lunetta et al ., 2007; Yashin et al ., 2010). The STARD13 gene has moreover been associated ( P  ≤ 1 × 10 −5 ) with plasma levels of amyloid beta peptides that, among other things, play a role in Alzheimer's disease and hypertension (Chouraki et al ., 2014). In addition, also the CCDC3 and IRAK1BP1 genes could be speculated to play a role in human lifespan, as they have been reported to inhibit inflammation (Conner et al ., 2008, 2010; Azad et al ., 2014), and as revealed by the GO enrichment analysis, the majority of the other genes are involved in cell adhesion, which has previously been linked to longevity and age‐related diseases (Wolfson et al ., 2009; Tian et al ., 2013).…”

Alzheimer’s Disease Genetics: From the Bench to the Clinic

“…It is also likely that some of the problems in these analyses may be due to measurement problems for the Aβ phenotype (reviewed in (Mattsson et al, 2013)). A recent GWAS of plasma Aβ in over 3,500 individuals failed to observe any genome-wide significant signals including APOE (Chouraki et al, 2014). It is unclear whether this reflects differences in systemic versus CNS regulation of Aβ levels by APOE or evidence of differences in measurement of Aβ across studies that can decrease the power of a meta-analysis or both.…”

Whole exome sequence-based association analyses of plasma amyloid-β in African and European Americans; the Atherosclerosis Risk in Communities-Neurocognitive Study

“…These findings echoed those of the published GWAS meta-analysis of plasma aβ concentrations which failed to identify significant genetic variants in non-demented elderly participants [12]. Plasma aβ concentrations change with age, at least until dementia or brain plaques appear [22, 43], and could have a dynamic genetic architecture across the lifespan.…”