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Eur J Hum Genet. 2019 Feb;27(2):244-253. doi: 10.1038/s41431-018-0273-5. Epub 2018 Sep 26.

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

Author information

1
Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands.
2
Department of Clinical Genetics, Amsterdam UMC, Amsterdam, The Netherlands.
3
Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands.
4
Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, VU, Amsterdam, The Netherlands.
5
Department of Epidemiology and Biostatistics, Amsterdam UMC, Amsterdam, The Netherlands.
6
Amsterdam Public Health Research Institute, Amsterdam, The Netherlands.
7
Alzheimer Center Amsterdam, Department of Neurology, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands. h.holstege@vumc.nl.
8
Department of Clinical Genetics, Amsterdam UMC, Amsterdam, The Netherlands. h.holstege@vumc.nl.
9
Delft Bioinformatics Lab, Delft University of Technology, Delft, The Netherlands. h.holstege@vumc.nl.

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.

PMID:
30258121
PMCID:
PMC6336855
DOI:
10.1038/s41431-018-0273-5
[Indexed for MEDLINE]
Free PMC Article

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