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Centenarian Controls Increase Variant Effect-sizes by an average two-fold in an Extreme Case-Extreme Control Analysis of Alzheimer's Disease

By Niccolò Tesi, Sven J. van der Lee, Marc Hulsman, Iris E. Jansen, Najada Stringa, Natasja van Schoor, Hanne Meijers-Heijboer, Martijn Huisman, Philip Scheltens, Marcel J.T. Reinders, Wiesje M. van der Flier, Henne Holstege

Posted 13 Apr 2018
bioRxiv DOI: 10.1101/298018 (published DOI: 10.1038/s41431-018-0273-5)

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=9.0x10-4). 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-ε2 (2.2-fold) and APOE-ε4 (2.0-fold). Comparing extreme phenotypes enabled us to replicate the AD association for 10 variants (p<0.05) in relatively small samples. The increase in effect-sizes depended mainly on using centenarians as extreme controls: the average variant effect-size was not increased in a comparison of extreme AD cases and age-matched controls (0.94-fold, p=6.8x10-1), suggesting that on average the tested genetic variants did not explain the extremity of the AD-cases. Concluding, using centenarians as extreme controls in AD case-controls studies boosts the variant effect-size by on average two-fold, allowing the replication of disease-association in relatively small samples.

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