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

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

Research output: Contribution to JournalArticleAcademicpeer-review

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-ε2 (2.2-fold), and APOE-ε4 (twofold). 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 = 6.8 × 10-1), 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-control studies boosts the variant effect size by on average twofold, allowing the replication of disease-association in relatively small samples.

Original languageEnglish
Pages (from-to)244-253
Number of pages10
JournalEuropean Journal of Human Genetics
Volume27
Issue number2
DOIs
Publication statusPublished - Feb 2019

Funding

Acknowledgements Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience (www.amsterdamresearch.org). The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland (WE09.2014-03) and Stiching VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte (VSM 14 04 14 02). The Dutch case–control study is part of EADB (European Alzheimer DNA biobank) funded by JPcofundNL (ZonMW project number: 733051061). This work was in part carried out on the Dutch national e-infrastructure with the support of SURF Cooperative.

FundersFunder number
EADB
European Alzheimer
JPcofundNL
SURF Cooperative
ZonMw733051061
Alzheimer NederlandWE09.2014-03

    Keywords

    • Aged
    • Aged, 80 and over
    • Alzheimer Disease/genetics
    • Control Groups
    • Female
    • Genome-Wide Association Study/methods
    • Humans
    • Male
    • Middle Aged
    • Patient Selection
    • Polymorphism, Single Nucleotide
    • Sample Size

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