TY - JOUR

T1 - Challenges at the APOE locus

T2 - a robust quality control approach for accurate APOE genotyping

AU - Belloy, Michael E.

AU - Eger, Sarah J.

AU - Le Guen, Yann

AU - Damotte, Vincent

AU - Ahmad, Shahzad

AU - Ikram, M. Arfan

AU - Ramirez, Alfredo

AU - Tsolaki, Anthoula C.

AU - Rossi, Giacomina

AU - Jansen, Iris E.

AU - de Rojas, Itziar

AU - Parveen, Kayenat

AU - Sleegers, Kristel

AU - Ingelsson, Martin

AU - Hiltunen, Mikko

AU - Amin, Najaf

AU - Andreassen, Ole

AU - Sánchez-Juan, Pascual

AU - Kehoe, Patrick

AU - Amouyel, Philippe

AU - Sims, Rebecca

AU - Frikke-Schmidt, Ruth

AU - van der Flier, Wiesje M.

AU - Lambert, Jean Charles

AU - He, Zihuai

AU - Han, Summer S.

AU - Napolioni, Valerio

AU - Greicius, Michael D.

AU - European Alzheimer & Dementia BioBank (EADB)

N1 - Publisher Copyright: © 2022. The Author(s).

PY - 2022

Y1 - 2022

N2 - 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.

AB - 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.

KW - Alzheimer’s disease (AD)

KW - Apolipoprotein E (APOE)

KW - Genetics

KW - Haplotypes

KW - Novel approaches

KW - rs439401

U2 - 10.1186/s13195-022-00962-4

DO - 10.1186/s13195-022-00962-4

M3 - Journal article

C2 - 35120553

AN - SCOPUS:85124172825

VL - 14

JO - Alzheimer's Research and Therapy

JF - Alzheimer's Research and Therapy

SN - 1758-9193

IS - 1

M1 - 22

ER -