Universität zu Köln

Belloy, Michael E., Eger, Sarah J., Le Guen, Yann, Damotte, Vincent, Ahmad, Shahzad, Ikram, M. Arfan, Ramirez, Alfredo ORCID: 0000-0003-4991-763X, Tsolaki, Anthoula C., Rossi, Giacomina, Jansen, Iris E., de Rojas, Itziar, Parveen, Kayenat, Sleegers, Kristel, Ingelsson, Martin, Hiltunen, Mikko, Amin, Najaf, Andreassen, Ole, Sanchez-Juan, Pascual, Kehoe, Patrick ORCID: 0000-0002-7542-1139, Amouyel, Philippe, Sims, Rebecca, Frikke-Schmidt, Ruth, van der Flier, Wiesje M., Lambert, Jean-Charles, He, Zihuai ORCID: 0000-0002-8220-4183, Han, Summer S., Napolioni, Valerio and Greicius, Michael D. (2022). Challenges at the APOE locus: a robust quality control approach for accurate APOE genotyping. Alzheimers Res. Ther., 14 (1). LONDON: BMC. ISSN 1758-9193

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Abstract

Background Genetic 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. Methods We 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. Results Using 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. Conclusions We 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Belloy, Michael E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Eger, Sarah J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Le Guen, Yann UNSPECIFIED UNSPECIFIED UNSPECIFIED Damotte, Vincent UNSPECIFIED UNSPECIFIED UNSPECIFIED Ahmad, Shahzad UNSPECIFIED UNSPECIFIED UNSPECIFIED Ikram, M. Arfan UNSPECIFIED UNSPECIFIED UNSPECIFIED Ramirez, Alfredo UNSPECIFIED orcid.org/0000-0003-4991-763X UNSPECIFIED Tsolaki, Anthoula C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Rossi, Giacomina UNSPECIFIED UNSPECIFIED UNSPECIFIED Jansen, Iris E. UNSPECIFIED UNSPECIFIED UNSPECIFIED de Rojas, Itziar UNSPECIFIED UNSPECIFIED UNSPECIFIED Parveen, Kayenat UNSPECIFIED UNSPECIFIED UNSPECIFIED Sleegers, Kristel UNSPECIFIED UNSPECIFIED UNSPECIFIED Ingelsson, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Hiltunen, Mikko UNSPECIFIED UNSPECIFIED UNSPECIFIED Amin, Najaf UNSPECIFIED UNSPECIFIED UNSPECIFIED Andreassen, Ole UNSPECIFIED UNSPECIFIED UNSPECIFIED Sanchez-Juan, Pascual UNSPECIFIED UNSPECIFIED UNSPECIFIED Kehoe, Patrick UNSPECIFIED orcid.org/0000-0002-7542-1139 UNSPECIFIED Amouyel, Philippe UNSPECIFIED UNSPECIFIED UNSPECIFIED Sims, Rebecca UNSPECIFIED UNSPECIFIED UNSPECIFIED Frikke-Schmidt, Ruth UNSPECIFIED UNSPECIFIED UNSPECIFIED van der Flier, Wiesje M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lambert, Jean-Charles UNSPECIFIED UNSPECIFIED UNSPECIFIED He, Zihuai UNSPECIFIED orcid.org/0000-0002-8220-4183 UNSPECIFIED Han, Summer S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Napolioni, Valerio UNSPECIFIED UNSPECIFIED UNSPECIFIED Greicius, Michael D. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-698366
DOI:	10.1186/s13195-022-00962-4
Journal or Publication Title:	Alzheimers Res. Ther.
Volume:	14
Number:	1
Date:	2022
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1758-9193
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; ASSOCIATION; DEMENTIA; RISK; GENE; POLYMORPHISMS; REPLICATION; DISCOVERY; INFERENCE Multiple languages Clinical Neurology; Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69836