| Title: | Challenges at the APOE locus: a robust quality control approach for accurate APOE genotyping |
| Journal: | Alzheimer's Research & Therapy |
| Published: | 4 Feb 2022 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/35120553/ |
| DOI: | https://doi.org/10.1186/s13195-022-00962-4 |
| URL: | https://alzres.biomedcentral.com/counter/pdf/10.1186/s13195-022-00962-4 |
| Citations: | 9 (8 in last 2 years) as of 8 Aug 2024 |
Publication 12544
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Abstract
BackgroundGenetic variants within the APOE locus may modulate Alzheimer's disease (AD) risk independently or in conjunction with APOE*2/3/4 genotypes. Identifying such variants and mechanisms would importantly advance our understanding of APOE pathophysiology and provide critical guidance for AD therapies aimed at APOE. The APOE locus however remains relatively poorly understood in AD, owing to multiple challenges that include its complex linkage structure and uncertainty in APOE*2/3/4 genotype quality. Here, we present a novel APOE*2/3/4 filtering approach and showcase its relevance on AD risk association analyses for the rs439401 variant, which is located 1801 base pairs downstream of APOE and has been associated with a potential regulatory effect on APOE.MethodsWe used thirty-two AD-related cohorts, with genetic data from various high-density single-nucleotide polymorphism microarrays, whole-genome sequencing, and whole-exome sequencing. Study participants were filtered to be ages 60 and older, non-Hispanic, of European ancestry, and diagnosed as cognitively normal or AD (n = 65,701). Primary analyses investigated AD risk in APOE*4/4 carriers. Additional supporting analyses were performed in APOE*3/4 and 3/3 strata. Outcomes were compared under two different APOE*2/3/4 filtering approaches.ResultsUsing more conventional APOE*2/3/4 filtering criteria (approach 1), we showed that, when in-phase with APOE*4, rs439401 was variably associated with protective effects on AD case-control status. However, when applying a novel filter that increases the certainty of the APOE*2/3/4 genotypes by applying more stringent criteria for concordance between the provided APOE genotype and imputed APOE genotype (approach 2), we observed that all significant effects were lost.ConclusionsWe showed that careful consideration of APOE genotype and appropriate sample filtering were crucial to robustly interrogate the role of the APOE locus on AD risk. Our study presents a novel APOE filtering approach and provides important guidelines for research into the APOE locus, as well as for elucidating genetic interaction effects with APOE*2/3/4.</p>
8 Keywords
- Alzheimer Disease
- Apolipoprotein E4
- Apolipoproteins E
- Genetic Predisposition to Disease
- Genotype
- Humans
- Middle Aged
- Quality Control
28 Authors
- Michael E. Belloy
- Sarah J. Eger
- Yann Le Guen
- Vincent Damotte
- Shahzad Ahmad
- M. Arfan Ikram
- Alfredo Ramirez
- Anthoula C. Tsolaki
- Giacomina Rossi
- Iris E. Jansen
- Itziar de Rojas
- Kayenat Parveen
- Kristel Sleegers
- Martin Ingelsson
- Mikko Hiltunen
- Najaf Amin
- Ole Andreassen
- Pascual Sánchez-Juan
- Patrick Kehoe
- Philippe Amouyel
- Rebecca Sims
- Ruth Frikke-Schmidt
- Wiesje M. van der Flier
- Jean-Charles Lambert
- Zihuai He
- Summer S. Han
- Valerio Napolioni
- Michael D. Greicius
1 Application
| Application ID | Title |
|---|---|
| 61054 | Social and Environmental Adversity in Relation to All-Cause Mortality |
Enabling scientific discoveries that improve human health