Duara, Ranjan

Abstract Introduction Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. Methods We conducted a transethnic genome‐wide association study (GWAS) for late‐onset AD in Stage 1 sample including whites of European Ancestry, African‐Americans, Japanese, and Israeli‐Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Results Genome‐wide significant (GWS) associations in single‐nucleotide polymorphism (SNP)–based tests ( P < 5 × 10 −8 ) were identified for SNPs in PFDN1/HBEGF , USP6NL/ECHDC3 , and BZRAP1‐AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence ( P < 2.7 × 10 −6 ) for gene‐based association in the total sample with a novel locus, TPBG ( P = 1.8 × 10 −6 ). Discussion Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.

We conducted a comprehensive screening of rare coding variants in an African American cohort to identify novel pathogenic mutations within the early-onset Alzheimer’s disease (EOAD) genes ( APP, PSEN1 , and PSEN2) in this understudied population. Whole-exome sequencing of 238 African American subjects identified 6 rare missense variants within the EOAD genes, which were observed in AD cases but never among controls. These variants were analyzed in an independent cohort of 300 African American subjects in which PSEN2 :NM_000447:exon5:c.T331C:p.Phe111Leu and PSEN1-minilin rs777923890 variants were again not observed, indicating that these novel rare variants, may contribute to AD risk in this population.