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 missense variants (rs3764647 and rs3752239) demonstrated significant association with AD risk. Variants in , , and showed significant gene-based association. In addition, coding variants in (rs6465770) and (rs10250905 and rs62001869) showed association with memory endophenotypes.
Conclusions: Our findings support a role for missense variants in conferring AD risk in African Americans, highlight allelic heterogeneity at this locus, suggest the presence of AD-risk variants in , , and , 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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| http://dx.doi.org/10.1212/NXG.0000000000000141 | DOI Listing |
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