Centenarian controls increase variant effect sizes by an average twofold in an extreme case-extreme control analysis of Alzheimer's disease.

ABSTRACT: The detection of genetic loci associated with Alzheimer's disease (AD) requires large numbers of cases and controls because variant effect sizes are mostly small. We hypothesized that variant effect sizes should increase when individuals who represent the extreme ends of a disease spectrum are considered, as their genomes are assumed to be maximally enriched or depleted with disease-associated genetic variants. We used 1,073 extensively phenotyped AD cases with relatively young age at onset as extreme cases (66.3?±?7.9 years), 1,664 age-matched controls (66.0?±?6.5 years) and 255 cognitively healthy centenarians as extreme controls (101.4?±?1.3 years). We estimated the effect size of 29 variants that were previously associated with AD in genome-wide association studies. Comparing extreme AD cases with centenarian controls increased the variant effect size relative to published effect sizes by on average 1.90-fold (SE?=?0.29, p?=?9.0?×?10-4). The effect size increase was largest for the rare high-impact TREM2 (R74H) variant (6.5-fold), and significant for variants in/near ECHDC3 (4.6-fold), SLC24A4-RIN3 (4.5-fold), NME8 (3.8-fold), PLCG2 (3.3-fold), APOE-?2 (2.2-fold), and APOE-?4 (twofold). Comparing extreme phenotypes enabled us to replicate the AD association for 10 variants (p?

SUBMITTER: Tesi N 

PROVIDER: S-EPMC6336855 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature