TY - JOUR
T1 - African American exome sequencing identifies potential risk variants at Alzheimer disease loci
AU - N'songo, Aurelie
AU - Carrasquillo, Minerva M.
AU - Wang, Xue
AU - Burgess, Jeremy D.
AU - Nguyen, Thuy
AU - Asmann, Yan W.
AU - Serie, Daniel J.
AU - Younkin, Steven G.
AU - Allen, Mariet
AU - Pedraza, Otto
AU - Duara, Ranjan
AU - Custo, Maria T.Greig
AU - Graff-Radford, Neill R.
AU - Ertekin-Taner, Nilüfer
N1 - Publisher Copyright:
Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
PY - 2017
Y1 - 2017
N2 - Objective: In African Americans, we sought to systematically identify coding Alzheimer disease (AD) risk variants at the previously reported AD genome-wide association study (GWAS) loci genes. Methods: We identified coding variants within genes at the 20 published AD GWAS loci by whole-exome sequencing of 238 African American participants, validated these in 300 additional participants, and tested their association with AD risk in the combined cohort of 538 and with memory endophenotypes in 319 participants. Results: Two ABCA7 missense variants (rs3764647 and rs3752239) demonstrated significant association with AD risk. Variants in MS4A6A, PTK2B, and ZCWPW1 showed significant genebased association. In addition, coding variants in ZCWPW1 (rs6465770) and NME8 (rs10250905 and rs62001869) showed association with memory endophenotypes. Conclusions: Our findings support a role for ABCA7 missense variants in conferring AD risk in African Americans, highlight allelic heterogeneity at this locus, suggest the presence of AD-risk variants in MS4A6A, PTK2B, and ZCWPW1, nominate additional variants that may modulate cognition, and importantly provide a thorough screen of coding variants at AD GWAS loci that can guide future studies in this population.
AB - Objective: In African Americans, we sought to systematically identify coding Alzheimer disease (AD) risk variants at the previously reported AD genome-wide association study (GWAS) loci genes. Methods: We identified coding variants within genes at the 20 published AD GWAS loci by whole-exome sequencing of 238 African American participants, validated these in 300 additional participants, and tested their association with AD risk in the combined cohort of 538 and with memory endophenotypes in 319 participants. Results: Two ABCA7 missense variants (rs3764647 and rs3752239) demonstrated significant association with AD risk. Variants in MS4A6A, PTK2B, and ZCWPW1 showed significant genebased association. In addition, coding variants in ZCWPW1 (rs6465770) and NME8 (rs10250905 and rs62001869) showed association with memory endophenotypes. Conclusions: Our findings support a role for ABCA7 missense variants in conferring AD risk in African Americans, highlight allelic heterogeneity at this locus, suggest the presence of AD-risk variants in MS4A6A, PTK2B, and ZCWPW1, nominate additional variants that may modulate cognition, and importantly provide a thorough screen of coding variants at AD GWAS loci that can guide future studies in this population.
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U2 - 10.1212/NXG.0000000000000141
DO - 10.1212/NXG.0000000000000141
M3 - Article
AN - SCOPUS:85041504010
SN - 2376-7839
VL - 3
JO - Neurology: Genetics
JF - Neurology: Genetics
IS - 2
M1 - e141
ER -